A Universal Boosting Strategy for Adoptive T-cell Therapy Using a Paired Vaccine/Chimeric Antigen Receptor
Researchers at McMaster University, collaborating with the Ottawa Hospital Research Institute, have found that a paired vaccine plus CAR strategy can broadly boost adoptively transferred T cells without needing patient-specific tumor epitope selection. In this study, published in Cancer Immunology Research, they engineered tumor-reactive T cells to carry an additional “boosting” CAR against a separate surrogate antigen, then administered a vaccine encoding that CAR antigen to drive in vivo expansion. The main message is that CAR-mediated vaccine boosting can generate strong early expansion and antitumor activity, but durable control depends on how T cells are restimulated and whether endogenous tumor-reactive immunity is engaged.
Adoptive T-cell therapies often fail because transferred cells do not expand or persist long enough, and vaccine boosting is a proven way to amplify tumor-specific T cells. However, conventional boosting requires knowing the relevant tumor epitopes, isolating matching epitope-specific T cells, and building personalized vaccines, which limits scalability. To overcome this, the authors tested a universal design in immunocompetent mice: they started with murine T cells bearing a TCR specific for a syngeneic tumor antigen, then added a CAR that recognizes an unrelated “boosting antigen.” They boosted these dual-receptor T cells using vesicular stomatitis virus (VSV) vaccines encoding the CAR antigen and assessed expansion, tumor control, and persistence, including experiments without prior lymphodepletion and with interferon signaling blockade (IFNAR1 inhibition) to enhance responses.
Vaccine boosting through the CAR produced robust early T cell expansion and delayed tumor progression even without lymphodepletion, and IFNAR1 blockade further amplified CAR T cell expansion and antitumor effects. However, this CAR-driven boost was followed by rapid contraction of the transferred T cells and relapse driven by outgrowth of antigen-positive tumors. In contrast, when the same transferred T cells were boosted with a vaccine encoding antigen recognized through the TCR, the cells showed improved persistence, endogenous tumor-specific T cells expanded alongside the transferred cells, and tumor cells carrying the relevant antigen were completely eradicated. These findings show that universal CAR-vaccine boosting can be powerful but may be intrinsically less durable than TCR-mediated boosting, and they highlight that long-term tumor control likely requires vaccination strategies that recruit endogenous tumor-reactive immunity rather than relying only on CAR-based restimulation.
Reference:
Burchett R, Morris CG, Ishak M, et al. A universal boosting strategy for adoptive T-cell therapy using a paired vaccine/chimeric antigen receptor. Cancer Immunol Res. Published online December 8, 2025.