Advances in the field of tumor immunotherapy have given great hope for those treating cancer. We are in an era of unprecedented achievements, as evidenced by impressive clinical responses in patients treated with adoptive cell therapy and immune checkpoint inhibitors.
One could look no further than the ever-increasing numbers of lung cancer immunotherapy trials to see the excitement in the field of cancer. Many patients believe that the new immunotherapies are the “miracle drugs” of the 21st Century, therapies that cure all cancers.
At times, patients will push physicians to give them the drugs even when there is little evidence of effectiveness in their specific cancer.
Unfortunately, the success of these miracle drugs has not, as of yet, reached many in the rural or urban communities. Denise Grady clearly articulated many of the issues associated with minorities and clinical trials in her 2016 New York Times article titled “In Cancer Trials, Minorities Face Extra Hurdles.” She pointed out that, “as money pours into immunotherapy research and promising results multiply, patients getting the new treatments in studies have been overwhelmingly white. Minority participation in most clinical trials is low, often out of proportion with the groups’ numbers in the general population and their cancer rates.”1
While many investigators are aware of these issues, substantial action has not materialized past the framing of the problems.
The failure to address issues of widespread access to tumor immunotherapy remains an important 21st-century problem, one that could perpetuate ongoing inequities in cancer care. This failure could create an unintended “immunotherapy divide” that could potentially be catastrophic, as it will limit the role of this transformative therapy in minority patient populations and potentially widened the disparity gap in the United States.
We, therefore, propose a framework for addressing the divide. This framework is founded on being much more deliberate about including underrepresented populations in immunotherapy trials. It is unquestionable that all communities reflect the intersection of socioeconomic factors, culture, environmental exposures, and access to resources. Given that social disadvantage has been linked to poorer outcomes in cancer, we believe that the time is right to highlight the emerging work that has begun to examine the role of social determinants in tumor immunobiology.
Controlled clinical trials are considered the “gold standard” for evaluating clinical interventions, and numerous clinical trials have demonstrated the potential of immunotherapy in a variety of malignancies. Although many of these trials have treated patients with malignancies that present an unequal burden of incidence and mortality in underserved patients, minority populations continue to be grossly underrepresented in these trials.
This incongruence in clinical trials enrollment contributes to the continued growth of the immunotherapy divide. The inclusion of minority patients in immunotherapy trials may not only represent an essential component of addressing disparities in clinical outcomes, but it might also improve the delivery of immunotherapy approaches to these populations.
We undertook an evaluation of phase II and III clinical studies utilizing pembrolizumab or ipilimumab for the treatment of head and neck, prostate, and lung cancers. We found that 79% of trial participants were Caucasian, while 14% of the participants were Asian, 3% were African-American, and 4% were unknown/other. These data demonstrate ongoing inequities in clinical trial participation that will exacerbate the emerging immunotherapy divide by limiting the generalizability of research findings and access to high-quality oncology care.
While the shortcomings of the NIH Revitalization Act of 1993 have been widely discussed and hotly debated over the last quarter century, that law at a minimum mandated that all medical research sponsored by the National Institutes of Health include sufficient minorities and women to determine whether they respond to treatment differently than other groups.5 Interestingly, clinical trials outside the various federal agencies have not been required to encourage enrollment of populations underrepresented in biomedical research.
The most common reason cited for the failure to enroll patients from underserved communities into trials has been the need for companies to get studies done to gain drug approval quickly. The lack of enrollment of the underserved in trials sponsored by pharmaceutical companies may inadvertently delay important information on the potential differences that gender and racial heritage may play in treatment response. Indeed, recent work points to potential racial differences in immune gene expression as well as immune effector cell function in prostate and colorectal tumors.2-4
Worse, the lack of access to immunotherapeutics might increase the existing disparities in life expectancy between blacks and whites in the U.S.
