Cancer immunotherapy has flourished over the last 10–15 years, transforming the practice of oncology and providing long-term clinical benefit to some patients. During this time, three distinct classes of immune checkpoint inhibitors, chimeric antigen receptor-T cell therapies specific for two targets, and two distinct classes of bispecific T cell engagers, a vaccine, and an oncolytic virus have joined cytokines as a standard of cancer care. At the same time, scientific progress has delivered vast amounts of new knowledge. For example, advances in technologies such as single-cell sequencing and spatial transcriptomics have provided deep insights into the immunobiology of the tumor microenvironment. With this rapid clinical and scientific progress, the field of cancer immunotherapy is currently at a critical inflection point, with potential for exponential growth over the next decade. Recognizing this, the Society for Immunotherapy of Cancer convened a diverse group of experts in cancer immunotherapy representing academia, the pharmaceutical and biotechnology industries, patient advocacy, and the regulatory community to identify current opportunities and challenges with the goal of prioritizing areas with the highest potential for clinical impact. The consensus group identified seven high-priority areas of current opportunity for the field: mechanisms of antitumor activity and toxicity; mechanisms of drug resistance; biomarkers and biospecimens; unique aspects of novel therapeutics; host and environmental interactions; premalignant immunity, immune interception, and immunoprevention; and clinical trial design, endpoints, and conduct. Additionally, potential roadblocks to progress were discussed, and several topics were identified as cross-cutting tools for optimization, each with potential to impact multiple scientific priority areas. These cross-cutting tools include preclinical models, data curation and sharing, biopsies and biospecimens, diversification of funding sources, definitions and standards, and patient engagement. Finally, three key guiding principles were identified that will both optimize and maximize progress in the field. These include engaging the patient community; cultivating diversity, equity, inclusion, and accessibility; and leveraging the power of artificial intelligence to accelerate progress. Here, we present the outcomes of these discussions as a strategic vision to galvanize the field for the next decade of exponential progress in cancer immunotherapy.
The idea that an interplay existed between the immune system and cancer was initially posed well over 100 years ago, receiving mixed interest and support. Subsequently, in the late 19th and early 20th centuries, incremental findings began to support this concept. Dr. William Coley and colleagues reported that bacterial infections may contribute to cancer regression, and the cancer immunosurveillance hypothesis was introduced and refined during the mid-1900s to early 2000s. While the proposal to therapeutically harness the immune system to effectively fight or even cure cancer initially seemed like a far-off reality, tantalizing reports began to suggest substantial therapeutic promise. High-dose interleukin-2 in patients with advanced melanoma and renal cell carcinoma caused dramatic, complete tumor regressions in approximately 7% of patients. The first proof of concept trials testing expanded, adoptively transferred autologous tumor-infiltrating lymphocytes (TILs) demonstrated response rates of 50%–70% in patients with treatment-refractory metastatic melanoma. Sipuleucel-T immunotherapy was approved by the US Food and Drug Administration (FDA) in 2010 for patients with castration-resistant metastatic prostate cancer, providing the first evidence that therapeutic cancer vaccines can confer an overall survival benefit for patients. Ultimately, after decades of work to understand mechanisms of immunosurveillance and T cell activation and control through T cell receptors (TCRs) and immune checkpoint pathways, cancer immunotherapy reached an exciting inflection point. The first immune checkpoint inhibitor (ICI), the anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody ipilimumab, was approved by the FDA in 2011 for patients with advanced melanoma based on improved overall survival. Concurrently, based on promising phase II data for anti-programmed cell death protein 1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) ICIs, the phase III studies that led to the first anti-PD-(L)1 ICI approvals began to enroll patients. During this same period, early clinical trials using engineered chimeric antigen receptor (CAR)-T cells revealed sustained remissions in patients with refractory B cell malignancies.
At this critical juncture in the field, the Society for the Immunotherapy of Cancer (SITC) leadership recognized the importance of developing a roadmap to ensure continued progress in immunotherapy research. SITC convened a summit of international experts representing diverse organizations in cancer immunotherapy in 2009 and 2010. This group collaboratively defined nine major hurdles to progress in the landmark white paper, “Defining the critical hurdles in cancer immunotherapy”: (1) limitations of current animal models to predict efficacy of cancer immunotherapy strategies in humans; (2) prolonged time to obtain approval to initiate clinical trials; (3) complexity of cancer, tumor heterogeneity, and immune escape; (4) limited availability of reagents for combination immunotherapy studies; (5) limited funds available to translate science into patients; (6) lack of definitive biomarker(s) for the assessment of clinical efficacy of cancer immunotherapies; (7) conventional clinical response criteria that do not take into consideration differences between response patterns to cytotoxic agents and immunotherapies; (8) paucity of teams of scientists and clinicians dedicated to translational research in cancer immunotherapy; and (9) insufficient exchange of information critical to advancing the field.
