Targeted radiation and immunocytokine therapy for CEA positive malignancies - SUMMARY/ABSTRACT Image guided radiotherapy (IGRT) or systemically administered radionuclide therapy are attractive approaches that can perturb the tumor microenvironment (TME) so that targeted immunotherapy can convert a largely immunoresistant into an immunosusceptible tumor. Although this approach has been clinically explored using high or low or high plus low dose IGRT plus untargeted checkpoint immunotherapy, further improvements are warranted and require testing in appropriate clinical studies and preclinical models. In this application we propose three aims to test our hypothesis that IGRT and or targeted alpha therapy (TAT) followed immediately by immunocytokine (ICK), a form of targeted immunotherapy, will lead to increased tumor infiltration of IFN+ CD8s (Teff) and decreased Foxp3+ CD4s (Treg). This hypothesis is supported by two studies targeting CEA, a major marker of solid tumor malignancies (eg. colon and breast), in CEA transgenic mice that are immunocompetent, express CEA in normal tissues, and are tolerant to CEA. We now propose to test this hypothesis in two clinical trials, aims 1 (IGRT + ICK) and 2 (TAT), and perform immunocorrelate studies for Teff and Treg cells, among others, on pre- and post-therapy biopsies. Aim 2 is a TAT only study as a prelude to a third clinical trial combining TAT plus ICK, that will be initiated at the end of the project period. In aim 3, we will refine our animal studies to determine TME changes immediately after sequential therapy for both IGRT plus ICK or TAT plus ICK, by a combination of PET imaging for CEA, CD8s and stromal cells by fibroblast activated protein (FAPI), along with flow and IHC analysis of tumors, LNs and spleen. We expect the results of aims 1 and 2 to further guide aim 3, and the results of aim 3 to guide future trials that incorporate IGRT and/or TAT plus ICK in CEA positive malignancies.
