Cancer Immunology and Immunotherapy Showcased in the AACR Cancer Progress Report 2023

Each year, the American Association for Cancer Research (AACR) publishes an annual report to Congress and the American public highlighting how biomedical research extends and improves lives by accelerating advances in cancer prevention, detection, diagnosis, and treatment. Over the past decade, immunotherapy has become an increasingly central component of the report as the number of immunotherapies approved by the FDA has grown. The incredible progress that has been made in using immunotherapy for the benefit of patients with cancer is celebrated in the latest edition of the report—AACR Cancer Progress Report 2023 (freely available at https://cancerprogressreport.aacr.org/progress/)—with a dedicated section titled, “Immunotherapy: Pushing the Frontier of Cancer Medicine.” As part of that special feature, we provide a perspective on the advances that have been made in the use of immune checkpoint therapy (ICT) and on the approaches that we believe will bring more breakthroughs in ICT, in the form of new drugs and new combinations, in the future. Accurately communicating the work that we all do to the main audience of the AACR Cancer Progress Report—political leaders and the public—is an often-overlooked aspect of our roles as researchers working tirelessly to advance science and medicine to better peoples’ lives. Therefore, as editors of Cancer Immunology Research, a journal that has helped foster the growth of the field of cancer immunology and immunotherapy, we are delighted to share that perspective in this editorial.Immunotherapy has emerged in the last decade alongside surgery, chemotherapy, radiation, and targeted therapy as a pillar of cancer therapy. Notably, ICT against the T-cell checkpoints CTLA-4 and PD-1/PD-L1 has provided long-term remissions for some patients with previously intractable cancers, such as metastatic melanoma and lung cancer. The combination of the two provides an even higher response rate and is now FDA approved as a standard of care. Since anti–CTLA-4 and anti–PD-1/PD-L1 antibodies globally unleash T-cell responses, they are not specific for a given tumor type, and clinical data indicate responses against a wide range of cancers, including renal cell carcinoma, lung cancer, bladder cancer, and hepatocellular carcinoma. These immunotherapy agents drive diverse immune responses and enable formation of antigen-specific memory responses, thereby providing a “living drug” with the ability to eliminate the tumor indefinitely. Both anti–CTLA-4 and anti–PD-1/PD-L1 agents have been FDA approved as monotherapies and as combination therapies, including combinations with chemotherapy and targeted therapies such as tyrosine kinase inhibitors (TKI). Most recently, another immune checkpoint agent, anti–LAG-3, was approved in combination with anti–PD-1 for the treatment of patients with metastatic melanoma, revealing that there are additional inhibitory receptors that can be blocked for therapeutic benefit.Whereas ICT provides lasting remissions to some patients with specific cancers, many patients do not respond to treatment. Cancers with few immune cells in the tumor such as pancreatic cancer and glioblastoma generally do not respond. In addition, other immunosuppressive 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 TME 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, TME, and host factors. Immune profiling of pretreatment and on-treatment 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.P. Sharma reports other support from Achelois, other support from Adaptive Biotechnologies, other support from Affini-T, other support from Apricity, other support from Asher Bio, other support from BioAtla LLC, other support from BioNTech, other support from Candel Therapeutics, other support from Catalio, other support from Carisma, other support from Codiak Biosciences, Inc, other support from C-Reveal Therapeutics, other support from Dragonfly Therapeutics, other support from Earli Inc., other support from Enable Medicine, other support from Glympse, other support from Henlius/Hengenix, other support from Hummingbird, other support from ImaginAb, other support from Infinity Pharma, other support from Intervenn Biosciences, other support from JSL Health, other support from LAVA Therapeutics, other support from Lytix Biopharma, other support from Marker Therapeutics, other support from Oncoloytics, other support from PBM Capital, other support from Phenomic AI, other support from Polaris Pharma, other support from Sporos, other support from Time Bioadventures, other support from Trained Therapeutix Discovery, other support from Two Bear Capital, and other support from Xilis Inc outside the submitted work. J.P. Allison reports other support from Achelois, other support from Adaptive Biotechnologies, other support from Apricity, other support from BioAlta, other support from BioNTech, other support from Candel Therapeutics, other support from Codiak, other support from Dragonfly, other support from Earli, other support from Enable Medicine, other support from Hummingbird, other support from ImaginAb, other support from Lava Therapeutics, other support from Lytix, other support from Marker, other support from PBM Capital, other support from Phenomic AI, other support from Polaris Pharma, other support from Time BioVentures, other support from Trained Therapeutix, other support from Two Bear Capital, and other support from Venn Biosciences during the conduct of the study; other support from Achelois, other support from Adaptive Biotechnologies, other support from Apricity, other support from BioAlta, other support from BioNTech, other support from Candel Therapeutics, other support from Codiak, other support from Dragonfly, other support from Earli, other support from Enable Medicine, other support from Hummingbird, other support from ImaginAb, other support from Lava Therapeutics, other support from Lytix, other support from Marker, other support from PBM Capital, other support from Phenomic AI, other support from Polaris Pharma, other support from Time BioVentures, other support from Trained Therapeutix, other support from Two Bear Capital, and other support from Venn Biosciences outside the submitted work.