Hello. My name is John Maris, and I’m Chief of the Division of Oncology at The Children’s Hospital in Philadelphia (CHOP). Today I would like to talk to you about a recent report on cell phones and the potential that they might cause cancer.

This has received a lot of press, and this is one in a series of press releases about the potential of cell phones to cause cancer. What I want to say is: There is nothing at all to be worried about. As a cancer researcher and someone who spends a lot of time thinking about what might cause cancer, I applaud the World Health Organization for pulling together a report and asking for more information and data to be able to study this. I think that the way in which that has been spun in the media — that cell phones can cause cancer or that there is a concern among experts that cell phones cause cancer — is overblown. What I really want to drive home is that there is nothing at all to be concerned about.

When we think about what causes cancer, one of the first questions we need to ask ourselves is: Is it plausible? Is there a realistic or even little bit of an explanation of a cause and effect? Cell phones are used very commonly; there is a concern that cancer incidences might be increasing, so it is natural to think that these devices that we spend a lot of time with these days might have a harmful effect.

For a long time, people thought that cigarettes, which became a very common part of everyday life, were not harmful and, despite some increasing concern for a long time, people denied that. So, are cell phones similar to the cigarette or to tobacco? The answer is no. Smoking causes irritation that has a carcinogenic effect, and there is a biologically plausible explanation for how smoking could cause harm.

Radio waves that come from a cell phone are low energy. Very good research has shown that it is a million times lower, literally a million times lower, than the energy that is necessary to damage DNA genetic material and cause mutation and cancer. There is no known biologically plausible way that these devices and the frequency of energy that they emit, which is the same as that which comes from the radio waves that bombard us every day as we listen to our radios, can damage DNA.

Could there be another reason? There is no reason that can be surmised, and, more importantly, there have been dozens and dozens of studies in test tubes, in animal models, and — most importantly — in human beings that have all refuted the hypothesis that these things can hurt you.

The World Health Organization evaluated a very, very large study that looked at thousands and thousands of cell phone users. There was the inability to definitely say that these devices were not associated with cancer in this very large group of patients because it is a complicated thing to study and relied on phone interviews and not actual real observations. The World Health Organization released a cautionary statement to say that we just need more information. That does not mean that cell phones cause cancer. There is nothing that we might need to change in our everyday lives, and I applaud the effort to get more data, but we have nothing to be concerned about.

Eduardo J. Simoes; Ciro V. Sumaya

Authors and Disclosures

Posted: 05/21/2010; J Prim Prev. 2010;31:21-29. © 2010 Springer

Introduction

The US health care system and its reform has become a focal point of public debate, engaging many who traditionally have not participated in the dialogue around population health needs and resources. In this essay, we discuss aspects of a transformed health care system that addresses major health needs of Americans through health promotion, disease prevention, and personal health care (i.e., diagnosis and treatment). We bring attention to the role of communities and patients on the health issues with a focus on public (population) health practice, emphasizing collaboration among government health agencies at all levels and other health-related public and private organizations.

This discussion is necessary, relevant, and timely because it is occurring concurrently with the emerging national, state, and local discourse on health reform. Significant funding targeting health system changes are already unfolding with the American Recovery and Reinvestment Act (ARRA) of 2009. (Steinbrook 2009; Agency for Healthcare Research and Quality 2009; US Department of Health & Human Services 2009).

Given the context described, this commentary will specifically discuss recent health trends and systemic approaches that:

1. Engage communities and individuals through a participatory process in health promotion, disease prevention, and health care delivery;
2. Reorganize health insurance to create incentives for prevention; and
3. Promote collaboration across government agencies, community-based organizations, and other potential partners at the national, state, and local levels.

We conclude by defining the implications of taking a community-oriented approach to integrating these different aspects of the health system.

Trends: Health and Health Care Gaps

The role and level of effectiveness of health care in the United States is questionable if the health indicators of Americans (e.g., life expectancy at birth, infant mortality, number of years living with a disability, number of years of quality life, percent of people reporting poor health) are compared to those of populations of similarly developed countries and even of a few less developed countries (Avendano et al. 2009; Banks et al. 2006). Although Americans live longer than ever before, their life expectancy has stabilized over the past 10 years and is shorter than that of residents of most developed countries (Day et al. 2008). Contributing to this finding are the higher rates of death in the US, compared to these countries, from diseases and conditions such as ischemic heart disease, stroke, many forms of cancer, chronic obstructive pulmonary disease, diabetes, and infant-obstetric complications (Heron et al. 2009). However, most of these deaths are largely attributable to preventable risk factors such as tobacco smoking, hypertension, high cholesterol, physical inactivity, and overweight/obesity (Danaei et al. 2009). Yet, minimal funding support, an estimated 2–3% of total health care expenditures, is directed toward prevention (Satcher 2006). Although some have suggested that prevention is costly and not economically beneficial (Kahn et al. 2008; Russel 2009), evidence shows that promoting health and reducing disease through prevention can be cost-effective (Cohen et al. 2008).

Although the overall effect or influence of social determinants on the health of Americans may differ from that of other developed countries, problems within the US health care system(s) appear to have contributed considerably to the comparatively low health standing of the US. This conclusion is highlighted when scrutinizing particular inadequacies in disease prevention, health education, and access to health care. Moreover, the number of Americans without health insurance for an entire year has increased in recent years from 32 million (15% of the nonelderly population) in 1988 to 45 million (17% of the nonelderly population) in 2007 (DeNavas-Walt et al. 2008). Lack of health insurance and subsequent lack of access to health care is especially problematic for several minority groups, lower socioeconomic groups, and the less educated population—those who often need insurance the most (Bodenheimer 2004; Institute of Medicine 2002).

Health care costs in the US are becoming unmanageable, totaling 17.6% of the US gross domestic product in 2009, compared to an already high 13.6% in 1994 (Mercer Human Resource Consulting 2009). By 2018, national health care expenditures are expected to reach $4.4 trillion—more than double 2007 spending (Siska et al. 2009). Health care costs are also becoming unaffordable for industries and organizations offering health benefits to their employees, with health plan cost per employee increasing 3.3% in past 15 years (3.0% in 1994 vs. 6.3% in 2009; (Mercer Human Resource Consulting 2009). Dissatisfaction with the quality of health care has increased over time, as measured by a survey of both patients and health care practitioners (Kaiser Family Foundation 2008). A poor perception of what the health care system offers to address health problems has also been reported (Kaiser Family Foundation 2008).

Effective delivery of health care to patient populations, despite being beneficial, cannot fully address Americans’ risk for developing certain preventable conditions. For example, an estimated 26.6% of Americans were obese in 2008 and at risk for developing obesity-related chronic diseases such as type II diabetes and cardiovascular diseases (Centers for Disease Control and Prevention 2009). However, Green et al. 2001 have noted that of every 1,000 people in the US, on average each month, 80% experience symptoms of some type, 32.7% consider seeking medical care, 21.7% visit physician offices, and out of the latter, only about half (11.3% of the total group) visit primary care providers. Thus, if we aim to conduct prevention only through health care delivery, then we should expect that between 11.3 and 21.7% of those who are obese would receive preventive care—and only if all physicians offer preventive care. Thus, such an approach to prevention cannot address the health needs and risks of the majority of the population.

Further, health care delivery has developed in ways that reduce the role of health practitioners (e.g., physicians and other health professionals) as the main informants and decision makers with their patients regarding care. The changing physician-patient relationship has been affected by the minimal time allotted for patient encounters, particularly in managed care settings (Roland et al. 1986; Tamblyn et al. 1997), thus reducing or eliminating interactions that include health education and preventive communication to patients by their physicians.

Positive Trends: Incentives for Prevention and Individuals/Employers as Decision Makers

Although some trends in health and health care in the US should cause concern, other trends offer opportunities for new ways of thinking about health. Health insurance coverage is increasingly one of the most important components of an employment benefit package. In the current economic downturn, employees have a heightened awareness of the value of benefits packages associated with their jobs and may tend to stay in jobs longer if these packages are attractive (ConsumerReportsHealth.org 2008; Employee Benefit Research Institute 2009). However, offering and funding health insurance require employers to achieve a fine balance because of the dramatic increase in costs of health care, which in turn increases the cost of the total employment benefits package. One opportunity to positively shift the balance is implementation of health promotion and disease prevention strategies, which can lead to decreased absenteeism due to illness and increased employee productivity, recruitment, and retention—outcomes that may compensate for increased health insurance benefits costs (Prince 1999). For these reasons, many large employers, working with insurers, have developed health care benefits packages that include wellness programs that are steps beyond the current traditional promotion of physical activity and diet.

