Novel Molecular Targeted Radionuclide Therapies for Dosimetry-Guided Immunomodulation

用于剂量测定引导免疫调节的新型分子靶向放射性核素疗法

• 批准号: 10263245
• 负责人: JAMEY P WEICHERT
• 金额: $ 35.81万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10263245
• 关键词: 90Y; Affect; Anatomy; Antitumor Response; Binding; Biodistribution; Biological; Blood; Bone Marrow; Cancer Patient; Canis familiaris; Cell Count; Cellularity; Chelating Agents; Clinical; Companions; DNA Vaccines; Detection; Diagnostic Imaging; Disease; Dose; Dose-Rate; Exhibits; External Beam Radiation Therapy; FDA approved; FOLH1 gene; Goals; Image; Immune; Immune system; Immunologic Memory; Immunosuppression; Immunotherapy; In complete remission; Interferon Type I; Isotopes; Knowledge; Linear Energy Transfer; Location; Low Dose Radiation; Lymphopenia; Malignant Neoplasms; Measurement; Microscopic; Modality; Modeling; Molecular Target; Monoclonal Antibodies; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Normal tissue morphology; Organ; Patients; Play; Predisposition; Property; Radiation therapy; Radioactive; Radioisotopes; Radiolabeled; Radionuclide therapy; Regulatory T-Lymphocyte; Risk; Role; Scanning; Site; Spleen; Stimulator of Interferon Genes; Testing; Therapeutic; Time; Toxic effect; Translating; Tumor Tissue; Tumor-infiltrating immune cells; Vision; analog; cancer cell; checkpoint inhibition; dosimetry; draining lymph node; immunoregulation; in situ vaccination; in vivo; metaiodobenzylguanidine; mouse model; neoplastic cell; novel; peripheral blood; pre-clinical; response; side effect; synergism; theranostics; treatment optimization; tumor; tumor immunology; tumor microenvironment; uptake; vector

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.

项目摘要 - 项目1：安装临床前和临床证据表明外部 梁辐射疗法（EBRT）可以通过通过 以增强肿瘤免疫易感性的方式修饰肿瘤微环境（TME）。别人和我们 已经观察到，在多焦点或转移性疾病的情况下，局灶性EBRT的能力引起原位 通过提供低剂量辐射（RT; 2-4 Gy），可以进一步增强疫苗接种（最佳剂量为8-12 Gy） 到所有肿瘤部位。以这种能力，低剂量RT可能在克服肿瘤特异性免疫中起关键作用 RT敏感的免疫谱系抑制[例如调节性T细胞（Tregs）]，也可能增强 通过CGA/I型ITYFERON的CGA/刺激激活，肿瘤细胞在这些传播部位的免疫敏感性 （IFN）响应。 EBRT能够针对所有肿瘤部位而没有考虑毒性风险的有限能力是主要的 跨越限制EBRT以这种方式调节集体TME的能力的跨越。在 显微镜或转移性疾病，不可能以EBRT以EBRT的剂量处理所有TME 免疫调节也没有引起淋巴细胞减少症。因此，需要采取放射疗法的方式 可以将免疫调节的RT剂量输送到所有肿瘤部位，而不会触发全身免疫抑制。到 满足了这种需求，我们假设分子靶向放射线治疗（TRT），一种全身形式的 放射疗法将肿瘤选择载体与治疗性放射性同位素相结合，将提供免疫调节 对所有转移性肿瘤部位的RT，导致没有全身免疫抑制的明显肿瘤反应。 为了有效研究这些广泛的机制 恶性肿瘤，2）可以用于治疗和 诊断成像（例如，分别为90y和86y），以促进个性化剂量测定法，以及3）结合的能力 并提供不同的放射线，以研究它们的差异能力以免疫调节微型的TME 和宏观过程。当前，FDA批准的TRT的能力有限，以实现这一愿景。我们有 开发了一种新颖的TRT矢量NM600，最适合于剂量依赖性的广泛应用 免疫调节并产生了许多完整的反应，包括特定肿瘤的免疫记忆 合成鼠肿瘤模型的诱导与检查点抑制结合使用时（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将调查如何 不同TRT载体和放射线的特性（例如线性能量转移（LET），剂量速率和剂量 分布）在与每个项目相关的合成小鼠模型中影响TME和宿主免疫系统 并在伴侣犬类癌患者中评估平行效应是否可以翻译成较大的效果 物种。在项目2-4中，将利用此知识来优化TRT与每种类型的组合 INMRX并阐明观察到的协同作用的生物学机制。