Burchett et al. investigated various vaccine-based approaches to boost the effects of CMV gp33-targeted (P14) TCR T cells in a solid tumor model, particularly focused on a CAR/vaccine combination targeting a “universal” surrogate epitope (BCMA). A VSV-based vaccine expressing surface BCMA (but not a secreted BCMA-Ig-Fc) expanded the BCMACAR_P14 T cells at day 5, but persistence was very limited. Early tumor responses and a survival benefit, but no cures, were observed. VSV-induced IFN-I limited gp33 expression, but blocking IFNAR1 had minimal impact on persistence. Gp33-stimulation of P14 cells through the TCR enhanced persistence, induced endogenous T cells, and eliminated gp33+ tumor cells.
Contributed by Ed Fritsch
ABSTRACT: Vaccines that encode tumour-associated antigens are potent boosting agents for adoptively transferred tumour-specific T cells. Employing vaccines to boost adoptively transferred tumour-reactive T cells relies on a priori knowledge of tumour epitopes, isolation of matched epitope-specific T cells, and personalized vaccines, all of which limit clinical feasibility. Here, we investigated a universal strategy for boosting transferred tumour-specific T cells where boosting is provided through a chimeric antigen receptor (CAR) that is paired with a vaccine encoding the CAR target antigen. To this end, we developed and employed a model wherein murine T cells expressing a TCR specific for antigen on syngeneic tumours were engineered with boosting CARs against a distinct surrogate boosting antigen for studies in immunocompetent hosts. Boosting CAR-engineered tumour-specific T cells with paired vesicular stomatitis virus (VSV) vaccines was associated with robust T cell expansion and delayed tumour progression in the absence of prior lymphodepletion. CAR-T cell expansion and antitumour function was further enhanced by blocking IFNAR1. However, vaccine-boosted CAR-T cells rapidly contracted and antigen-positive tumours re-emerged. In contrast, when the same T cells were boosted with a vaccine encoding antigen that stimulates through the TCR, the adoptively transferred T cells displayed improved persistence, tumour-specific endogenous cells expanded in parallel, and tumour cells carrying the antigen target were completely eradicated. Our findings underscore the need for further research into CAR-mediated vaccine boosting, how this differs mechanistically from TCR-mediated boosting, and the importance of engaging endogenous tumour-reactive T cells during vaccination to achieve long-term tumour control.
Author Info: (1) McMaster University, Hamilton, ON, Canada. (2) McMaster University, Hamilton, Ontario, Canada. (3) McMaster University, Hamilton, Ontario, Canada. (4) McMaster University, Hami
Author Info: (1) McMaster University, Hamilton, ON, Canada. (2) McMaster University, Hamilton, Ontario, Canada. (3) McMaster University, Hamilton, Ontario, Canada. (4) McMaster University, Hamilton, ON, Canada. (5) McMaster University, Hamilton, Ontario, Canada. (6) McMaster University, Hamilton, ON, Canada. (7) Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. (8) McMaster University, Hamilton, Ontario, Canada. (9) McMaster University, Hamilton, ON, Canada. (10) Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. (11) McMaster University, Hamilton, Ontario, Canada. (12) McMaster University, Hamilton, Canada. (13) McMaster University, Hamilton, Ontario, Canada. (14) McMaster University, Hamilton, ON, Canada. (15) McMaster University, Hamilton, Ontario, Canada.