Many organizations now offer employees programs that screen for disease risk factors (e.g., biometric screening of weight and sugar levels to identify pre-type II diabetes) and check screening results against claims data to determine previously undiagnosed persons. The at-risk employee is given an opportunity to enroll in a preventive plan. Both screening and preventive measures are low-cost and cost-effective; compliance is monitored and incentivized (Chicoye et al. 1998; McCulloch et al. 1998). Value-based health care is another approach that increases employers’ awareness of the benefits of maximizing employees’ health and quality of life and, ultimately, productivity (Beauregard and Winston 1997; Chernew et al. 2007; Lopert and Moon 2007; Kelly et al. 2008; Rosenthal et al. 2007). These health insurance approaches involve patients in decision-making about maintaining their health and taking responsibility for prevention of disease and provide coverage for appropriate diagnostic and treatment regimens during times of illness. These strategies have been shown to improve health and to be cost-efficient.

Similarly, effective medical practice relies heavily on patients’ and their families’ knowledge of the natural history of a patient’s illness, family medical history, diagnostic and treatment measures, and other health care issues. Thus, individuals and their families can be important partners with health care providers and assist in decision making and compliance with health care (Kenyon and Gordon 2009). Although increased patient participation in health matters is relatively new, interest in greater involvement in the process of maintaining health and preventing and curing diseases has been growing at the individual and community levels (Buckley and Hutson 2004; Kenyon and Gordon 2009).

Positive Trends: Communities as Decision Makers

The community, with its resources, networks, and governance capabilities, is a natural locus to advance the protection and improvement of the public’s health. Community capacity can be refined, focused, and enhanced to engage the community effectively in creating and evolving a health vision and assuming accountability for health improvement efforts across its jurisdiction. Different levels and approaches to broad community involvement in health exist, but their commonality is centered within the community, which serves as a fulcrum of direction, input, and accountability (Kenyon and Gordon 2009; Neuwelt et al. 2009). This actively engaged community involvement represents a shift in emphasis, encompassing individuals, families and neighbors, and ultimately everyone in the community. Communities can craft and use processes that serve as integral mechanisms for planning, developing, implementing, and evaluating health and health-related activities. Robust community capacity and processes, because of their local and intimate character, can promote great interest in, acceptance of, and ability to sustain health improvement actions among community residents as they engage with members of the health professions and health systems. Moreover, a community approach lends itself to incorporating broader social determinants of health (e.g., the environment, education, economics, and transportation) into the mix of strategies and interventions to improve public health. Chen, 1989 in describing the four stages in the development of a health care system, placed community medicine (i.e., organized community effort to meet a population’s health care needs) near the top stage. It was surpassed only by the ultimate stage of health care systems, public health, which concerns all the circumstances and conditions affecting the health of an entire population.

Health care professionals, particularly from academic institutions, may be reluctant to adopt community engagement, being fearful or cautious about sharing decision-making responsibilities and power over health matters with the public. Such reservations can create substantial barriers to the community’s ability to have an appropriate voice in health care matters (Kenyon and Gordon 2009). However, when the public is able to make meaningful decisions, community engagement can lead to substantial health gains. Community engagement in the health arena is an expanding, dynamic process with continually emerging issues and challenges.

Community Capacity and Processes: Engagement through Three Major Public Health Frameworks

Organized community engagement and processes can have a significant impact on the health and well-being of the residents. For purposes of this discussion, the role of community engagement and processes can be viewed through three population-based, public health-related frameworks: (a) disease prevention, (b) health promotion, and (c) health care delivery. These frameworks provide major opportunities and avenues for meaningful community engagement. Although presented as separate frameworks, they have significant interplay and interdependence. Further, these frameworks enable collaboration of communities with federal, state, and other organizations in developing and implementing health activities. Communities can be adept at developing various community-wide, health-related programs through their ingenuity and resources; broad collaborations with or support from external agencies and organizations can further augment the impact and outcomes of community-based, health-related programs.

Services and activities in disease prevention, such as screening tests (e.g. blood pressure, blood cholesterol, Pap smear), vaccine administration, environmental assessments, dental prophylaxis, and well-baby examinations, are effective means of protecting our health. Nonetheless, they are often underutilized and undervalued and are not universally accessible. Community interventions organized to increase participation in and use of these preventive measures are essential to reach the entire community, particularly marginalized, poor, and undereducated groups. The media, working alongside the community, is a resource that can disseminate information and provide public service announcements about the need to receive these preventive measures. The availability of transportation to sites that have these preventive services could be addressed through community action.

Health promotion efforts can be augmented by the involvement of an organized community committed to improving its residents’ health. The leadership of communities can actively pursue community-wide events that address health education on topics of interest (e.g., nutrition, exercise, and at-risk behaviors) and can promote health assessment surveys to facilitate a better understanding of the status of local health issues. The community can play an important role in rallying residents toward appropriate action for addressing environmental problems in their neighborhoods or surrounding areas. The media as well as other community resources (e.g., faith-based institutions, schools, and neighborhood associations) can be driving forces to stimulate health promotion efforts and assure that these activities reach the general community. As with disease prevention efforts, health promotion interventions should be evaluated, and results and best practices should be disseminated.

Community engagement and processes can also have a significant impact on the health care delivery system(s). Although health care delivery may have a strong individual focus, it can and should also incorporate a population focus. Unfortunately, this population or community focus is often lacking or minimal, leaving a fragmented health care delivery system in need of integration, accessibility, affordability, quality, and efficiency. The community should be intimately engaged in discussions about developing model medical homes and integrative systems of health that address and coordinate the spectrum of health care services (e.g., primary, specialty, mental, rehabilitative) needed over the life span (Michener 2007). Health care systems need to better consider health-related issues such as patient transportation, access, outreach, cultural competency of providers, and appropriate use of services because these issues have a direct bearing on the health care triad of quality-access-cost. The community can provide valuable input and influence outcomes by participating in the planning, development, implementation, and evaluation of interventions that address these broad determinants of health. Community-driven boards of hospitals and clinic settings in both the private and public sector should play a model strategic role in making changes toward improvement.

Community Engagement in Other Vital Public Health (Population Health) Functions

Workforce Development

Members of the health professions workforce in the community predominantly take care of sick patients; a smaller number cover population-focused public health services. However, all health professionals should have a strong sense of and commitment to the community and its health needs as a whole. The Institute of Medicine states that “schools [of public health] should [integrate] this ecological view of public health, as well as a population focus, into all health professional education and practice” (Gebbie et al. 2003). To achieve this goal, all health professionals, but particularly the public health workforce, should be substantially exposed to education and training in diverse community-based settings. This training enables health professionals to have a more comprehensive understanding of the realities of health disparities, underserved people and their environments, and community-identified health priorities, as well as the array of technological advancements that may or may not be available to community residents.

Community-based education of the health professions workforce can provide a better basis for relevant policy development and advocacy for health improvement at all levels of society. In addition, in academic health centers and other health professions training programs, diverse community representation is important in the admissions process and in advisory and other committees established for the institutional training programs. Most importantly, the health professions educational and training programs should have accountability to the communities they serve.

Community health workers (e.g., lay advisors, promotoras, peer navigators) are emerging as vital links in health care systems, particularly in the engagement of hard-to-reach populations (Ahmed and Maurana 2000; Centers for Disease Control and Prevention 2005). Community health workers have credibility and trust from the community because they traditionally work with people who are their neighbors; they also often have an intimate understanding of and empathy with underserved neighborhoods.

Research

Research brings advancements in knowledge and development of evidence that documents the efficacy and impact of health promotion and disease prevention services and interventions as well as new diagnostic tools and treatment regimens. However, important health advancements through research may not reach the public effectively; that is, knowledge of advancements disseminate slowly from the laboratory to the patient and the community. Also, even if available, the research products or interventions are often too expensive for use, a problem experienced more often by noninsured or underinsured, minority, and rural populations. Moreover, considerable time may elapse before these new research findings or their products are put into practice (Corrigan et al. 2002).

