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.