Targeting Driver Oncogenes and Other Public Neoantigens Using T Cell Receptor-Based Cellular Therapy

Abstract

T cell reactivity to tumor-specific neoantigens can drive endogenous and therapeutically induced antitumor immunity. However, most tumor-specific neoantigens are unique to each patient (private) and targeting them requires personalized therapy. A smaller subset of neoantigens includes epitopes that span recurrent mutation hotspots, translocations, or gene fusions in oncogenic drivers and tumor suppressors, as well as epitopes that arise from viral oncogenic proteins. Such antigens are likely to be shared across patients (public), uniformly expressed within a tumor, and required for cancer cell survival and fitness. Although a limited number of these public neoantigens are naturally immunogenic, recent studies affirm their clinical utility. In this review, we highlight efforts to target mutant KRAS, mutant p53, and epitopes derived from oncogenic viruses using T cells engineered with off-the-shelf T cell receptors. We also discuss the challenges and strategies to achieving more effective T cell therapies, particularly in the context of solid tumors.

Keywords: T cell receptor; adoptive cellular therapy; immunotherapy; neoantigen.

Figure 1.. Next generation strategies for TCR-based adoptive T cell therapies.

(A) Current TCR-engineering strategies include retrovirus- or lentivirus-mediated delivery of the therapeutic TCR to CD8⁺ T cells. These TCR-transduced cells retain the endogenous TCR, and may express mispaired receptors on their surface. TAA or TSA are generated in the tumor cells through proteosome-mediated protein degradation in the cytosol, and are loaded onto HLA class I in the endoplasmic reticulum. In the TME, TCR-engineered T cells interact with peptide:HLA class I complexes presented on tumor cells, and deliver cytotoxic cargo leading to tumor cell death. TCR-engineered T cells eventually lose their cytotoxic function through a variety of mechanisms, including inhibitory signaling through PD-1 and death-signaling through Fas. (B) Emerging strategies involve CRISPR/Cas9-facilitated orthotopic replacement of the TCR (to promote physiological expression of the therapeutic receptor and eliminate the endogenous TCR), inhibitory receptor genetic deletion (to prevent inhibitory signaling), expression of immunomodulatory fusion proteins (such as Fas/4-1BB, to convert a death or inhibitory signal into an activation signal), and/or CD4⁺ T cell engineering (with addition of the therapeutic TCR HLA class I-restricted TCR, CD8αβ, and immunomodulatory fusion proteins). Created with Biorender.com.