Community leaders and residents can be significant resources for researchers by their ability to link community residents or organizations with research projects and to affirm the relevance and applicability of research efforts. Leaders and members of the community can also become involved with identifying priority health problems and the research focus needed to resolve these problems (i.e., determining the research question). Additionally, they can assist in crafting the research project—particularly as it relates to community participation as participants or volunteers—and can engage in the dissemination of findings after results and evaluation of the project have been completed. This process, more formally called community-based participatory research, is an emerging research arena that breaks with the traditional research process that is researcher driven (Boutilier et al. 2001; Green and Mercer 2001; Minkler 2005; University of Michigan School of Public Health 2009). Expansion of community-based participatory research efforts in all types of health research is needed, particularly research focused on health promotion, disease prevention, and health services efficacy and efficiency.

Policy

Although health policy development may seem to be dominated by high levels of government, powerful policy organizations in the nation’s capital, and special interest groups, the community and its citizens should be actively involved and consulted on policy goals and direction. Community capacity and processes provide mechanisms for strategically engaging the community with the leadership of organizations that can influence health policy. The community and its extensive collaborations and relationships with federal, state, and other public/private agencies and organizations in health-related activities should provide a platform for influencing health policy. Further, individuals and organizations of the community have the right to contact elected or appointed officials and make their health views known at all levels (i.e., local, regional, state, or federal). With the explosion of electronic and digital communication technology, community members may reach a multitude of people easily through such mechanisms as e-mails, blogs, or twitters.

Federal and National-level Programs

A number of federal and national-level programs are active in supporting community capacity-building and community processes targeting health. While representative examples are provided in this section, it is noted that many others exist, including state-level programs that are important partners in community engagement. The Kellogg and the Robert Wood Johnson Foundations, Centers for Disease Control and Prevention (CDC), and Health Resources and Services Administration (HRSA) have been strong proponents of community (or of state and community together) engagement approaches. The extensive network of community and migrant health centers overseen by HRSA requires a majority of community representatives on the governing boards of these centers, which are required by law to provide health services to all, regardless of insurance status. The CDC-sponsored Prevention Research Centers are leaders in integrating the concept of community-based participatory research as part of the entire research process from the research question to its development, conclusion, and translation into practice and policy. The Prevention Research Center program along with the CDC-sponsored Centers for Public Health Preparedness has a strong interest in connecting community resources with resources from academic health institutions. The National Institutes of Health incorporate significant community involvement in the Clinical and Translational Science Awards program, which is charged with the application and dissemination of new research findings (i.e., taking the research impact from the laboratory to patients and communities). The Agency for Healthcare Research and Quality gives major attention to health care quality, utilization, efficiency, and effectiveness through its health services research programs. An extensive network of health promotion and disease prevention programs are supported by CDC-sponsored state and local health agency public health programs (e.g., Obesity Prevention, Diabetes Prevention, and Smoking Prevention), by HRSA, and by state health department alliances. The Association of Schools of Public Health and public health training programs not only provide education and training for future public health professionals, but, through their large faculty base, address the development of population-focused research projects and community interventions to improve the health of the public

Implications for the Future

A number of major concerns with the nation’s health and health care systems are provoking calls for a major transformation of current approaches, performance, and direction. Not only is the country beset with health disparities and many health indicators inferior to those of other developed countries, but these issues are present despite per capita health care expenditures that are already inordinately high and continue to increase to unsustainable levels. Additional future health challenges posed by an expanding elderly population, a high rate of unhealthy lifestyles, and increasing problems with obesity with its attendant co-morbidities as well as problems with other chronic diseases will further aggravate this situation.

We propose that engagement of the community with its unique capacity and processes can be a pivotal strategy for initiating, developing, and sustaining the changes needed, particularly public health services, to transform the nation’s health and health care system. For example, although significant knowledge about disease prevention and health promotion exists, the infrastructure and support provided are insufficient to ensure that these strategic public health measures reach the American people, particularly those that need them most. Similarly, the many valuable new technologies in diagnostics, treatment, and rehabilitation that are being developed take prolonged periods of time (even years) before they reach the population. Even if available, they may benefit some segments of the US population more than others, such as the uninsured or underinsured. An improved, transformed health care system should have effective integration and coordination of the continuum of health promotion, disease prevention, and health care delivery throughout the life cycle. Effective integration and coordination will require crucial comingling of population (public) health with health care (personal) services to an unprecedented extent. This expansion of health services will require a major enhancement of essential public health functions that will bring a public health perspective on a par with health care services (Public Health in America 2009). A more robust community engagement will facilitate and put these new approaches to health care on a successful track.

Creating and sustaining an improved, transformed health and health care system will require more effective dialogue, partnerships, and coordination of resources at the federal level along with state- and local-level organizations, foundations, health workforces, hospital and health systems, and insurance companies, among many others. Community engagement can help coordinate resources and monitor the progress being made toward achieving the necessary transformational changes.

Rigorous evaluation and research activities are essential to advance the development of a new transformed health system. First, designs must be developed and tested for comparative effectiveness in terms of health outcomes, acceptability by the community, costs, and access. Mechanisms need to be put in place to assure that innovative approaches for improving individual and community health outcomes are put into routine practice, while also containing health care costs. Researchers must work with and listen to the community, incorporating community norms and capacity and harnessing community powers to effect change and improve and sustain the health of communities, not only individuals. This community-based participatory research is key to translating and disseminating research findings into practice and appropriate utilization by the community. It is also vital that the research questions being pursued effectively cover population (public) health as well as health care delivery (personal); that is, prevention, health promotion, and behavioral research must be supported in addition to biomedical and laboratory-based research.

The newly transformed system should yield outcome measures of both traditional health indicators (i.e., disease-specific status and trends) and non-health-related quality of life indicators (i.e., general well-being elements such as health adjusted life expectancy; Kindig 1998). Improving the social determinants of health, such as population employment and health care coverage, community literacy, and the capacity to organize populations around health issues can be as relevant to health as levels of tobacco smoking, physical inactivity, and obesity.

“The health of one is admirable; the health of all, supreme” (Sumaya 2002). The time has come to enable community-based and public health interventions to improve the public’s health.

This article is a CME certified activity. To earn credit for this activity visit:
http://cme.medscape.com/viewarticle/720825

Introduction

Treating cancer by harnessing a patient’s immune system has several major advantages over other forms of cancer therapy (Table 1). For example, some cells of the immune system can respond to specific immunogenic proteins, or antigens, expressed by the tumor. This characteristic allows specificity of the immune response to cancer without excessive toxicity to normal tissues, as is seen with cytotoxic chemotherapy. Antigen-specific T lymphocytes, presumably the most important component of the immune system in mediating an antitumor response, have the capability of homing to any site of cancer even if disease deposits are located deep in tissues.^[1] Therefore, unlike other standard forms of cancer treatment, the immune response has the potential to eradicate cancer in any location. Cancer-specific T and B lymphocytes are cells that can directly induce tissue destruction and will continue to proliferate and function as long as there is antigen present to stimulate their activity. For this reason, once a robust immune response is elicited, no further immune-based treatments would be necessary. Finally, a key characteristic of an effective immune response is the generation of immunologic memory, which is the persistence of an antigen-specific immune response over many years. If the cancer antigen is sensed again, even decades after the initial diagnosis of disease, immune cells will rapidly respond, proliferate, and destroy antigen-expressing cancer cells before those cells have the chance to become re-established.

