Project 2: TRT to enhance tumor cell immune susceptibility and response to immune checkpoint inhibitors

Summary

Metastatic cancers are typically incurable, despite advances in cancer treatments including immunotherapies, and to begin changing this we propose to develop and investigate a new treatment approach that combines the most common form of immunotherapy (immune checkpoint inhibitors) with targeted radionuclide therapy. Radiation can damage tumors in a way that renders them more responsive to immunotherapies, however conventional radiation therapy typically cannot treat all tumor sites in patients with metastatic disease because of toxicities and the inability to target small tumors that are not identified on imaging scans.

Targeted radionuclide therapies injected into a patient’s vein go throughout the body to preferentially deliver radiation to tumors wherever they are located and here we will  (1) determine the effect of this type of treatment on the susceptibility of tumors to immune response; and (2) test the effectiveness of this type of treatment when combined with the most common form of immunotherapy in order to determine which combinations should be most beneficial in patients with metastatic cancer.

Specific Aims

1. Determine whether and compare the extent to which TRTs modulate tumor cell immune susceptibility through cGAS/STING-mediated activation of a type I IFN response.

2. Evaluate the capacity of TRT and ICI combinations to elicit durable systemic anti-tumor immune response in syngeneic murine tumor models.

3. Evaluate whether and how distinct TRT agents (⁹⁰Y-, ¹⁷⁷Lu-, and ²²⁵Ac-NM600) may impact the adaptive anti-tumor T cell response in combination with ICIs in syngeneic murine tumor models.

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In a project that builds upon the ongoing collaborative progress of our multidisciplinary team, we will systematically evaluate mechanisms of cooperative interaction and optimize the potency of treatment regimens that combine targeted radionuclide therapies (TRT) with immune checkpoint inhibition (ICI; e.g. anti-PD- 1, anti-CTLA-4) to enhance the anti-tumor immune response against metastatic cancers. Moderate dose (8-12 Gy) external beam radiation therapy (EBRT) is capable of eliciting an in situ vaccine effect, converting the targeted tumor into a nidus for enhanced tumor antigen recognition. In preclinical and clinical studies, this results in diversification of the T cell receptor (TCR) repertoire. Consequently, in preclinical studies, EBRT improves the response to ICIs. This is at least in part dependent upon the capacity of EBRT to activate a type I interferon (IFN) response in radiated tumor cells. However, clinical studies have not yet conclusively demonstrated a benefit from combining EBRT with ICIs, and even in studies that suggest a benefit it is clear that more is needed if we aim to develop an effective approach to eradicating metastatic disease for all cancer patients. In pursuit of such a goal, we now propose to evaluate a next generation strategy to leveraging the capacity of radiation to enhance response to ICIs by using TRTs to deliver radiation to all tumor sites in settings of metastatic disease. To begin testing this approach, we will compare the relative capacities of different TRT agents to 1) activate a type I IFN response in tumor cells, 2) augment response to ICIs, and 3) increase the diversity and clonality of the TCR repertoire among tumor infiltrating lymphocytes. We hypothesize that TRT will enhance the rate and depth of response to ICIs and that this will correlated with effects on the TCR repertoire that are dependent on the ability of TRT to modulate tumor cell immune susceptibility by activating a type I IFN response. We expect that TRTs will also elicit immunogenic cell death, local inflammation, and temporary depletion of suppressive regulatory T cells (Tregs) from the tumor microenvironment (TME), and other Projects in this P01 will investigate those mechanisms further. Here, we will compare the relative effects of TRT radionuclides and vectors in order to develop a fundamental understanding of the interactions between these agents and anti-tumor immunity. In particular, we will evaluate the potential impacts of tumor size, type, and number as well as the type of radioactive decay products (e.g. α particle vs β particle vs γ-ray vs Auger electron), linear energy transfer (LET), dose, dose rate and half-life, and dose range. We will also examine the potential impact of the TRT vector, specifically testing how changes in TRT distribution at the organism, tumor, and subcellular level affect anti-tumor immunity. The insights and treatment regimens developed in these studies should enable rapid translation to clinical testing in patients with any type of metastatic cancer while also launching a generation of follow-up basic and translational preclinical studies.