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相互作用的机制，并优化一个 结合靶向放射性核素治疗（TRT）和免疫检查点抑制的治疗方案 (ICI例如抗PD-1）以增强针对转移性或复发性头部肿瘤的抗肿瘤免疫应答。 和颈部鳞状细胞癌（HNSCC）。中等剂量（8 - 12戈伊）体外放射治疗 （EBRT）能够引发原位疫苗效应，将靶向肿瘤转化为病灶， 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)保留曲目。因此，在临床前研究中，EBRT改善了对ICI的反应。但临床 在HNSCC患者中的研究尚未证明EBRT与ICI联合使用的益处。需要更多，如果 我们的目标是开发一种有效的方法，在转移性肿瘤患者中实现持续的肿瘤控制， 或复发性HNSCC。为了实现这一目标，我们建议评估一项新的战略， 通过使用TRT将放射递送到转移性肿瘤环境中的所有肿瘤部位， 疾病我们的团队已经开发并领导了一种新型TRT的临床前和临床试验， 烷基磷酸胆碱（APCh）类似物，其被IV注射并在体内向癌症递送辐射。这些表明 在大多数哺乳动物肿瘤细胞和肿瘤部位（包括原发性和转移性）中的肿瘤选择性摄取 HNSCC的位置。在我们目前的SPORE资助中，我们已经证实了提供一种 在HNSCC患者中结合卤素放射性核素（131 I-NM 404）的第一代APCh类似物。我们有 现在开发了下一代APCh类似物（NM 600），与NM 404相比， 由于减少的白蛋白结合，具有剂量测定的能力，并且具有螯合多种放射性核素的能力。在这里我们建议 使用NM 600比较不同放射性核素以某种方式免疫调节HNSCC肿瘤的能力， 增强对ICI的反应并增加肿瘤细胞中TCR库的多样性或克隆性， 浸润淋巴细胞。我们假设NM 600将提高对ICI的反应速率和深度， 这将与依赖于NM 600调节TCR库的能力的效应相关， 通过激活I型IFN应答增强肿瘤细胞的免疫易感性。我们预计，NM 600也将引起 免疫原性细胞死亡、局部炎症和抑制性调节性T细胞的暂时耗竭（T细胞） 从肿瘤微环境中分离出来通过比较不同放射性核素引发这些的相对能力，我们 将发展TRT和抗肿瘤免疫的相互作用的基本理解。在i期 在临床研究中，我们将测试NM 600是否可以与抗PD-1联合安全递送， 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 应能够转化为HNSCC患者的晚期临床试验，并可指导 开发TRT和ICI的类似组合用于其他类型的转移性癌症。

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.