Immunomodulation of the Tumor Microenvironment with Molecular Targeted Radiotherapy to Facilitate an Adaptive Anti-Tumor Immune Response to Combined Modality Immunotherapies

通过分子靶向放疗对肿瘤微环境进行免疫调节，促进联合免疫疗法的适应性抗肿瘤免疫反应

• 批准号: 9788087
• 负责人: Zachary Scott Morris
• 金额: $ 76.5万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788087
• 关键词: 90Y; Address; Anatomy; Animals; Antibodies; Antigen Presentation; Biology; Cancer Model; Canis familiaris; Cells; Clinical; Clinical Data; Clinical Oncology; Clinical Research; Clinical Treatment; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Companions; Data; Disease; Disseminated Malignant Neoplasm; Distant; Dose; Epitope spreading; External Beam Radiation Therapy; Generations; Goals; Half-Life; Head and Neck Squamous Cell Carcinoma; Human; IL2 gene; Image; Immune; Immune Evasion; Immune Tolerance; Immune checkpoint inhibitor; Immune response; Immunocompetent; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In Situ; Injections; Intravenous; Isotopes; Length; Location; Low Dose Radiation; Malignant Neoplasms; Mediating; Metastatic Melanoma; Modality; Modeling; Molecular Target; Monoclonal Antibodies; Multi-Institutional Clinical Trial; Mus; Mutation; Neoplasm Metastasis; Pathway interactions; Patients; Preclinical Testing; Radiation; Radiation therapy; Radioisotopes; Regimen; Regulatory T-Lymphocyte; Safety; Site; Soft tissue sarcoma; Spatial Distribution; T cell response; T memory cell; T-Lymphocyte; Targeted Radiotherapy; Testing; Therapeutic; Therapy trial; Translations; Treatment Protocols; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; Ursidae Family; Vaccination; Vaccines; Veins; Vision; Work; analog; anti-tumor immune response; cancer site; checkpoint inhibition; dosimetry; efficacy testing; immunogenic; immunoregulation; improved; in vivo; insight; mRNA Expression; melanoma; mouse model; multidisciplinary; neoantigens; neoplastic cell; next generation; novel; novel strategies; pre-clinical; prevent; protein expression; radiation delivery; radiation effect; research clinical testing; response; sarcoma; synergism; systemic toxicity; treatment effect; tumor; tumor eradication; tumor microenvironment; uptake; virtual

ABSTRACT We are developing a combined modality therapeutic approach to eradicating metastatic cancers that are immunologically “cold” and do not respond to immune checkpoint inhibition (ICI). Using an “in situ vaccine” regimen consisting of 12 Gy focal external beam radiation therapy (EBRT) and intratumoral (IT) injection of tumor-specific antibody (mAb) + IL2, we have eradicated solitary, large, cold syngeneic tumors in mice. This in situ vaccine converts the targeted tumor into a focus of enhanced tumor antigen presentation resulting in increased T-cell infiltration and potent T-cell memory. However, the presence of an identical but untreated second tumor (2°) on a mouse’s opposite flank inhibits the effect of this treatment, preventing eradication of the primary (1°) tumor treated with EBRT + IT mAb-IL2. In this setting, the untreated 2° tumor causes tumor- specific immune unresponsiveness to EBRT + IT mAb-IL2 at the 1° tumor. We refer to this as concomitant immune tolerance (CIT). We can overcome CIT, and eliminate both tumors by giving IT mAb-IL2 to the 1° tumor and EBRT to both the 1° and 2° tumors. Delivering as little as 2 Gy EBRT to the 2° tumor can overcome CIT. Clinically, delivery of EBRT (even low dose) to all sites of metastatic disease is problematic, but this can effectively be achieved using molecular targeted radiation therapy (MTRT). MTRT is increasingly entering clinical oncology practice and our UW team has led preclinical and clinical testing of a novel class of MTRT using alkylphosphocholine (APCh) analogs that selectively deliver radiation to cancers in vivo. These show tumor-selective uptake in virtually all mammalian tumor cells and tumor locations tested (including > 90 tumor lines and in patients across various clinical trials). In a syngeneic murine melanoma model, we have observed a potent synergy between systemically administered ICI and MTRT delivered using our next-generation APC analog, 90Y-NM600. In a project that builds upon the ongoing collaborative progress of our multidisciplinary team, we will now systematically optimize the potency of combining MTRT with immunotherapy to enhance the immune response against immunologically cold tumors. In murine models, we will: 1) expand on preliminary data showing potent synergy with the combination of MTRT and ICI, 2) evaluate the capacity of MTRT to overcome CIT and enhance systemic anti-tumor immune response in the setting of multiple tumors where one is treated with in situ vaccine (EBRT + IT mAb-IL2) alone or in combination with ICI. Because murine models do not replicate the size and spatial distribution of human metastatic cancer and because these factors strongly influence the dosimetry of MTRT, we will test the immunomodulatory effects of MTRT + in situ vaccine in large breed companion canines (pet dogs) with naturally occurring metastatic melanoma. The insights and treatment regimens developed in these studies should enable rapid translation to clinical testing in patients and potentially for any type of metastatic cancer.

