Aiming to focus thinking and rational design around immunotherapy for a specific disease setting, Braun and Bakouny et al. adapted the Chen and Mellman “Cancer Immunity Cycle” and comprehensively summarized the immunotherapy literature around renal cell carcinoma – a tumor with paradoxical strong CD8+ T cell infiltration and a history of being immune responsive, but generally suboptimal and non-durable responses to current checkpoint blockade. This roadmap provides a useful backdrop for selecting and prioritizing novel individual and combination therapies, highlighting mechanism-based therapeutic synergies and antigen-targeting approaches.
Contributed by Ute Burkhardt
ABSTRACT: The management of advanced-stage renal cell carcinoma (RCC) has been transformed by the development of immune-checkpoint inhibitors (ICIs). Nonetheless, most patients do not derive durable clinical benefit from these agents. Importantly, unlike other immunotherapy-responsive solid tumours, most RCCs have only a moderate mutational burden, and paradoxically, high levels of tumour CD8(+) T cell infiltration are associated with a worse prognosis in patients with this disease. Building on the successes of antibodies targeting the PD-1 and CTLA4 immune checkpoints, multiple innovative immunotherapies are now in clinical development for the treatment of patients with RCC, including ICIs with novel targets, co-stimulatory pathway agonists, modified cytokines, metabolic pathway modulators, cell therapies and therapeutic vaccines. However, the successful development of such novel immune-based treatments and of immunotherapy-based combinations will require a disease-specific framework that incorporates a deep understanding of RCC immunobiology. In this Review, using the structure provided by the well-described cancer-immunity cycle, we outline the key steps required for a successful antitumour immune response in the context of RCC, and describe the development of promising new immunotherapies within the context of this framework. With this approach, we summarize and analyse the most encouraging targets of novel immune-based therapies within the RCC microenvironment, and review the landscape of emerging antigen-directed therapies for this disease.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Department of Medical Oncology, Gustave Roussy, Villejuif, France. (4) Department of Medical Oncology, Gustave Roussy, Villejuif, France. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (7) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. toni_choueiri@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. toni_choueiri@dfci.harvard.edu.
