Combining targeted radionuclide therapy with a localized in situ vaccine to overcome immune suppression in the tumor microenvironment and augment T cell responses

将靶向放射性核素治疗与局部原位疫苗相结合，克服肿瘤微环境中的免疫抑制并增强 T 细胞反应

• 批准号: 10263248
• 负责人: PAUL M SONDEL
• 金额: $ 32.76万
• 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/10263248
• 关键词: 90Y; Adult; Ambulatory Care; Antibodies; Antigens; Biological Models; Biology; Blood; Cancer Patient; Child; Childhood; Clinical; Combination immunotherapy; Differentiation Antigens; Distant; Dose; Effector Cell; Elements; Epitope spreading; External Beam Radiation Therapy; Generations; Goals; Histologic; Human; IL2 gene; Immune; Immune Tolerance; Immune checkpoint inhibitor; Immune response; Immunocompetent; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infiltration; Injections; Lead; Local Therapy; Low Dose Radiation; MYCN gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Mission; Modeling; Molecular; Molecular Analysis; Molecular Target; Monoclonal Antibodies; Mus; Mutation; National Cancer Institute; Natural Immunity; Neoplasm Metastasis; Neuroblastoma; Oncogenic; Pathway interactions; Patient Isolation; Patients; Pattern; Phosphorylcholine; Primary Neoplasm; Privatization; Radiation therapy; Radioisotopes; Radionuclide therapy; Recurrent tumor; Refractory; Regimen; Regulatory T-Lymphocyte; Relapse; Resistance; Site; Specimen; Spleen; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic; Tissues; Transgenic Organisms; Translating; Translations; Transplantation; Tumor Antigens; Tumor Escape; Tumor-infiltrating immune cells; Universities; Veins; Vision; Wisconsin; Xenograft procedure; adaptive immunity; analog; cancer site; checkpoint inhibition; clinical translation; clinically translatable; curative treatments; effector T cell; fetal; high risk; immunoregulation; improved; in situ cancer vaccination; in situ vaccination; in situ vaccine; in vivo; individual patient; insight; lead candidate; lymph nodes; melanoma; metaiodobenzylguanidine; mouse model; neoantigens; neoplastic cell; novel; novel strategies; overexpression; pre-clinical; prevent; reconstitution; refractory cancer; research clinical testing; response; sarcoma; synergism; targeted delivery; targeted treatment; therapy resistant; treatment effect; tumor; tumor microenvironment; tumor-immune system interactions; uptake; vector; virtual

PROJECT SUMMARY - PROJECT 3: We are developing a combination of immunotherapy (ImmRx) and radiotherapy (RT) that shows potent synergy in eradicating cancer in mice with multiple sites of immunologically “cold” tumors, which have few infiltrating T cells and do not respond to immune checkpoint inhibition (ICI). Virtually all pediatric cancers and most cancers of adults are cold, with few mutations or neoantigens. We are now taking a systematic approach to enable potent immune-induced eradication of most cold tumors aimed towards clinical translation. We have eradicated large, cold tumors in mice by combining immunomodulatory (12 Gy) external beam RT (EBRT) with intratumoral (IT) injection of tumor-specific antibody (mAb) + IL2. This approach induces T-cell infiltration into these tumors, potent T-cell memory, epitope spread, and protection from tumor re-challenge. 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 2-5 Gy RT to the 2° tumor can overcome CIT. However, the provision of systemic EBRT to treat many sites of metastases is problematic, due to systemic immune suppression from EBRT; but this can effectively be achieved without immune-suppression using molecular targeted radionuclide therapy (TRT). 131I-MIBG is a common TRT for neuroblastoma (NBL). Our University of Wisconsin P01 team has led preclinical/clinical testing of a novel TRT using alkyl-phospho-choline (APCh) analogs that selectively deliver radionuclides to cancers in vivo. These show >10-fold uptake over 131I-MIBG in NBL xenografts, but unlike MIBG, show similar uptake in NBL and virtually all tumors tested. Our lead-candidate form of TRT, 90Y-NM600 has many conceptual and clinical advantages over 131I-MIBG, including potential outpatient treatment with no need for patient isolation. We have demonstrated potent synergy with 90Y-NM600 and ImmRx in our mouse models. This project expands the ongoing collaborative progress of the several collaborative projects and cores in this P01 proposal to systematically develop the potency of combining TRT with our combination ImmRx. We will pursue this synergy in immunocompetent mouse models of cold NBL and sarcomas. Our in vivo goal is the ability to use TRT to help eradicate all cancer in mice bearing macroscopic tumors in two separate sites as well as disseminated micro-metastases. We will carefully analyze tumor and immune parameters at the histological, cellular, and molecular levels in treated and control mice and in mice that are cured vs. mice that show progression or relapse. In addition, we will integrate into our testing novel new vectors for delivering TRT. The insights/regimens developed here should enable rapid translation to cold clinical cancers.

