elements in the tumor microenvironment (TME), found on both immune and nonimmune cells, may lead to resistance to ICT. Efforts to unleash the immune response directly at the level of the T cell may be largely saturated as CTLA-4 and PD-1 appear to act at the beginning and end of the T cell activation process. A combinatorial therapy approach that also targets other aspects of the complex tumor-immune interactions in the TME offers increased promise to expand ICT benefit to all patients and overcome acquired resistance. Clinical trials of immunotherapy combinations against a wider range of cancers have been hampered by the number of potential combinations, a limited patient pool, and our still restricted knowledge of immune regulatory networks within the tumor. A more complete understanding of the immune system and how it is affected by cancer therapies is also necessary to guide the development of more effective, rationally designed immunotherapy combinations. In addition, multiple ongoing research studies and clinical trials include efforts to unravel the complex interplay between immune responses and specific tumor processes, with hopes of identifying biomarkers that define specific subsets of patients more likely to respond to specific immunotherapy combinations. Many of these efforts are being performed in the metastatic disease setting; however, there have been promising data to indicate that ICT can also provide significant benefit in earlier stages of disease, and neoadjuvant treatment with ICT will clearly be an area of future FDA approvals. Our group conducted the first neoadjuvant clinical trials with ICT, which consisted of anti-CTLA-4 therapy prior to surgery for patients with localized bladder cancer and prostate cancer. These studies not only provided safety data for the use of ICT in the neoadjuvant setting, but also analysis of the resected tumor demonstrated changes in immune responses that occur in the tumor microenvironment as a result of ICT. More recently, in a randomized phase 2 clinical trial with melanoma patients who received anti-PD-1 prior to surgery (neoadjuvant therapy), as compared to treatment after surgery (adjuvant therapy), clinical outcomes were better in patients who received the neoadjuvant therapy. These data fit with the observation that ICT is more effective earlier in treatment when the immune system has a greater chance of encountering tumor antigens and initiating a response. Furthermore, neoadjuvant immunotherapy in select subsets of patients has the potential to eliminate tumors such that patients will not need additional treatments such as chemotherapy, radiation, or even surgery. In a study with rectal cancer patients who had mismatch repair defects in their tumors, anti-PD-1 neoadjuvant therapy led to complete responses with elimination of all tumors in 12 patients. These patients not only did not need to undergo additional treatments with chemotherapy and radiation therapy, but remarkably also did not need to undergo surgery. These data highlight the importance of biomarkers (in this case the evidence of mismatch repair defects) to select appropriate patients and the power of immunotherapy to revolutionize cancer treatment. Realization of the full promise of cancer immunotherapy lies in the accumulation and integration of a wide range of data, incorporation of multiple immune responses, addressing tumor-specific factors, and inclusion of patient-specific history, including data such as the use of antibiotics or microbiome data. Given the large number of ongoing clinical trials, we need to adopt a “reverse translational approach” and invest in obtaining longitudinal samples from patients for assessing evolving immune responses, tumor microenvironment, and host factors. Immune profiling of pretreatment and ontreatment longitudinal biopsy samples from patients can provide critical information about changes in relevant targets in defined patient cohorts. These targets can then be evaluated and therapeutic opportunities validated in animal models, which can guide rational combination therapy strategies in future clinical trials. The “reverse translational model” will require access to patients, the ability to gather relevant data (genomic, epigenomic, transcriptomic, spatial, microbiome, phenotypic) at scale, a strong data science program, discovery science that can answer the questions that arise from immune profiling, and the ability to initiate or guide therapeutic development programs. The goal is to accelerate the path of new drugs and drug combinations to the clinic. By bringing clinical trials, immune profiling, discovery science, data science, and drug development together on a coordinated team, we can make this vision a reality. Such an ambitious undertaking requires the strong and continuous support of academic institutions with large research teams, generous funding sources, efficient regulatory teams to effectively open and monitor new clinical trials, and pharmaceutical partners, but the benefits should be enormous. Immunotherapy: Pushing the Frontier of Cancer Medicine AACR Cancer Progress Report 2023 105
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