Unfortunately, the development of actual immune-based therapies for the treatment of cancer has been challenging. In large part, the challenges have been due to the nature of the immunogenic proteins that are expressed by human tumors. Over the last decade, a host of human tumor antigens have been identified as potential therapeutic targets. Some antigens expressed in tumors are viruses — hepatitis B virus (HBV) in hepatocellular carcinoma, Epstein-Barr virus (EBV) in lymphomas and nasopharyngeal carcinomas, and human papillomavirus (HPV) in cervical cancer are just a few examples — but most immunogenic cancer-associated proteins are normal cellular proteins (self proteins) that have become qualitatively or quantitatively altered in the malignant state as compared with their expression in normal tissues. Clinical responses to immunotherapies targeting either viral or self proteins have been reported.^[2] Immunologic targeting of a cancer-related self protein is hampered by the multiple mechanisms our bodies have of preventing autoimmunity. The inflammatory response that develops when cancer grows elicits immune system cells that are likely to turn off a destructive cancer-specific immune response because the antigens being recognized are perceived as “self.” Certain types of macrophage, termed M2, will secrete cytokines that prevent T-cell proliferation.^[3] Immature myeloid cells, myeloid-derived suppressive cells, are also present in the tumor bed and can inhibit the generation of a clinically productive immune response by preventing antigen-specific T cells from functioning correctly.^[4] T cells themselves can differentiate into regulatory cells when they sense self antigens and prevent further tumor recognition via secretion of interleukin (IL)-10 and transforming growth factor (TGF)-beta, which are immune-suppressant cytokines.^[5] These are just a few of the natural defense mechanisms in place for preventing the development of autoimmune disease; unfortunately, these same mechanisms limit the tumor-specific immune response. Effective cancer immunotherapy must generate a destructive immune response as well as control tolerizing mechanisms that are in place to limit self-specific immunity.

Despite the challenges, there are several immune-based therapies that are routinely used in the treatment of cancer patients. Cancer immunotherapy is generally classified as being “active” or “passive” (Table 2). Active immunotherapy is a treatment modality that functions by stimulating the patient’s own immune system to generate the cells needed to impart an antitumor effect. An example of an active immunotherapy would be a vaccine. The vaccine is administered to stimulate T or B lymphocytes to recognize and destroy the cancer. The use of nonspecific immunomodulators such as bacillus Calmette-Guerin (BCG) would also be considered active immunotherapy. After administration of BCG, it is assumed that cells of the innate immune system, present in the patients, would respond and cause inflammation that could result in the eradication of superficial bladder cancer. In the case of active immunotherapy, patients must have immune systems capable of competently responding to stimulation. For this reason, in general, active immunotherapy is not effective in patients with advanced-stage refractory disease who may have a depressed number of immune system cells able to adequately function. Passive immunotherapy provides the immune response to the patients. Monoclonal antibody therapy is considered a passive immunotherapy. Rather than stimulating a patient’s own antibody response, the infusion of monoclonal antibodies provides the antigen-specific antibodies to the patient. Similarly, rather than stimulating a patient’s own T cells via vaccination, adoptive T-cell therapy infuses high numbers of antigen-specific T cells into patients, thus providing immediate robust immunity to a specific target. Because patients do not have to generate their own endogenous immune response, passive immunotherapy is often used in the treatment of patients with well established and even refractory cancers. An example of adoptive T-cell therapy would be the use of donor lymphocyte infusions in the treatment of chronic myeloid leukemia (CML) that has relapsed after allogeneic hematopoietic stem cell transplant (HSCT).

The potential mechanisms of action of many cancer immunotherapies are multifactorial and often not fully understood because the immune system is a complex organization of numerous components, pathways, and interdependent interactions. The cell types involved in mediating tumor-specific immunity will define the clinical efficacy as well as the toxicities associated with targeted immune-based treatments.

Components of the Immune System

Immunity is described as either “innate” or “adaptive.” Innate immune cells are those that are the first responders to abnormalities that are detected by the immune system. These cells include monocytes, macrophages, and other antigen-presenting cells (APCs), as well as neutrophils, eosinophils, mast cells, and natural killer (NK) cells. Innate immune cells do not recognize specific antigens; rather, they recognize substances expressed by pathogens via receptors, known as toll-like receptors (TLRs) on their cell surface. DNA, RNA, glycans, and other substances that are present in broad categories of pathogens such as bacteria and other infectious organisms will stimulate innate immunity via these receptors. Recognition of pathogens results in an immediate influx of a variety of phagocytic cells that can eliminate the pathogen. Moreover, in certain conditions, some cells of the innate immune system play an important role in processing and presenting the pathogens they enveloped to adaptive immune system cells, resulting in long-lasting immunity. Cells of the innate immune system do not proliferate in response to specific antigens, nor do they maintain immunologic memory. Innate immune system cells are the major component of most inflammatory responses.

B and T lymphocytes, or B and T cells, are the main constituents of the adaptive immune response. These cells display all the characteristics shown in Table 1 and respond to specific antigens. B cells produce proteins called antibodies that bind to soluble antigens. Among other functions, antibody binding to antigen can result in:

• Internalization of the antigen into the B cell, where it is processed and presented to T cells;
• Fixation of complement to the antibody and the initiation of an enzymatic cascade that will result in the destruction of the cell expressing the antigen; and/or
• Fixation of APCs to receptors on the antibody that will result in further phagocytosis of the antigen and death to antigen-expressing cells.

T cells have the capability of directly killing abnormal cells. The cytotoxic CD8-positive T cell (CTL) is thought to be the most important effector cell in the immune eradication of cancer. CTLs can kill cells directly via enzyme-mediated mechanisms or can induce senescence in cells expressing antigen. T cells recognize antigen that has been processed and presented in immune receptor molecules, major histocompatibility molecules (MHCs), on the surface of APCs, or other cells. After processing, the protein antigen is cleaved into amino acid fragments called peptides. The placement of antigenic peptides in the MHC is specific, and either CTL or CD4-positive T-helper (Th) cells will recognize the peptide-MHC complex, depending on the amino acid sequence of the peptide and the type of MHC molecule. CTLs recognize peptide fragments in the context of MHC class I, and Th cells recognize peptides presented in MHC class II. Th cells are critical to the overall function of the adaptive immune response. Th cells secrete cytokines in response to antigen recognition. These cytokines can either stimulate further proliferation of CTLs (interferon [IFN]-gamma, TNF-alpha, and IL-2) or the proliferation of B cells (IL-4, IL-5, IL-10), which often results in a dampening of the CTL response. Furthermore, Th cells can differentiate into T regulatory cells and secrete cytokines (IL-10 and TGF-beta), which will turn off tissue-destructive CTL. Therefore, Th cells can either generate destructive inflammation or immune suppression, depending on the antigen and the conditions in which the antigen is presented to the T cells.

Because the therapeutic function of B and T cells is linked with the effective processing function of APCs, immune-based therapies must take both the innate and adaptive immune systems into account to be clinically effective.

Cancer Immune-Based Therapies

There are many types of immune-based therapies routinely used in the treatment and prevention of both solid tumors as well as hematopoietic malignancies. Both active and passive immune therapies have been approved for clinical use, and treatments can target both the innate and adaptive immune systems. The majority of immunotherapeutic approaches currently used and/or under development are designed to elicit an adaptive immune response due to the unique characteristics of such a response in the treatment of cancer and prevention of relapse (Table 1). Immune-based cancer therapies either aim to directly stimulate B or T cells (monoclonal antibodies, vaccines, adoptive T-cell therapy) or indirectly generate an adaptive immune response via providing appropriate growth factors and a cytokine milieu to support adaptive immunity (cytokine therapy) or enhance APC function so that T cells can be stimulated via cross priming (immunomodulators). Cross priming, the presentation of tumor antigens to T cells indirectly via APCs, is the primary mode by which T cells recognize tumors.

Monoclonal Antibodies

Monoclonal antibodies directed against growth factor receptors on the surface of tumors have become integrated into cancer therapy for multiple human malignancies and have been shown to improve overall survival when used as part of standard therapy. A few examples of clinically approved monoclonal antibodies for cancer therapy include:

• HER2/neu-specific monoclonal antibodies that are used in the treatment of breast cancer;
• Epidermal growth factor receptor (EGFR)- and vascular endothelial growth factor (VEGF)-specific monoclonal antibodies that are part of the treatment regimen for colon, non-small-cell lung, head and neck, and breast cancer; and
• CD20-specific monoclonal antibodies, a mainstay of lymphoma treatment.

There are several other different monoclonal antibodies approved for clinical use in the treatment of both solid tumors and hematopoietic cancers (Table 3).

A few selected agents clinically approved for treating solid tumors are described below as examples of the mechanisms of action, response rates, and toxicities that can be expected with this class of agents. Moreover, although many of these agents are used in multiple tumor types, only a few examples are reviewed for each monoclonal antibody.