Galvanized by a shared roadmap, SITC supported the cancer immunotherapy community as the field continued to expand and flourish. A plethora of diverse immunotherapies—including three distinct ICIs, multiple ICI combinations, CAR-T cell therapies, two distinct classes of bispecific T cell engagers, cytokines, a vaccine, and an oncolytic virus—are now FDA-approved, transforming cancer treatment for both solid and hematologic malignancies. Immunotherapy is now a standard of care for many cancers, offering long-term clinical benefits to patients, including those with cancers previously associated with dismal prognoses. Many therapeutic successes over the last decade were achieved by overcoming the hurdles described in the 2011 manuscript. For example, one hurdle described was the lack of radiographic response criteria that captured the unique response patterns seen with immunotherapy, such as delayed responses, pseudoprogression, and/or hyperprogression. Several radiographic response criteria have since been developed that incorporate these response patterns, allowing for more accurate assessments of the clinical response to cancer immunotherapy. In addition, researchers have made rapid progress in understanding tumor heterogeneity and immune escape through new technologies such as single-cell sequencing and spatial transcriptomics, among others. These studies provided insights leading to a more comprehensive understanding of the diverse spatial composition of the tumor microenvironment (TME) and to more refined genotypic and phenotypic characterization of distinct classes of immune cells and their activated and/or suppressed states. As a result, targeting immune cells beyond T cells, such as NK cells and macrophages, by engineering the cells or by administering agents that target their unique regulatory pathways, are now being tested in early-phase clinical trials.
Progress in cancer immunotherapy over the last 10 years has been awe-inspiring, and the collaborative field-wide refocusing in 2011 undoubtedly contributed to that rapid progress. 13 years later, cancer immunotherapy has reached another critical inflection point, creating a mandate to again convene leaders in the field to both revisit the original challenges and identify new challenges and opportunities that have emerged with the astounding advances of the last decade. For example, the number of agents that show efficacy in preclinical testing yet fail in early-phase human studies remains unacceptably high, in large part due to animal models that inadequately recapitulate human tumors, the human immune system, and the interplay between the two. The development of mouse models with humanized immune systems represents some progress in this area, but interspecies variability remains a major challenge. Unfortunately, the lack of preclinical models that accurately reflect the tumor immunobiology of patients with cancer remains a significant limiting factor in investigating the mechanisms of antitumor activity, toxicity, and therapeutic resistance associated with immunotherapy. Other remaining challenges that continue to slow progress are challenges related to data sharing, and the continuing need for more effective predictive biomarkers of response, and new predictive biomarkers of toxicity and therapeutic resistance. Limited funding continues to be a major obstacle to progress, particularly considering the expense of developing and using cutting-edge technologies like single-cell sequencing and spatial transcriptomics to advance the field. In addition to the expense of generating the highly complex datasets associated with these technologies, expertise in the use and analysis of complex datasets is essential and in short supply, further compounding the cost burdens. Additionally, the plethora of new immunotherapy agents and combinations for testing in clinical trials has strained the clinical research ecosystem. Although innovative clinical trial designs—including adaptive trials, basket trials, and multiarm umbrella trials—have powered the clinical development of new immunotherapy agents and combinations, they have also introduced new challenges for clinical researchers, clinical research sites, regulators, and funding bodies.
Today, the cancer immunotherapy field is poised for another phase of exponential growth. Innovative, next-generation agents with great potential to expand the number of patients with cancer who benefit from immunotherapy are in early clinical trials. A wealth of translational and clinical data is being collected by researchers across the globe. Integration of this creative and productive community will no doubt accelerate progress. It is also imperative to include patients and their advocates as key stakeholders in determining the path forward. Given this evolving landscape of old and new challenges along with the potential for exponential progress over the next decade, SITC leadership recognized the need for a contemporary roadmap for the field to refocus and galvanize the community around the most pressing current opportunities for advancing lifesaving cancer immunotherapies. Accordingly, SITC organized a multistakeholder consensus meeting with experts in cancer immunotherapy, including representation from academic, pharmaceutical, biotechnology, patient advocacy, and regulatory institutions, with the goal of defining and prioritizing present-day opportunities and challenges.
This manuscript is the first in a special review series in the Journal for ImmunoTherapy of Cancer (JITC) that will describe the current state of the field, address pressing challenges, and identify the greatest opportunities for high clinical impact in the scientific, clinical, and regulatory arenas of cancer immunotherapy. While this overarching manuscript will introduce these broad areas of opportunity, identify high-impact cross-cutting tools relevant to several of them, and define the priorities with the highest potential for significant clinical impact, the upcoming topic-focused manuscripts will take a deeper dive into the current state of the field by area of opportunity and report on the expert-identified challenges and opportunities within each area. The special series will provide insights on the roadmap to success from some of the most experienced leaders in cancer immunotherapy, serving as a resource for the scientific community working to overcome the challenges facing the field and effectively capitalize on current and future opportunities for rapid progress.
The updated areas of opportunity identified by the consensus panel encompass challenges across the scientific, regulatory, and clinical arenas and include the following: (1) mechanisms of antitumor activity and toxicity; (2) mechanisms of drug resistance; (3) biomarkers and biospecimens; (4) unique aspects of novel therapeutics (new); (5) host and environmental interactions (expanded); (6) premalignant immunity, immune interception, and immunoprevention (new); and (7) clinical trial design
