Developing an engineered T cell product for universal vaccination-based boosting in adoptive cell therapies

Abstract

Creating a universal-prime boost strategy using multi-specific T cells from the tumour infiltrating lymphocytes (TIL) population can enhance the success of adoptive T cell therapies (ACT). ACT, as a personalized living-drug, is often a last resort due to its extensive time, cost, and labor requirements, making it largely inaccessible. Vaccines encoding personalized tumour-associated antigens (TAA) have proven to be potent boosters for ACT. This combination has shown success in (1) promoting T cell proliferation in vivo and (2) inducing immune infiltration into the solid tumour microenvironment. TIL offer a plethora of TAA-specific T-cell receptors (TCRs) when successfully isolated and expanded. Synthetic receptors can be engineered into TIL to recognize any specified antigen, including those matched in vaccines. Previously, we validated combining ACT with an oncolytic virus vaccine (OVV) “boost” through a synthetic receptor to promote in vivo expansion of naïve splenocytes in a proof-of- concept TCR-transgenic synergetic murine model. Here, we report on the feasibility of isolating and engineering polyclonal, tumour-specific T cells from TIL and tumour- draining lymph nodes, evaluating them functionally. We further investigate the matched CAR/OVV system in another distinct TCR transgenic model and return to the first proof- of-concept model to uncover the biological mechanisms of our combination therapy to improve anti-tumour efficacy. Uniting a universal OV vaccine with a matched universal CAR creates an “off-the-shelf” combination, allowing any T cell product to be engineered. This approach reduces the resource burden of traditional ACT, making it more accessible to all cancer types.