As we begin to address inequities in immunotherapy trial participation, we must be mindful of the well-described system- and individual-level barriers to clinical trial participation. It is imperative that immunotherapy investigations not only focus on conditions that disproportionately impact at-risk populations, but that they must also address barriers to participation, including inadequate health care infrastructure, distrust of the medical system, and implicit and sometimes remaining explicit biases.
One main reason for the lack of minorities enrolled in immunotherapy clinical trials is the infrequency by which health care providers fail to ask patients from underserved backgrounds to participate in trials due to false beliefs that underserved populations will refuse to enter into trials. Unconscious bias in the health profession remains a significant obstacle to obtaining health equity even to date.
By extension, engagement with community stakeholders will enhance advocacy in the community. By developing the input of community stakeholders more deliberately in clinical trials, we may make the importance of clinical trials more relevant to the concerns of the community. The traditional approach of developing and delivering health interventions without community stakeholder involvement until late in the translational research continuum engenders distrust and the resurgence of feelings around historical injustices that have been visited on these communities by the medical establishment.
This paternalistic posture leads to a lack of authentic engagement in the research process and the ultimate rejection of the proposed intervention. An approach that broadens interactions between patients, researchers, industry stakeholders, and the community will aid in the design of “community-informed” immunotherapy trials that can overcome many of the well-described barriers to clinical investigation. These efforts will result in increased engagement in clinical trials thereby helping to address the emerging immunotherapy divide.
Bridging the immunotherapy divide will also require intentionality in training a diverse workforce that can reduce the mistrust that currently exists among underserved populations. We must first provide training on tumor immunotherapy to a diverse workforce of physicians who currently provide oncology care to patients in under-resourced areas.
The Society for the Immunotherapy of Cancer and the American Society for Clinical Oncology have published educational resources that provide fundamental knowledge on immunotherapy principles. Utilizing these resources and training programs that are designed and delivered by experts in tumor immunotherapy will help ensure that current immunotherapy approaches are delivered to minority patients.
Finally, we must be deliberate in developing a robust and diverse number of pipeline programs that will push progress against the immunotherapy divide by producing research scientists from under-represented groups. Pipeline programs, including those supported by the Health Resources and Services Administration (HRSA) under Titles VII and VIII of the Public Health Service Act, are proven solutions to producing a diverse biomedical research workforce that will enhance patient care and ensure health equity.
Training minority research scientists in tumor immunology will not only diversify the portfolio of immunotherapy research to include issues that are important to minority communities and subsequently engender the trust of the research enterprise in the research enterprise.
Our overall goal should be to provide equal access to immunotherapeutic approaches to cancer for all patients. Failure to provide equal access will undoubtedly result in the creation of an even wider immunotherapy divide.
We believe that a holistic model that leverages benchtop research, clinical trials, and community engagement will serve as an essential first step in the fight to prevent the emergence of this potential cancer inequity.
The “community” aspect of our work should not be lost as it is incumbent upon us to include a community perspective on tumor immunotherapies when feasible and collect more precise community-based health data. As with any program, it is vitally important to create a culture of sustainability. The development of immunotherapy research pathways that include members of our research community to enhance investigator diversity, community trust, and dissemination is essential as we seek to grow our research networks. If we are not careful and deliberate about minding the immunotherapy divide, it is likely that its continued growth will inadvertently increase healthcare disparities.
We believe that there are several action items needed to address the immunotherapy divide:
- The first is seeking more direct input from the rural and urban underserved communities, which are too frequently absent from the discussion around immunotherapy.
- Second, there should be some consideration given to revamping the NIH Revitalization Act of 1993 to better fit our current diverse population and to extend it to include commercial companies as well the NIH and other federal agencies.
- Third, we must focus on training a robust and diverse workforce that will design more diverse clinical trial participation in the future.
- Lastly, we must do a much better job as a health system of asking, not just some, but all patients if they are interested in clinical trials; to do this, we need to come to grips and then address our unconscious bias around race head-on.
No one would argue that statistics are unimportant in clinical trials, but it is becoming increasingly clear that there is also a social justice need that must be balanced and accounted for in our modern-day efforts to carry out clinical trials that are meaningful for all.