Friday, April 19, 2024
4/19/2024
Project Summary/Abstract We aim to improve the cure rates for metastatic cancers. To achieve this we propose a combined modality approach to stimulate and diversify an endogenous anti-tumor immune response capable of recognizing and destroying metastatic cancers in a manner that will prevent recurrence and enable long-term cancer free survival. Our intention is to develop a strategy that will overcome current challenges that limit the role of immunotherapy. Immune checkpoint inhibitors (ICI; e.g. anti-PD-L1), are a class of immunotherapies that modulate immune tolerance of a tumor by blocking specific inhibitory receptor-ligand interactions on the surface of T cells and thereby overcoming T cell inhibition or exhaustion. In patients with immunologically “hot” tumors, characterized by a pre-existing but exhausted anti-tumor immune response, ICIs can restore efficacy to the anti-tumor immune response, sometimes resulting in complete and durable tumor regression even in settings of advanced metastatic disease. However, ICIs have not shown clinical benefit in the treatment of immunologically “cold” cancers that are characterized by low levels of T cell infiltrate and low mutation burden resulting in few mutation-created neo-antigens. Further, patients with immunologically hot tumors that initially respond to ICI therapy often show signs of disease progression over time. To improve the extent and duration of response to ICIs in patients with immunologically “hot” tumors and to prime a de novo anti-tumor immune response in patients with “cold” tumors, we propose to combine systemic delivery of ICIs with local delivery of a heterogeneous dose of radiation administered using brachytherapy (BT) at a single tumor with the intent of stimulating an in situ vaccine effect. To date, nearly all approaches to combining radiation and immunotherapy have used external beam radiotherapy (EBRT) which delivers a homogenous dose of radiation. Preclinical studies indicate that the immunogenic effects of radiation are sensitive to dose and field size. Due to its unmatched conformality and dose heterogeneity, BT may confer meaningful advantages over EBRT when it comes to priming an in situ vaccine effect. Our broad hypothesis is that a heterogeneous dose of radiation delivered by BT will allow enhanced activation of multiple dose-dependent immune effects in a single tumor and will elicit a superior in situ vaccine effect in combination with systemically administered immunotherapies compared to homogeneous radiation. In a project that builds upon the ongoing collaborative progress of the Morris and McNeel labs, we will now determine the potency of combining BT with immunotherapy to enhance the immune response against immunologically cold tumors. In murine models, we will: 1) expand on preliminary data showing potent synergy with the combination of BT and ICI, 2) use the inherent dose heterogeneity of BT to characterize dose dependent effects of radiation in a single tumor microenvironment. The insights and treatment regimens developed in these studies should enable rapid translation to clinical testing in patients and potentially for any type of metastatic cancer.
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