Eradication of tumors with pre-existing antigenic heterogeneity by vaccine-mediated co-engagement of CAR T and endogenous T-cells
Ma, L.; Morgan, D. M.; Sulkaj, I.; Yousefpour, P.; Whittaker, C. A.; Abraham, W.; Li, N.; Love, J. C.; Irvine, D. J.
Show abstract
Chimeric Antigen Receptor (CAR) T-cell therapy can be effective in treating human cancer but loss of the antigen recognized by the CAR poses a major obstacle. Here, we report an approach for vaccine boosting CAR T-cells, which triggers engagement of the endogenous immune system to circumvent antigen-negative tumor escape. Vaccine-boosted CAR T-cells promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited priming of endogenous anti-tumor T-cells (antigen spreading). This process was accompanied by a shift in toward oxidative phosphorylation in CAR T-cells and was critically dependent on CAR-T-derived IFN-{gamma}. Antigen spreading induced by vaccine-boosted CAR-T enabled a proportion of complete responses even when the initial tumor was 50% CAR-antigen-negative, and heterogenous tumor control was further enhanced by genetically amplifying CAR-T IFN-{gamma} expression. Thus, CAR T-cell-derived IFN-{gamma} plays a critical role in promoting antigen spreading, and vaccine boosting provides a clinically-translatable strategy to drive such responses against solid tumors.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- An mRNA-encoded, long-lasting Interleukin-2 restores CD8+ T cell neoantigen immunity in MHC class I-deficient cancers 98%
- MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors 97%
- Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer 97%
Similar papers in this journal
- Opposing effects of pre-existing antibody and memory T cell help on the dynamics of recall germinal centers 96%
- IL-9 as a naturally orthogonal cytokine with optimal JAK/STAT signaling for engineered T cell therapy 95%
- Soluble CTLA-4 mainly produced by Treg cells inhibits type 1 inflammation without hindering type 2 immunity to allow for inflammation resolution 95%
Similar papers in this journal
- In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer 97%
- Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors 96%
- Combinatorial immunotherapies overcome MYC-driven immune evasion 96%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.