Trastuzumab is an immunoglobulin G(1) kappa monoclonal antibody that is directed against the extracellular domain of the HER2/neu growth factor receptor. HER2/neu is upregulated in approximately 20% of all breast cancers.^[6] The antitumor functions of trastuzumab are associated with its ability to modulate signaling through the HER-2/neu receptor as well as initiate antibody-dependent cell-mediated cytotoxicity (ADCC). Recent studies suggest that trastuzumab disrupts HER2/HER3 interactions, leading to downregulation of AKT signaling, which results in decreased cell proliferation.^[7] Additional biologic mechanisms of action also include inhibition of extracellular domain cleavage, antiangiogenic effects, and decreased DNA repair.^[8] Several preclinical models have demonstrated the ability of trastuzumab to mediate direct cell killing via ADCC.^[9,10] Moreover, specific single nucleotide polymorphisms in Fc receptors, which are involved in the binding of APCs during ADCC, are associated with improved objective response rates and progression-free survival (PFS) in HER2/neu-positive metastatic breast cancer patients who are receiving trastuzumab therapy.^[11] This finding further underscores the importance of ADCC as a mechanism of action of the agent. Trastuzumab is an integral part of the therapy of HER2/neu-positive breast cancer from early stage tumors to advanced stage disease. In the adjuvant setting, at any stage, the use of trastuzumab reduces recurrence by about 50% and increases overall survival by about 30%.^[12] In women with metastatic HER2/neu-positive breast cancer, the use of trastuzumab may result in an improved prognosis compared with women with metastatic HER2/neu-negative breast cancer. A single institution study^[13] evaluating more than 2000 women with metastatic breast cancer demonstrated a 44% reduction in the risk for death among women with HER2/neu-positive disease who received trastuzumab compared with women with HER2/neu-negative breast cancer (P < .0001, hazard ratio [HR] = 0.56). The major toxicity associated with trastuzumab therapy is cardiac dysfunction. Most of the cardiac toxicity seen with treatment is limited to asymptomatic decreases in the left ventricular ejection fraction (LVEF); however, severe congestive heart failure will occur in approximately 4% of patients.^[14] In cases where left ventricular dysfunction is asymptomatic, most studies have withheld treatment if the LVEF decreased by more than 15% of baseline or fell below 40%-45%.^[15] It should be noted that observed cardiac toxicity is almost always reversible with discontinuation of the drug, and the drug can often be restarted once left ventricular function has been restored.

Cetuximab is a humanized monoclonal antibody that binds to the extracellular domain of EGFR. Similar to trastuzumab, the antitumor effects of cetuximab include blocking EGFR phosphorylation and activation, inhibition of angiogenesis and invasion, activation of proapoptotic proteins, and ADCC.^[16] Cetuximab is approved for use in the treatment of metastatic colorectal cancer as well as head and neck squamous cell carcinoma. Cetuximab combined with standard chemotherapy has been shown to improve PFS among patients with metastatic colon cancer. In a study of almost 2000 patients randomized to receive either cetuximab and FOLFIRI (irinotecan, fluorouracil, and leucovorin) or FOLFIRI alone as primary therapy,^[17] the HR for PFS for the cetuximab-treated group was 0.85 (P = .048). The benefit was more pronounced among patients with wild-type KRAS mutation. Indeed, multiple studies have shown that patients who have a KRAS mutation detected in codon 12 or 13 do not benefit from anti-EGFR monoclonal antibody therapy.^[18] For this reason, KRAS mutation testing is recommended as part of the evaluation of patients under consideration for anti-EGFR monoclonal antibody therapy.^[18] For the treatment of locally advanced head and neck cancer, the addition of cetuximab to radiation therapy has improved both local-regional control and overall survival.^[19] The major toxicity associated with cetuximab therapy is a severe acneiform rash — although research has shown that the development of a rash is associated with improved survival with the use of cetuximab.^[20] A follicular eruption will occur in about 90% of patients treated with cetuximab, and the reaction will be severe (Grade 3-4) in about 15% of cases.^[21] Low-grade skin toxicity is effectively treated with topical therapy, while more significant skin reaction may require drug discontinuation until it resolves.^[22] What type of impact intermittent discontinuation of the drug may have on clinical outcome is not known at this time.

Bevacizumab is a humanized monoclonal antibody that binds VEGF and inhibits the development of angiogenesis. Bevacizumab has been studied extensively in and is approved for the treatment of non-small-cell lung cancer (NSCLC), colon cancer, and breast cancer. In 2006, a study of almost 900 patients was reported evaluating bevacizumab with or without paclitaxel for the treatment of Stage IIIB or IV NSCLC.^[23] Both median survival and PFS were improved (P = .003 and P < .001, respectively) in the arm that received bevacizumab. A recent meta-analysis^[24] of over 2000 patients evaluating the use of bevacizumab in unresectable NSCLC found that high doses of the agent were associated with improved 2-year overall survival and PFS, though at an increased risk for treatment-related death. Low-dose bevacizumab was associated with improved PFS and no greater risk for treatment-related death. Bevacizumab, when combined with irinotecan, fluorouracil, and leucovorin, has also demonstrated a survival benefit in patients with metastatic colorectal cancer.^[25] Finally, a randomized study of over 700 patients with metastatic breast cancer demonstrated that bevacizumab, given in combination with paclitaxel, improved PFS, but not overall survival, compared with paclitaxel alone.^[26] Grade 3-4 hypertension, seen in almost 15% of patients, was the most common serious side effect in the study — and, in fact, the major toxicity associated with bevacizumab treatment is the development of hypertension. It is presumably due to the effect of the drug on the vasculature. Bevacizumab should be used with caution in patients with a history of hypertension and not used in patients with uncontrolled hypertension. The drug is also associated with an increased risk for thromboembolic events. A recent study^[27] evaluated the impact of the development of hypertension on clinical outcome in patients receiving bevacizumab with chemotherapy in the context of a large randomized trial. Both overall survival and PFS were improved in those patients who developed hypertension after starting treatment.

It is unclear how much of the success of monoclonal antibody therapy is due to the initiation of ADCC and the subsequent generation of an adaptive immune response. It is presumed that the toxicities that predict improved outcomes that have been seen with the use of specific monoclonal antibodies are a surrogate for successful tissue targeting of these agents.

Vaccines

Cancer vaccines are a form of active immunotherapy. Most vaccines are constructed to stimulate APCs to present specific antigens to T cells, which will generate either a robust endogenous T-cell response and CTLs or a B-cell response with resultant neutralizing antibodies. In the case of vaccines, the patient’s immune system must have the capability of responding to antigen-specific stimulation. A variety of cancer vaccines have been tested for both prophylactic and therapeutic indications. Multiple studies, enrolling hundreds of patients, have demonstrated that vaccines targeting cancer — even those targeting self proteins — are associated with rare toxicity; the most common are injection site reactions due to the immunologic adjuvants that are often included in the vaccine to assist in boosting the immune response.

There are several vaccines that are used today to prevent the development of cancer. These vaccines target viral antigens. The chronic infections induced by these pathogens are associated with the development of malignancy. Vaccines constructed for the prevention of viral infections, such as HBV and HPV, are designed to generate neutralizing antibodies that will clear the infectious pathogen. HBV vaccines have been routinely administered since the 1980s, and recent reports suggest that the prevention of the development of HBV chronic carriers via the prevention of infection is having an impact on the incidence of hepatocellular carcinoma (HCC) in endemic areas. In a 20-year follow-up study among individuals in Taiwan, the rate of HCC was significantly lower (relative risk of 0.31, P < .001) among patients who had been vaccinated compared with those who were not.^[28] Similarly, a recently approved vaccine for the HPV virus has shown great efficacy in preventing the development of cervical cancer. A double-blind study^[29] of an HPV type-16 vaccine was conducted in over 2000 young women. There was 100% efficacy in preventing the development of HPV infection, while all cases of cervical intraepithelial neoplasia (CIN) occurred in the control arm. HPV vaccines have shown efficacy in preventing other HPV-associated cancers as well. A quadrivalent (HPV 6, 11, 16, and 18) vaccine was effective in preventing vulvar intraepithelial neoplasia (VIN) in most patients enrolled in a large randomized clinical trial.^[30]

Unfortunately, once patients have already developed infection and/or preinvasive lesions, the ability of a vaccine to induce disease resolution is limited.^[31] The inability to clear disease is most likely due to the type of immune response generated with these vaccines. B cell-based antibody production is most commonly induced with immunization. Once malignant disease has developed, a CTL/Th cell immune response is needed for eradication. These data suggest that prophylactic cancer vaccines have and will play an important role in the prevention of human malignancy. Although the antigens to target with vaccination for infectious disease are well established, antigens that would give broad coverage for prevention of malignancies such as colon and breast cancer have not yet been identified.

