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

摘要-项目1 我们建议系统地评估合作互动的机制，并优化一个 靶向放射性核素治疗(TRT)与免疫检查点抑制相结合的治疗方案 (ICI；例如，抗PD-1)以增强针对转移或复发头部的抗肿瘤免疫反应 和颈部鳞状细胞癌(HNSCC)。中剂量(8-12Gy)外照射治疗 (EBRT)能够产生原位疫苗效应，将靶向肿瘤转化为病灶进行增强 肿瘤抗原识别。在临床前和临床研究中，这导致T细胞受体的多样化 (TCR)曲目。因此，在临床前研究中，EBRT改善了对ICIS的反应。然而，临床上 对HNSCC患者的研究还没有证明EBRT和ICIS联合应用的好处。在以下情况下需要更多 我们的目标是开发一种有效的方法来实现转移性患者持续持久的肿瘤控制。 或复发性HNSCC。为了实现这一目标，我们建议评估一项新战略，以利用 通过使用TRT将辐射传递到转移环境中的所有肿瘤部位来增强对ICIS的反应的放射 疾病。我们的团队已经开发并领导了一种新型TRT的临床前和临床测试，该测试使用 静脉注射的烷基磷胆碱(APCH)类似物，可向体内的癌症提供辐射。这些节目展示了 大多数哺乳动物肿瘤细胞和肿瘤部位的肿瘤选择性摄取，包括原发和转移 HNSCC网站。在我们目前的孢子赠款中，我们已经确认了选择性吸收和安全性 第一代APCH类似物，可与HNSCC患者的卤素放射性核素(131I-NM404)结合。我们有 现在开发的下一代APCH模拟器(NM600)，与NM404相比，具有更有利的 由于白蛋白结合减少而产生的剂量学效应，并具有螯合不同放射性核素的能力。在这里，我们建议 使用NM600比较不同放射性核素对HNSCC肿瘤的免疫调节能力 这增强了对ICIS的反应，并增加了肿瘤中TCR谱系的多样性或克隆性 浸润性淋巴细胞。我们假设NM600将提高对ICIS的响应速度和深度 这将与对TCR曲目的影响相关，这取决于NM600的调制能力 肿瘤细胞通过激活I型干扰素反应而免疫易感性。我们预计NM600也将引发 免疫原性细胞死亡、局部炎症和抑制性调节性T细胞(Tregs)的暂时耗竭 来自肿瘤的微环境。通过比较不同放射性核素的相对能力来引发这些，我们 将对TRT和抗肿瘤免疫的相互作用有一个基本的了解。在第一阶段 临床研究，然后我们将测试NM600是否可以安全地与抗PD-1和 增强对这种免疫疗法的反应。在这些研究中形成的见解和治疗方案 应使HNSCC患者能够转换到晚期临床测试，并可指导 为其他类型的转移性癌症开发类似的TRT和ICIS组合。

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.