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.

项目总结-项目1：越来越多的临床前和临床证据表明，外部 射束放射治疗（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）。其他人和我们 已经观察到，在多灶性或转移性疾病的情况下，局灶性EBRT能够原位诱导 接种疫苗（最佳剂量为8-12戈伊）可通过提供低剂量辐射（RT; 2-4戈伊）进一步增强 所有肿瘤部位。在这种能力下，低剂量RT可能在克服肿瘤特异性免疫中发挥关键作用。 抑制RT-敏感的免疫谱系[例如调节性T细胞（Tcells）]，也可以增强免疫抑制。 通过cGAS/STING激活I型干扰素在这些播散部位的肿瘤细胞的免疫易感性 (IFN)反应EBRT靶向所有肿瘤部位而没有相当大的毒性风险的有限能力是一个主要的问题。 限制EBRT以这种方式调节集体TME能力的障碍。背景下 显微镜或转移性疾病，不可能用EBRT治疗所有TME， 免疫调节，而不引起淋巴细胞减少症。因此，需要一种放射治疗方式， 可将免疫调节RT剂量递送至所有肿瘤部位而不触发全身性免疫抑制。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），一种全身性的放射性核素治疗方法， 将肿瘤选择性载体与治疗性放射性同位素组合的放射疗法将递送免疫调节剂。 RT至所有转移性肿瘤部位，导致显著的肿瘤应答而无全身免疫抑制。 为了有效地研究这些广泛的机制，需要具有1）跨宽度选择性摄取的TRT试剂 恶性肿瘤，2）输送可用于治疗和治疗的成对同位素的治疗诊断能力 诊断成像（例如，分别为90 Y和86 Y），以促进个性化剂量测定，以及3）结合 并提供不同的放射性核素，以研究这些免疫调节TME的微 和大转移。目前FDA批准的TRT在实现这一愿景的能力方面有限。我们有 开发了一种新的TRT载体，NM 600，这是最适合这种广泛的应用，剂量依赖性 免疫调节，并产生了许多完整的反应，包括肿瘤特异性免疫记忆 当与检查点抑制联合使用时，在同基因小鼠肿瘤模型中诱导（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）影响与每个项目相关的同系小鼠模型中的TME和宿主免疫系统 以及在伴侣犬癌症患者中，以评估平行效应是否可以转化为更大的 物种在项目2-4中，这些知识将用于优化TRT与每种类型的 ImmRx和阐明所观察到的协同作用的生物学机制。