项目摘要 - 项目 3：我们正在开发免疫疗法 (ImmRx) 和 放疗 (RT) 在消除多个免疫位点小鼠的癌症方面显示出强大的协同作用 “冷”肿瘤，浸润性 T 细胞很少，并且对免疫检查点抑制 (ICI) 没有反应。 事实上，所有儿童癌症和大多数成人癌症都是冷癌，很少有突变或新抗原。 现在正在采取系统的方法来有效地通过免疫诱导根除大多数冷肿瘤 临床转化。我们通过结合免疫调节剂消除了小鼠体内的大的冷肿瘤（12） Gy) 肿瘤特异性抗体 (mAb) + IL2 瘤内 (IT) 注射的外照射 RT (EBRT)。 方法诱导 T 细胞浸润到这些肿瘤中、有效的 T 细胞记忆、表位扩散和保护 然而，小鼠的肿瘤上存在相同但未经治疗的第二个肿瘤（2°）。 对侧抑制了这种治疗的效果，阻止了用治疗的原发性（1°）肿瘤的根除 EBRT + IT mAb-IL2 在这种情况下，未经治疗的 2° 肿瘤会导致肿瘤特异性免疫无反应。 1° 肿瘤的 EBRT + IT mAb-IL2 我们可以克服这一点。 通过对 1° 肿瘤给予 IT mAb-IL2 并对 1° 和 2° 肿瘤给予 EBRT 进行 CIT 并消除两个肿瘤。 向 2° 肿瘤提供低至 2-5 Gy 的 RT 就可以克服 CIT，但是，提供全身 EBRT 可以克服 CIT。 由于 EBRT 的全身免疫抑制，治疗许多转移部位存在问题；但这可以 使用分子靶向放射性核素治疗（TRT）可以在不进行免疫抑制的情况下有效地实现这一目标。 131I-MIBG 是神经母细胞瘤 (NBL) 的常见 TRT，我们威斯康星大学 P01 团队领导。 使用烷基磷酸胆碱 (APCh) 类似物选择性递送新型 TRT 的临床前/临床测试 这些显示在 NBL 异种移植物中对 131I-MIBG 的吸收超过 10 倍，但与 MIBG 不同， 我们的 TRT 的主要候选形式 90Y-NM600 在 NBL 和几乎所有测试的肿瘤中都显示出相似的吸收。 与 131I-MIBG 相比，它具有许多概念和临床优势，包括无需门诊治疗即可进行治疗 我们在小鼠模型中证明了与 90Y-NM600 和 ImmRx 的有效协同作用。 该项目扩展了多个协作项目和核心的持续协作进展 这个 P01 提案旨在系统地开发 TRT 与我们的组合 ImmRx 相结合的效力。 在冷 NBL 和肉瘤的免疫活性小鼠模型中追求这种协同作用，我们的体内目标是这种能力。 使用 TRT 帮助根除在两个不同部位患有肉眼可见肿瘤的小鼠中的所有癌症 我们将仔细分析组织学和免疫参数。 治疗小鼠和对照小鼠以及治愈小鼠与显示出结果的小鼠的细胞和分子水平 此外，我们将整合到我们的测试中来提供 TRT。 这里开发的见解/方案应该能够快速转化为冷临床癌症。