No cancer vaccine is currently approved to either treat cancer or to prevent disease recurrence, although vaccines have been tested in patients with advanced stage malignancy for decades. A review of over 400 patients with melanoma, immunized with a variety of vaccines targeting the disease, estimated that overall response rates range from 2% to 9%.^[32] Still, as a better understanding of T-cell stimulation and function has evolved over the last 10 years, newer vaccine technologies have been developed that are much more successful in eliciting CTL/Th cell immunity than previous platforms. For this reason, recent studies are beginning to suggest that cancer vaccines may have an impact on disease outcome. Clinical response appears to be related to the level of immunity achieved. In a study of 20 women with grade 3 VIN,^[33] the use of a long synthetic peptide vaccine targeting HPV-16 was correlated with a clinical response in 79% of patients (47% complete responses) at 12 months of follow-up. Moreover, patients with complete responses had significantly higher levels of HPV-specific IFN-gamma producing T cells than those who did not achieve a response. Phase 2 clinical trials of vaccines targeting breast (HER2/neu peptide vaccine) and prostate (prostate-specific antigen vaccine) cancer as well as melanoma (gp100/MART1/tyrosinase peptide vaccine) have suggested that a survival benefit can be achieved with active immunization and that the magnitude of the IFN-gamma antigen-specific T-cell response obtained is associated with survival.^[34-37]

In the last year, phase 3 studies of cancer vaccines targeting a variety of malignancies have reported positive results. An integrated analysis of 2 randomized phase 3 studies evaluating the therapeutic efficacy of a vaccine targeting prostatic acid phosphatase (PAP) in 225 patients with hormone-refractory prostate cancer demonstrated a survival benefit with vaccination.^[38] Patients randomized to the vaccine arm experienced a 33% reduction in the risk for death (P = .011, HR = 1.5) compared with those receiving a placebo. The vaccine, a cell-based vaccine consisting of autologous APCs loaded with a PAP-GM-CSF fusion protein, was well tolerated with few side effects. An additional randomized phase 3 study of high-dose IL-2 with or without a peptide-based vaccine targeting the gp100 melanoma tumor antigen demonstrated survival benefit in 185 patients with advanced stage melanoma after vaccination.^[39] PFS in the vaccinated arm was 2.9 months compared with 1.6 months in the control arm (P = .010), while overall survival had a trend toward significance (17.6 months vs 12.8 in the control; P = .096). It is notable that both of these studies were performed in patients with end-stage metastatic disease that was no longer responding to standard therapy and that clinical benefit was still observed, considering that active immunization has proven to have the greatest benefit in the prophylactic setting.

Ultimately, therapeutic vaccination may be most effective when used in the adjuvant setting to prevent disease recurrence. This was the rationale behind a phase 3 study designed to evaluate the benefit of immunization against idiotype antigens expressed on follicular lymphoma.^[40] Follicular lymphoma expresses unique surface immunoglobulin, and the idiotype determinants of those immunoglobulins have been shown to be immunogenic.^[41] In the phase 3 study,^[40] patients with follicular lymphoma, who had achieved a complete clinical response with standard therapy, were randomized to receive an idiotype vaccine vs control immunization. At a median follow-up of almost 57 months, the median disease-free survival was 44.2 months in the vaccine arm compared with 30.6 months in the control arm (P = .045, HR = 1.6). Over the next few years, many more vaccines will be progressing to phase 3 clinical trials, and the likelihood of the development of a variety of vaccines to aid in the prevention of cancer relapse is high.

Adoptive T-Cell Therapy

The infusion of tumor competent T cells into a patient is a form of passive immunotherapy. Once the T cells are stimulated by antigen in vivo, they will proliferate and induce tumor eradication. If both Th cells and CTLs are infused, there is the potential for the infused cells to persist as memory T cells, which could result in a prolonged antitumor effect related to the initial infusion. The mechanism of action of T-cell transfer depends on the infused cancer-specific CTL-killing tumor cells expressing antigen and the Th cells supporting sustained proliferation and function of the CTLs. Adoptive T-cell therapy is most widely used in the HSCT setting for relapsed hematologic malignancy as a donor lymphocyte infusion (DLI), particularly for CML. DLI is the collection and infusion of peripheral blood mononuclear cells from the transplant donor into the transplant recipient after the transplant has failed. The treatment has been shown to reinduce a remission in some patients, most likely due to the infused T cells recognizing and responding to minor histocompatibility antigens (MHAs) expressed on the surface of the recipient’s relapsed tumor cells, a phenomenon called graft vs tumor effect. MHAs are recognized as foreign to the donor T cells and stimulate a destructive immune response. Unfortunately, MHAs are also expressed on normal tissues in the recipient, resulting in a higher risk for graft vs host disease (GVHD) in patients who receive DLI as part of their treatment.

DLI has shown the greatest therapeutic efficacy in the treatment of CML that has relapsed after HSCT. After DLI in this setting, a 3-year survival in more than 60% of patients can be obtained.^[42] The results with DLI are less impressive in other hematologic malignancies. In acute myeloid leukemia (AML), multiple myeloma, and lymphoma, survival associated with DLI after HSCT relapse is well below 50%.^[42] In a recent evaluation of over 500 AML patients in first hematologic relapse after HSCT, those who received DLI as part of their treatment for relapse had an estimated survival at 2 years of 21% compared with 9% for those who did not receive DLI.^[43] Of note, the time to achieve remission after DLI is quite prolonged compared with the time to response observed after administration of a cytotoxic chemotherapy. A study of CD4-positive DLI in 19 patients with relapsed CML demonstrated a 13-week (range, 9-30 weeks) time to cytogenetic response from the time of the first DLI and a 34-week (range, 11-56 weeks) time to molecular remission.^[44] Presumably, the delayed time to achieve maximal response or remission is due to the need for in vivo proliferation of T cells to achieve a level of magnitude that is therapeutically effective. Most likely, this is the reason that DLI is much more effective in cases with minimal residual disease rather than overt relapse: the immune response has time to overwhelm the cancer, whereas in frank relapse there is not time for T-cell expansion before the leukemia has grown out of control.

As stated, the major toxicity after DLI is the development of GVHD. In a study of over 300 patients who received DLI for CML that relapsed after HSCT, 38% of patients developed either acute or chronic GVHD.^[45] Risk factors for developing GVHD included an initial cell dose greater than 10⁷, DLI administered within 2 years of the initial transplant, and DLI derived from unrelated donors. Indeed, the risk for death was 2.3-fold greater in patients who underwent DLI and developed GVHD than in patients who did not develop GVHD after DLI. There are several approaches — including the use of low-dose immunosuppression prior to DLI or the purification and infusion of T cells specific for MHA — being studied to minimize the development of GVHD after DLI in an effort to improve overall survival rates.^[46,47]

In large part due to the success seen with DLI in inducing remissions in refractory hematologic malignancy, adoptive T-cell therapy is being studied as a treatment in several tumor types. EBV-mediated malignancies have been particularly amenable to the evaluation of T-cell transfer. Patients have a vigorous endogenous immune response to EBV because it is a foreign virus, and T cells are more easily collected and expanded ex vivo. Further, EBV-specific T cells can be of high avidity and easily demonstrate lytic activity in culture. Finally, EBV is directly implicated in the malignant transformation. A phase 2 study of the infusion of allogeneic EBV-specific T cells for the treatment of EBV-positive posttransplant lymphoproliferative disease demonstrated a 52% response rate at 6 months with minimal toxicity in 33 patients.^[48] The infusion of autologous EBV-specific CTLs was associated with a 20% response rate in patients with stage IV nasopharyngeal carcinoma (n=10).^[49] Infusions were well tolerated; notably, 2 patients developed inflammatory responses at the site of the tumor after T-cell infusion, indicating the cells were capable of homing and inducing the generation of significant inflammation.