抽象的 我们正在开发一种合并的方式治疗方法来消除转移性癌症 在免疫学上“冷”，对免疫抑制作用（ICI）不反应。使用“原位疫苗” 由12 Gy局灶性外束辐射疗法（EBRT）和肿瘤内注射（IT）注射的方案 肿瘤特异性抗体（MAB） + IL2，我们在小鼠中具有放射性固体，大，冷的合子肿瘤。这是 原位疫苗将靶向肿瘤转化为增强的肿瘤抗原表现的重点，导致 增加T细胞浸润和潜在的T细胞记忆。但是，存在相同但未治疗的存在 在小鼠的相对侧面上的第二肿瘤（2°）抑制了这种治疗的作用，以防止消灭 用EBRT + IT mAb-il2处理的原发性（1°）肿瘤。在这种情况下，未处理的2°肿瘤会导致肿瘤 在1°肿瘤下对EBRT + IT mAb-il2的特异性免疫反应。我们将其称为伴随 免疫耐受性（CIT）。我们可以克服CIT，并通过将MAB-IL 2给1°来消除两个肿瘤。 肿瘤和EBRT至1°和2°肿瘤。向2°肿瘤输送至2 Gy EBRT可以克服 引用在临床上，将EBRT（甚至低剂量）递送到所有转移性疾病的部位都是有问题的，但这可以 MTRT有效地成为靶向辐射疗法（MTRT）。 MTRT越来越进入 临床肿瘤学实践和我们的UW团队领导了一类新型MTRT的临床前和临床测试 使用烷基磷胆碱（APCH）类似物，这些类似物有选择地向体内癌症传递辐射。这些表演 几乎所有哺乳动物肿瘤细胞和肿瘤位置的肿瘤选择性吸收（包括> 90个肿瘤） 线条和各种临床试验的患者）。在合成鼠黑色素瘤模型中，我们观察到 使用我们的下一代APC提供的系统管理的ICI和MTRT之间的潜在协同作用 模拟，90Y-NM600。在一个基于我们多学科的持续协作进步的基础上 团队，我们现在将系统地优化将MTRT与免疫疗法相结合以增强的效力 针对免疫学冷肿瘤的免疫响应。在鼠模型中，我们将：1）扩展 初步数据显示了与MTRT和ICI的组合潜在协同作用，2）评估能力 在多个肿瘤的情况下，MTRT克服CIT并增强全身性抗肿瘤免疫冲源 单独使用原位疫苗（EBRT + IT mAb-il2）或与ICI结合的原位疫苗处理。因为 鼠模型不会复制人类转移性癌的大小和空间分布，因为这些 因素强烈影响MTRT的剂量测定法，我们将测试MTRT +原位的免疫调节作用 大型犬种犬（宠物犬）的疫苗，天然发生转移性黑色素瘤。这 这些研究中成立的见解和治疗方案应能够快速转化为临床 对患者进行测试，并可能对任何类型的转移性癌症进行测试。