Figure 3. Strategies for precision immunotherapy in RCC.

Antigen-directed therapies can target either surface antigens or HLA-restricted antigens, and may require personalization or be available “off-the-shelf” for multiple patients. Upper left panel, autologous CAR T therapy targeting an RCC surface antigen, like CAIX. Novel CAR constructs will improve specificity (through logic gates), increase persistence, add safety features (“suicide switch”), and/or secrete additional immunomodulatory molecules. Bottom left panel, CRISPR technology may enable “off-the-shelf” allogeneic CAR T cells. Other non-personalized, surface antigen-specific therapies include monoclonal antibodies, with or without an additional conjugated cytotoxic payload (drug or radionuclide). Upper right panel, numerous strategies to target HLA-restricted antigens require personalized therapy, including expansion and infusion of TILs, engineered TCR therapy against one specific HLA-restricted antigen, or neoantigen vaccination therapies. Bottom right panel, using next generation sequencing and mass spectrometry tools, a priority moving forward is to identify shared HLA-restricted antigenic targets (such as peptides derived from aberrantly expressed ERVs) that could be administered “off-the-shelf” to multiple RCC patients. CAR – chimeric antigen receptor; TCR – T cell receptor; TIL – tumor-infiltrating T lymphocyte; ERV – endogenous retrovirus; HLA – human leukocyte antigen; RCC – renal cell carcinoma; CRISPR – clustered regularly interspaced short palindromic repeats.

NOTE: Permission for reproduction of this figure was not granted by the publisher. For Figure 3, please refer to Figure 3 in the manuscript by Braun et al.:

Braun DA, Bakouny Z, Hirsch L, Flippot R, Van Allen EM, Wu CJ, Choueiri TK. Beyond conventional immune-checkpoint inhibition - novel immunotherapies for renal cell carcinoma. Nat Rev Clin Oncol. 2021 04; 18(4):199–214.