Exploiting viral infection/vaccination to focus high-affinity T cell populations into tumors using oncolytic viro-immunotherapy

Immune tolerance restricts the number of T cells with significant affinity for self-tumor-associated antigens (TAAs), thereby limiting successful cancer immunotherapy through an inability to generate populations of high-affinity anti-tumor T cells. In contrast, viral infection/vaccination primes and expands high-affinity effector and memory T cells against viral antigens. We show here that it is possible to exploit population-wide preexisting, anti-viral memory recall responses against SARS-CoV-2 antigens to focus a high-affinity, immunodominant T cell response into tumors by oncolytic virus (OV)-mediated or chimeric antigen receptor (CAR)-mediated delivery of viral antigens that are not themselves related to TAAs. Heterologous prime and OV/boost led to CD8⁺ T cell-dependent tumor cures using either SARS-CoV-2 Mem or Spike (S) proteins as vaccinating/tumor-focusing T cell targets, associated with epitope spreading against TAAs. We also show that CAR-T cells carry SARS-CoV-2 antigen-expressing vectors systemically to tumors even in pre-immune mice. Finally, S-specific CAR-T cells could be boosted in vivo with S protein vaccines to enhance anti-tumor activity and persistence. Thus, where high affinity anti-tumor T cells are not available, boosting preexisting infection- or vaccination-induced T cell populations within tumors using OV-mediated immunogen delivery provides a therapeutically valuable alternative.