Vaccine-boosted CAR T Cell Therapy as a Platform to Define Mechanisms Underlying Antigen Spreading During Immunotherapy

ASPIRE AWARD (2021-2022)

Darrell Irvine, PhD, Massachusetts Institute of Technology

Darrell Irvine, PhD

Current immunotherapies target one or only a few tumor antigens. But tumors are antigenically heterogeneous; antigen expression can vary in different metastases and even within different regions of the same lesion. Antigen spreading is a process that leads to a progressive increase in the number of cancer-expressed antigens targeted by the immune response. It occurs when a therapy-elicited immune response kills cancer and causes the release of secondary antigens in the presence of inflammatory cues, resulting in immune responses to new antigens. Studies have suggested that antigen spreading can lead to improved therapeutic outcomes, but the mechanisms that drive this process, as well as how to therapeutically promote it, remain unclear.

Darrell Irvine of the Massachusetts Institute of Technology is using vaccine-boosted chimeric antigen receptor (CAR) T therapy as a platform to dissect mechanisms of antigen spreading. Irvine’s team recently developed a vaccine-like technology (amph-vaccination, or amph-vax) to boost CAR T cells, which they are using for this project. Amph-vax is unique in that it bypasses major histocompatibility complex (MHC) presentation and enables direct presentation of the cognate ligand for a CAR from the surface of antigen-presenting cells in native lymph nodes. The group has shown that amph-vax achieves substantial enhancements in the outcome of CAR T treatment of solid tumors in immunocompetent mouse models. For this project, Irvine’s team is assessing the generality of amph-vax-driven antigen spreading and its capacity to enable treatment of antigenically heterogeneous solid tumors. They are studying the key steps leading to T-cell priming impacted by vaccine-boosted CAR T treatment, defining key molecular pathways and cell types required for CAR T vax-driven antigen spreading, and identifying targets that might enhance this process in diverse immunotherapies. The results of these efforts will lead to the identification of key pathways that could be targeted to enhance antigen spreading in diverse immunotherapies in clinical and preclinical development.

published research

Gordon KS, Kyung T, Perez CR, Holec PV, Ramos A, Zhang AQ, Agarwal Y, Liu Y, Koch CE, Starchenko A, Joughin BA, Lauffenburger DA, Irvine DJ, Hemann MT, Birnbaum ME. Screening for CD19-specific chimaeric antigen receptors with enhanced signalling via a barcoded library of intracellular domains. Nat Biomed Eng. 2022.

Irvine DJ, Maus MV, Mooney DJ, Wong WW. The future of engineered immune cell therapies. Science. 2022.

Zhang AQ, Hostetler A, Chen LE, Mukkamala V, Abraham W, Padilla LT, Wolff AN, Maiorino L, Backlund CM, Aung A, Melo M, Li N, Wu S, Irvine DJ. Universal redirection of CAR T cells against solid tumours via membrane-inserted ligands for the CAR. Nat Biomed Eng. 2023.

Ma L, Hostetler A, Morgan DM, Maiorino L, Sulkaj I, Whittaker CA, Neeser A, Pires IS, Yousefpour P, Gregory J, Qureshi K, Dye J, Abraham W, Suh H, Li N, Love JC, Irvine DJ. Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity. Cell. 2023.

Yousefpour P, Ni K, Irvine DJ. Targeted modulation of immune cells and tissues using engineered biomaterials. Nat Rev Bioeng. 2023.