Perspective: Looking to the Future of Immunology

James P. Allison, PhD, FAACR
2018 Nobel Laureate in Physiology or Medicine
Vice President, Immunobiology; Chair, Department of Immunology;
Executive Director, Immunotherapy Platform; Director, James P Allison Institute;
Olga Keith Weiss Distinguished University Chair for Cancer Research
The University of Texas MD Anderson Cancer Center
Houston, Texas

Padmanee Sharma, MD, PhD
Professor of Genitourinary Medical Oncology; Professor of Immunology;
Scientific Director of Immunotherapy Platform; Associate VP of Immunobiology;
Director of Scientific Programs, James P. Allison Institute
MD Anderson Cancer Center
Houston, Texas

Immunotherapy has emerged in the last decade alongside surgery, chemotherapy, radiation, and targeted therapy as a pillar of cancer therapy. Notably, immune checkpoint therapy (ICT) agents against the T cell checkpoints CTLA-4 and PD-1/PD-L1 have provided long-term remissions against 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, hepatocellular carcinoma, and many others. These immunotherapy agents drive diverse immune responses and enable formation of antigen-specific memory responses, thereby providing a “living drug” with the capability to eliminate the tumor indefinitely. Both anti-CTLA-4 and anti-PD-1/ PD-L1 agents have been FDA approved as monotherapy and as combination therapies, including combinations with chemotherapy and targeted therapies such as tyrosine kinase inhibitors (TKIs). 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 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 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.

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