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: 10672913
• 负责人: JAMEY P WEICHERT
• 金额: $ 35.1万
• 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/10672913
• 关键词: 90Y; Affect; Anatomy; Antitumor Response; Binding; Biodistribution; Biological; Blood; Bone Marrow; Cancer Patient; Canis familiaris; Cell Count; Cellularity; Chelating Agents; Clinical; Combined Modality Therapy; 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; Radiation Dose Unit; 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; absorption; analog; cancer cell; checkpoint inhibition; chelation; dosimetry; draining lymph node; immunoregulation; in situ vaccination; in vivo; metaiodobenzylguanidine; mouse model; neoplastic cell; novel; peripheral blood; pre-clinical; radiation delivery; radiation effect; 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：越来越多的临床前和临床证据表明，外部 束放射治疗 (EBRT) 可以通过以下方式增强对免疫疗法 (ImmRx) 的全身抗肿瘤反应： 以增强肿瘤免疫易感性的方式改变肿瘤微环境（TME）。别人和我们 已经观察到，在多灶性或转移性疾病的情况下，局灶性 EBRT 能够引发原位治疗。 可以通过提供低剂量辐射（RT；2-4 Gy）进一步增强疫苗接种（最佳剂量为 8-12 Gy） 到达所有肿瘤部位。在这种能力下，低剂量放疗可能在克服肿瘤特异性免疫方面发挥关键作用 RT 敏感免疫谱系的抑制 [例如调节性 T 细胞 (Treg)] 也可能增强 通过 cGAS/STING 激活 I 型干扰素来评估这些播散部位肿瘤细胞的免疫易感性 (干扰素)反应。 EBRT 靶向所有肿瘤部位且没有相当大的毒性风险的能力有限，这是一个主要问题。 限制 EBRT 以这种方式调节集体 TME 的能力的障碍。在设置中 微观或转移性疾病，不可能用 EBRT 所需的剂量治疗所有 TME 免疫调节也不会引起淋巴细胞减少。因此，需要一种放射治疗方式 可以向所有肿瘤部位提供免疫调节 RT 剂量，而不触发全身免疫抑制。到 为了满足这一需求，我们假设分子靶向放射性核素治疗（TRT）是一种系统形式 放射疗法将肿瘤选择性载体与治疗性放射性同位素相结合，将提供免疫调节作用 对所有转移性肿瘤部位进行放疗，导致显着的肿瘤反应，而无需全身免疫抑制。 为了有效地研究这些广泛的机制，需要一种具有以下特性的 TRT 药物：1) 广泛的选择性吸收 恶性肿瘤的治疗诊断能力，2) 输送可用于治疗的配对同位素的治疗诊断能力 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) 结合的能力 并提供不同的放射性核素来研究它们对微量 TME 的免疫调节能力的差异 和宏观转移。目前 FDA 批准的 TRT 实现这一愿景的能力有限。我们有 开发了一种新型 TRT 载体 NM600，它最适合剂量依赖性的广泛应用 免疫调节并产生许多完整的反应，包括肿瘤特异性免疫记忆 与检查点抑制联合使用时在同基因小鼠肿瘤模型中的诱导（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 将研究如何 不同 TRT 载体和放射性核素的特性（例如线性能量转移 (LET)、剂量率和剂量 分布）影响与每个项目相关的同基因小鼠模型中的 TME 和宿主免疫系统 还在伴侣犬癌症患者中评估平行效应是否可以转化为更大的效应 物种。在项目 2-4 中，这些知识将用于优化 TRT 与每种类型的组合 ImmRx 并阐明观察到的协同作用的生物学机制。