In solid tumors, adoptive T-cell therapy has been most widely studied for the treatment of advanced stage melanoma. Early trials that infused nonspecifically expanded T cells derived from the tumor (ie, tumor infiltrating T cells or TIL) demonstrated minimal response rates.^[50] Lymphodepletion prior to T-cell infusion, however, has increased responses dramatically. Studies have shown that pretreatment with lymphodepletion regimens such as radiation, cyclophosphamide, and/or fludarabine prior to T-cell infusion removes cells that consume essential cytokines needed for in vivo T-cell expansion such as IL-7 and IL-15.^[51] The addition of myeloablative preparative regimens has increased the response rate of adoptive T-cell therapy in metastatic melanoma patients to as high as 70% but with significant added toxicity.^[52] The durability of the clinical response is variable with few long-term survivors. To optimize response rates and the number of durable responders, investigators are evaluating the use of:

• Highly purified T-cell populations, especially those T cells responsible for maintaining immunologic memory;
• Novel targeted pretreatment methods that may improve T-cell proliferation in vivo with decreased toxicity; and
• The development of engineered T cells that demonstrate high avidity for antigens expressed by the tumor and may, therefore, be more efficient killers.^[53-55]

Similar to DLI, adoptive T-cell transfer for solid tumors may have more sustained efficacy if used in minimal residual disease states rather than in refractory established tumors.

Immunomodulators

There are several categories of immunomodulators: cytokines, modulators of innate immunity, and, identified more recently, agents targeting specific immunosuppressive pathways. Cytokines are biologic proteins that are naturally secreted by immune system cells to initiate and sustain an immune response. Recombinant cytokines have been manufactured, evaluated in clinical trials, and have shown some benefit in the treatment of diseases such as melanoma, renal cell carcinoma, and CML, where they are approved for clinical use. Over the last few years, several novel targeted agents such as kinase inhibitors and mammalian target of rapamycin (mTor) inhibitors have shown much greater therapeutic efficacy in the treatment of these diseases than cytokines such as IL-2 and IFN-alfa 2b. For this reason, cytokines are much less commonly used for the treatment of cancer now than they were a decade ago.

IL-2 is approved for use in the treatment of metastatic renal cell carcinoma and melanoma, where the drug is associated with about a 10% response rate and less than 2% durable responses. The mechanism of action of IL-2 is unknown, but the cytokine significantly stimulates the proliferation and activation of both T cells and NK cells which are thought to have lytic activity against tumors. In renal cell carcinoma, response to IL-2 is most likely to be associated with a good performance status, minimal sites of metastatic disease and no liver metastasis, as well as normal neutrophil counts.^[56] In melanoma, high-dose IL-2 results in a response in a small minority of patients; the response rate improves when it is combined with chemotherapy, an approach called “biochemotherapy,” but there is no benefit to overall survival.^[57] Clinical response to IL-2 in melanoma has been associated with having only cutaneous metastasis as a site of metastatic disease and the development of lymphocytosis after treatment.^[58] The approved doses for IL-2 for treatment of advanced stage melanoma are quite high, 600,000 IU/kg; lower doses have not shown as great a clinical benefit as high-dose therapy. However, side effects are significant at this dose and include vascular leak syndrome often requiring systemic blood pressure support, diuresis, and, at times, intubation for respiratory support after the development of pulmonary edema. Along with expanding effector T cells, IL-2 has also recently been shown to expand the regulatory T-cell populations that inhibit the function of effector T cells such as CTLs.^[59] It may be that the minimal efficacy of IL-2 in inducing remissions is related to the lack of specificity of the cytokine to antitumor effector cells.

IFN-alfa 2b is the only approved treatment for the adjuvant therapy of melanoma associated with a high risk for relapse. The drug is also used in the treatment of renal cell carcinoma, CML, and other myeloproliferative disorders. The mechanisms of action of IFN in mediating tumor regressions are multifactorial. IFN has been shown to be antiproliferative and antiangiogenic, and to induce the apoptosis of tumor cells and regulate the function of T cells.^[60] The use of IFN-alfa 2b is controversial in melanoma: some studies have shown survival benefit in the adjuvant setting whereas others have not duplicated this result. An Eastern Cooperative Oncology Group study randomizing almost 300 patients to receive IFN vs observation demonstrated an improvement in both relapse-free survival (P = .0023) and overall survival (P = .0237), but a pooled analysis of multiple studies by the same group showed only an improvement in relapse-free survival (P = .006), not overall survival.^[61,62] IFN treatment is toxic, with common side effects including flu-like symptoms that can be debilitating, gastrointestinal disorders including hepatotoxicity, arthralgias, and neuropsychiatric symptoms. Because the success of the therapy depends on patient compliance to the treatment, symptom management is key; guidelines have been published on the medical management of IFN toxicity.^[63] Lower doses of IFN are less toxic but do not improve survival rates.^[64]

Immunomodulation with intravesicular BCG has been a mainstay of the treatment of early bladder cancers. BCG is a mycobacterial cell wall preparation that potentially functions by stimulating cells of the innate immune system via TLRs. Studies have shown that BCG will activate APCs such as dendritic cells and induce these cells to secrete cytokines that will elicit an inflammatory adaptive T-cell response.^[65] A recent systemic review of randomized trials and meta-analyses demonstrated that intravesicular BCG given after transurethral resection for superficial bladder cancer reduced the risk for recurrence by almost 70% compared with surgery alone.^[66] Complications associated with the use of BCG include urinary frequency, cystitis, fever, and hematuria.

A newer class of immunomodulators are antibodies that have been designed to block proteins that inhibit the generation of an immune response or engage receptors that stimulate immunity. One of the first in class is anticytotoxic T lymphocyte antigen 4 antibody (CTLA-4). CTLA-4 is a protein expressed by T cells that will bind receptors on APCs, turning off a T-cell response. The CTLA-4 signaling pathway is a major mechanism of self-regulation of T cells whereby immunologic tolerance is maintained. Recent studies in murine models demonstrate that anti-CTLA-4 can both directly enhance T-cell effector function as well as block T regulatory cell activity.^[67] A published phase 2 study of 56 patients with progressive metastatic melanoma recorded an overall response rate to anti-CTLA 4 of 13%.^[68] Treatment was associated with significant toxicity, mostly autoimmune phenomena such as colitis, vitiligo, and hypophysitis. Investigators demonstrated that grade 3 and 4 autoimmune toxicity was associated with a higher clinical response (P = .008).^[68] Another antibody in clinical trials is anti-CD137. CD137 is expressed on T cells; when the antibody binds its ligand, T cells will activate and proliferate. Because these approaches are not specific to an antigen and have been shown to be general immune stimulators, the issue of toxicity is a concern.

Conclusions

There are several classes of immune-based cancer treatment that are currently used in the clinic. As technology and our understanding of how the immune system recognizes and responds to cancer have advanced, so has the development of new immune-based cancer therapeutics. We should expect to see immunotherapy further integrated at all stages of cancer prevention and treatment within the next decade.

Supported by an independent educational grant from Bristol-Myers Squibb.

This article is a CME certified activity. To earn credit for this activity visit:
http://cme.medscape.com/viewarticle/720825

Authors and Disclosures

As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines “relevant financial relationships” as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.

Author(s)

Mary L. Disis, MD

Associate Professor of Medicine, University of Washington, Seattle, Washington Disclosure: Mary L. “Nora” Disis, MD, has disclosed the following relevant financial relationships: Received grants for clinical research from: Hemispherx Biopharma; GlaxoSmithKline Served as an advisor or consultant for: VentiRx Pharmaceuticals, Inc. Dr. Disis does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics not approved by the US Food and Drug Administration (FDA) for use in the United States. Dr. Disis does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

New observational data from the Cardiovascular Health Study show that centrally active angiotensin-converting enzyme (ACE) inhibitors reduce cognitive decline by 65% per year of exposure, an effect that is likely due to their ability to cross the blood-brain barrier.

Please read on…

http://cme.medscape.com/viewarticle/706868

Reduced Incidence Likely Not Due to Antihypertensive Effect

“Our most important findings in this observational study were that centrally acting ACE inhibitors were associated with a 65% reduction in cognitive decline per year of taking the centrally active ACE inhibitors,” said Dr. Sink.

“In addition, compared with participants with high blood pressure who took other types of blood-pressure–lowering medications, non–centrally active ACE inhibitors did not have this effect and might be associated with a greater risk for incremental dementia, and  that cumulative (or chronic) exposure to ACE inhibitors may be needed to achieve the protective effect,” Dr. Sink said.

