Novel Molecular Targeted Radionuclide Therapies for Dosimetry-Guided Immunomodulation

项目摘要-项目1：越来越多的临床前和临床证据表明 放射治疗(EBRT)可通过以下途径增强免疫疗法(ImmRx)的全身抗肿瘤反应 改善肿瘤微环境(TME)以增强肿瘤免疫敏感性。其他人和我们 已经观察到在多灶性或转移性疾病的背景下，局灶性EBRT这种原位诱导的能力 疫苗接种(最佳剂量为8-12Gy.)可通过提供低剂量辐射(RT；2-4Gy.)进一步加强 所有的肿瘤部位。在这一能力中，低剂量RT可能在克服肿瘤特异性免疫方面发挥关键作用。 抑制RT敏感的免疫谱系[例如调节性T细胞(Tregs)]，也可能增强 CGAS/STING激活I型干扰素对这些播散部位肿瘤细胞的免疫敏感性 (干扰素)反应。EBRT靶向所有肿瘤部位的能力有限，没有相当大的毒性风险，这是一个主要的 限制EBRT以这种方式调节集体TME的能力的障碍。在环境中 微小或转移性疾病，不可能用EBRT治疗所有的TME 免疫调节而不会引起淋巴细胞减少。因此，需要一种放射治疗方式 可将免疫调节性RT剂量传递到所有肿瘤部位，而不会引发全身免疫抑制。至 为了满足这一需求，我们假设分子靶向放射性核素治疗(TRT)是一种系统性的 结合肿瘤选择载体和治疗性放射性同位素的放射治疗将提供免疫调节 对所有转移的肿瘤部位进行放射治疗，可导致显著的肿瘤反应，而不会产生全身免疫抑制。 为了有效地研究这些广泛的机制，需要一种具有1)跨广度选择性摄取的TRT试剂 恶性肿瘤，2)提供可用于治疗的成对同位素的治疗能力和 诊断成像(例如，分别为90Y和86Y)，以促进个性化剂量测定，以及3)绑定的能力 并递送不同的放射性核素来研究这些核素对微量TME的免疫调节能力 和大范围转移。目前FDA批准的TRT在实现这一愿景方面的能力有限。我们有 开发了一种新的TRT载体NM600，它最适合在剂量依赖的这种广泛应用中 免疫调节，已经产生了许多完整的反应，包括肿瘤特异性免疫记忆 联合使用检查点抑制对同基因小鼠肿瘤模型的诱导(项目2) 免疫细胞因子(项目3)和DNA疫苗(项目4)免疫疗法。项目1将调查 不同TRT载体和放射性核素的性质(例如线性能量转移(LET)、剂量率和剂量 分布)与每个项目相关的同基因小鼠模型对TME和宿主免疫系统的影响 并在伴发犬癌患者中评估平行效应是否可以转化为更大的 物种。在项目2-4中，将利用这些知识来优化TRT与每种类型的 ImmRx，并阐明观察到的协同作用的生物学机制。

PROJECT SUMMARY – PROJECT 1: Mounting preclinical and clinical evidence demonstrates that external beam radiation therapy (EBRT) can enhance the systemic anti-tumor response to immunotherapies (ImmRx) by modifying the tumor microenvironment (TME) in ways that enhance tumor immune susceptibility. Others and we have observed that in the setting of multifocal or metastatic disease this capacity of focal EBRT to elicit in situ vaccination (optimal at doses of 8-12 Gy) may be further enhanced by delivering low dose radiation (RT; 2-4 Gy) to all tumor sites. In this capacity, low dose RT may play a critical role in overcoming tumor-specific immune suppression from RT-sensitive immune lineages [e.g. regulatory T cells (Tregs)] and may also enhance the immune susceptibility of tumor cells at these disseminated sites by cGAS/STING activation of a type I interferon (IFN) response. The limited ability of EBRT to target all tumor sites without considerable risk of toxicity is a major hurdle that limits the capacity of EBRT to modulate the collective TME in this manner. In the setting of microscopic or metastatic disease, it is not possible to treat all TMEs with EBRT at the doses required for immunomodulation without also incurring lymphopenia. Consequently, a radiotherapy modality is needed that can deliver immunomodulatory RT doses to all tumor sites without triggering systemic immunosuppression. To meet this need, we hypothesize that molecularly targeted radionuclide therapy (TRT), a systemic form of radiotherapy combining a tumor-selective vector with a therapeutic radioisotope, will deliver immunomodulatory RT to all metastatic tumor sites resulting in significant tumor responses without systemic immune suppression. To effectively study these broad mechanisms requires a TRT agent with 1) selective uptake across a breadth of malignancy, 2) a theranostic capacity for delivery of paired isotopes that can be used for therapy and diagnostic imaging (e.g. 90Y and 86Y, respectively) to facilitate personalized dosimetry, and 3) the ability to bind and deliver diverse radionuclides to study the differential capacity of these to immunomodulate the TME of micro- and macro-metastases. Current FDA-approved TRTs are limited in their capacity to achieve this vision. We have developed a novel TRT vector, NM600, which is optimally suited for this broad application in dose-dependent immunomodulation and which has produced many complete responses including tumor specific immune memory induction in syngeneic murine tumor models when used in combination with checkpoint inhibition (Project 2), immunocytokine (Project 3), and DNA vaccine (Project 4) immunotherapies. Project 1 will investigate how the properties of different TRT vectors and radionuclides (e.g. linear energy transfer (LET), dose rate, and dose distribution) influence the TME and the host immune system in syngeneic mouse models relevant to each Project and also in companion canine cancer patients to assess whether parallel effects can be translated to a larger species. In Projects 2-4, this knowledge will be utilized to optimize the combination of TRT with each type of ImmRx and to elucidate biological mechanisms of observed synergies.