Project 1: Priming and propagating immunity against head and neck cancer using targeted radionuclide therapy

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ABSTRACT – PROJECT 1 We propose to systematically evaluate mechanisms of cooperative interaction and to optimize the potency of a treatment regimen that combines a targeted radionuclide therapy (TRT) with immune checkpoint inhibition (ICI; e.g. anti-PD-1) to enhance the anti-tumor immune response against metastatic or recurrent head and neck squamous cell carcinoma (HNSCC). 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. However, clinical studies in HNSCC patients have not demonstrated a benefit from combining EBRT with ICIs. More is needed if we aim to develop an effective approach to achieving consistent durable tumor control in patients with metastatic or recurrent HNSCC. In pursuit of this goal, we propose to evaluate a new strategy to leverage the capacity of radiation to enhance response to ICIs by using TRTs to deliver radiation to all tumor sites in settings of metastatic disease. Our team has developed and led preclinical and clinical testing of a novel class of TRT using alkylphosphocholine (APCh) analogs that are IV injected and deliver radiation to cancers in vivo. These show tumor-selective uptake in most mammalian tumor cells and tumor locations, including primary and metastatic sites of HNSCC. In our current SPORE grant we have confirmed the selective uptake and safety of delivering a first generation APCh analog that binds halogen radionuclides (131I-NM404) in patients with HNSCC. We have now developed a next generation APCh analog (NM600) that, compared to NM404, has more favorable dosimetry due to reduced albumin binding and has the ability to chelate diverse radionuclides. Here we propose to use NM600 to compare the capacity of distinct radionuclides to immuno-modulate HNSCC tumors in a manner that augments response to ICIs and increases the diversity or clonality of the TCR repertoire among tumor infiltrating lymphocytes. We hypothesize that NM600 will enhance the rate and depth of response to ICIs and that this will correlate with effects on the TCR repertoire that are dependent on the ability of NM600 to modulate tumor cell immune susceptibility by activating a type I IFN response. We expect that NM600 will also elicit immunogenic cell death, local inflammation, and temporary depletion of suppressive regulatory T cells (Tregs) from the tumor microenvironment. By comparing the relative capacity of distinct radionuclides to elicit these, we will develop a fundamental understanding of the interactions of TRTs and anti-tumor immunity. In a phase I clinical study, we will then test whether NM600 can be delivered safely in combination with anti-PD-1 and enhance response to this immunotherapy. The insights and treatment regimens developed in these studies should enable translation to advanced phase clinical testing in patients with HNSCC and may guide the development of similar combinations of TRTs and ICIs for other types of metastatic cancer.