The researchers suspect that this difference is due primarily not to the antihypertensive effects of centrally acting ACE inhibitors but to their effect on the brain’s intrinsic renin-angiotensin system, which is involved in memory and cognition.

“In a single-payer system, the government will fund health insurance, but private providers will continue to deliver care. Economies of scale will save the money to make this possible. Many Americans, including Democratic presidential nominee Barack Obama, concede that single-payer insurance is probably our most efficient option.^[2] But they worry that it lacks the spirit of the American market. Nothing could be further from the truth.

A single-payer system will harness the market’s strengths while addressing its limitations. The private health insurance market is inefficient, bloated by advertising, duplicated bureaucracies, dividends, and executive compensation. What’s worse, insurance policies are so complex and individuals’ future needs so unpredictable that consumers cannot make the informed selections that induce competition between insurers.

“However, consumers can create competition among healthcare providers. This is paramount because patients need the best healthcare, not the best middlemen to pay for it. Currently, providers are insulated from competition because private insurers often restrict coverage to select physicians. In addition, the 47 million uninsured Americans^[3] have little impact on the market. A single-payer system will give all consumers the power of choice and open all healthcare providers to the effects of consumer decisions.

Single-payer works because of the efficiency of specialization. The government will manage the paperwork and private entities will provide the care. Adam Smith would be proud.”

Prajwal Ciryam, a second-year MD/PhD student in the Medical Scientist Training Program at Northwestern University and a Co-Founding Member of Health Care for All Illinois

Integrative Medicine (IM), according to the Consortium of Academic Health Centers for Integrative Medicine, is the practice of medicine that reaffirms the importance of the relationship between practitioner and patient, focuses on the whole person, and makes use of all appropriate therapeutic approaches that are informed by evidence. It is important to differentiate IM from complementary and alternative medicine (CAM), which is associated with IM therapies for which much of the evidence is still unsettled. The Medscape IM Resource Center seeks to help clarify these evolving issues for health professionals with best-evidence articles, educational activities, and expert commentary.

For further reading, please refer:

www.medscape.com/resource/integrativemed

Posted 03/12/2009

Nancy R. Terry
“Healthcare reform cannot wait, it must not wait, and it will not wait another year.” With those words, President Barack Obama, in his first address to a joint session of Congress, rallied Congress and the American people to tackle the “crushing cost of healthcare.” Yet, it remains to be seen whether the President’s reform efforts will target one of the most wasteful sectors of healthcare — the health insurance industry.

Recent postings on Medscape’s Physician Connect (MPC), an all-physician discussion board, deride the excesses of health insurance companies and exhort the need to restructure, if not eliminate, the for-profit health insurance industry.

“Commercial, for-profit health insurance is one of the greatest Ponzi schemes ever foisted on the public,” says a family medicine physician. “The executives are the ones that benefit to the detriment of everyone else. How else does the president of one of the largest insurance companies get to be a billionaire? By being at the top of the pyramid of companies’ and individuals’ premium payments.”

“The single most important factor in the atrociously high cost of healthcare in the United States is the rapacious, money-hungry insurance companies and their fat cat CEOs,” comments an MPC contributor.

“The damage that the insurance companies do is not limited to the salaries of the CEOs,” says another contributor. “They waste the time and resources of healthcare workers, institutions, and patients. They are clearly a negative, wasteful element in healthcare today that needs to be heavily regulated, changed, or eliminated.”

Physicians point to a number of supposedly routine practices of the health insurance companies that cry out for oversight. One MPC participant remarks that health insurance companies increase their premiums even as they decrease coverage. Another discussant notes that insurers typically burden physicians and patients with filing requirements as part of a strategy to delay or deny legitimate claims. According to one contributor, some companies frequently change their coding schemas to avoid paying legitimate claims. “The insurance companies make billions of dollars in profit each year,” says one MPC commentator, “and they do it by limiting care, denying claims, limiting contracts, and limiting reimbursements.”

The practice of systematically denying legitimate reimbursement claims by insurance companies has been the focus of an ongoing investigation by New York Attorney General Andrew Cuomo. In January 2009, Cuomo reached an agreement with UnitedHealth Group, Inc. that the insurer would shut down its controversial Ingenix database and pay $50 million to fund a nonprofit, independent database for the purpose of establishing fair compensation rates. The Ingenix database, which was owned by UnitedHealth, served all the major insurers and, according to The Wall Street Journal, skewed downward the “usual and customary” rates of out-of-network insurance reimbursements through “faulty data collection, poor pooling procedures, and lack of audits, thus forcing customers to pay more out of their own pockets for healthcare.” In February, WellPoint, Inc., the nation’s largest health insurer, agreed to Cuomo’s request to pay $10 million to help fund the new database. WellPoint is the sixth insurance company to make such an agreement with Cuomo’s office. As quoted by New York Daily News, Cuomo commented on the insurers’ use of the Ingenix database, saying, “This is as egregious a situation as I’ve seen, of a virtual monopoly.”

Is health insurance a scam? The 100 MPC postings in response to that question are unanimous in their assertion that the health insurance industry needs reform. Yet, MPC contributors are divided as to the extent and nature of that reform.

“The health insurance system is so profoundly flawed,” says one MPC contributor, “that the only solution is a nonprofit, single-payer healthcare system.” Other MPC contributors contend that a single-payer system would harbor its own set of problems. Comments a psychiatrist, “I would rather have evil insurance companies than absolute power concentrated in a single agency. If you have a complaint about an insurance company, you can complain to the regulators and drop the insurance. If you have a complaint about the government, you are screwed.”

Advocates of a single-payer system singled out Physicians for a National Health Program as a resource outlining the salient features of a single-payer system. Similarly, several advocates for reorganization of the for-profit insurance system directed readers to Real Health Reform, which proposes, among other healthcare reforms, the restructuring of private health insurance into a regulated utility.

Other contributors less concerned about the overall structure of the industry advocate that health insurance coverage should more closely resemble other types of insurance. “When we protect our house and car, the purpose has traditionally been to provide a safety net if the unforeseen happens to us,” points out an endocrinologist. “Health insurance is not that way. We have come to expect medical insurance to subsidize ordinary expenses, like our prescriptions and our office visits and any number of interventions that are not in themselves financially devastating, the way an auto collision or a home fire would be.” A family medicine physician comments, “Health insurance needs to be made into real insurance that only covers catastrophic events. Then it will be cheaper for everyone.”

Evident throughout the postings is a sense of frustration. One participant comments, “The people are not happy with health insurance, the physicians and allied personnel are not happy with health insurance. What is the government waiting for?”

Some MPC contributors refuse to take a wait-and-see attitude. They advocate that physicians who are disgruntled with the health insurance industry should effectively boycott health insurance.

“We need to immediately stop taking all third-party payments,” says an MPC contributor.

“Bill patients at the time of service,” advises another contributor. “Provide them with the invoice and tell them the truth, the larger truth — that you, the doctor, are not in the business of bandying about with insurance clerks and petty tyrants whose motivation is nothing but to frustrate payment and cost you valuable time and energy, which is duly relegated to patient care.”

“Stop making contracts with HMOs, hospitals, and health insurance,” recommends a neurologist. “Return to cash payment. When other doctors see it works for them the way it has for many, guess what? The yoyos who keep your insurance clerk and billing staff on hold for 2 hours asking for notes and records will be collecting pink slips.”

But the question remains: will the President’s health reform initiative take on the health insurance industry? MPC contributors hope the answer to that question is yes. “Our healthcare system is broken largely due to the insurance companies,” comments an MPC contributor. A urologist agrees, “Only through insurance reform can we begin the process of real healthcare reform.”

View these and other discussions in Physician Connect (physicians only; click here to learn more).

We are glad you can join us here at HMP! It is my heartfelt pleasure to inform you that the repacking of all our existing services under the umbrella of HMP has been very well received by all of you, many who cite the reasons as saving more time and costs.

For those of you who are new to us, we welcome you, and hope you may be able to find some of the services or packages which may appeal to you or your company’s needs.

As in my previous addresses, our work here at HMP has always been about the relationships we maintain and treasure with you our clients and whom many has over the years become dear [Read more →]