What are the two or three critical issues facing the field of cancer immunotherapy?
1. Immunotherapy has transformed cancer care for many patients providing unprecedented durable benefits to some patients with advanced cancer. The last decade has witnessed a tremendous diversification in the immunotherapy armamentarium entering clinical testing with cell therapy becoming a standard of care for some hematological malignancies, and accelerated development of next generation engineered cells, antibodies, vaccines and other biomolecules. In parallel, clinical testing of immunotherapy, often in combination with other treatments, has moved to earlier disease stages. These exciting developments generate incredible opportunities but also challenges that need to be addressed to move the field forward. The remarkable response rate observed in patients with DNA mismatch repair deficient colorectal cancer treated with anti-PD1 is one of the most powerful demonstrations of the importance of patient selection. To date only a few biomarkers predictive of response to immunotherapy have been defined, and many are dynamic and context-dependent. Thus, a critical challenge for the field is the implementation of precision immunotherapy, which will also spare patients unlikely to derive a benefit from the sometimes very serious toxicities of some immunotherapy agents. Meeting this challenge will require a multi-pronged and multi-disciplinary approach that involves efforts to develop and leverage new preclinical models, cutting-edge techniques and system biology strategies to study patients undergoing immunotherapy, and innovative clinical trials.
2. A growing wealth of data shows that it is critical to evaluate not only the tumor microenvironment but also patient's germline genetics and overall “macro-environment” to understand the determinants of response and resistance to cancer immunotherapy. In this respect, a key issue to address is ethnic and societal diversity in clinical trials of immunotherapy. The immune system’s polymorphisms have been shaped by thousands of years of selective pressure driven by infectious pathogens that are reflected in a patient’s ancestry. Thus, there is a dire need to identify biomarkers of response and toxicity that differ by ancestry. In addition, other variables such as sex, age, metabolic state, quality of nutrition, antibiotic use, stress level and physical activity need to be systematically studied to define their influence on the cross-talk between cancer and the immune system. Some of these factors are actionable but influenced by socio-economic status and other structural, cultural and educational barriers. Thus, interventions will require the engagement of multiple entities and stakeholders, including patient advocates, community leaders and social workers.
3. Progress in engineering, computational sciences and artificial intelligence is occurring at an accelerated pace, providing the tools that will enable unprecedented progress in the field of cancer immunotherapy. However, these advances come with multiple challenges: among them are the lack of standards and consensus guidelines for the use of these new tools to study patients, their exorbitant costs, and the scarcity of investigators trained to implement these technologies and critically assess their output. Thus, there is a need to engage the immuno-oncology community at large, from clinical oncologists to basic immunologists, regulatory agencies and patients, in contributing to a safe and effective collection, sharing and use of medical and scientific information. A continuous investment in research and education is essential for the training of new generations of investigators that will become increasingly multidisciplinary. Public support is critical to secure this investment. The recent pandemic has brought to the attention of the general public the importance of the immune system but has also exposed the fragility of public trust in science and the critical need to improve education and communication with multiple stakeholders, working with cancer patients as partners in the quest for more effective therapies.