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: 10024884
• 负责人: PAUL M SONDEL
• 金额: $ 32.67万
• 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/10024884
• 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; In Situ; 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; Vaccination; Vaccines; Veins; Vision; Wisconsin; Xenograft procedure; adaptive immunity; analog; cancer site; cancer vaccination; checkpoint inhibition; clinical translation; clinically translatable; curative treatments; effector T cell; fetal; high risk; immunoregulation; improved; in vivo; individual patient; insight; lead candidate; lymph nodes; melanoma; metaiodobenzylguanidine; mouse model; neoantigens; neoplastic cell; novel; novel strategies; overexpression; pre-clinical; prevent; reconstitution; 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）显示了多个免疫部位的小鼠根除癌症的潜在协同作用 “冷”肿瘤几乎没有浸润的T细胞，并且对免疫抑制作用无反应（ICI）。 几乎所有的儿科癌症和大多数成年人的癌症都是冷的，几乎没有突变或新抗原。我们是 现在采用系统的方法来实现大多数瞄准的大多数冷肿瘤的有效免疫诱导的放射 迈向临床翻译。通过结合免疫调节，我们在小鼠中具有放射性大肿瘤（12 Gy）外束RT（EBRT），肿瘤内（IT）注射肿瘤特异性抗体（MAB） + IL2。这 接近可诱导T细胞浸润到这些肿瘤中，潜在的T细胞记忆，表位传播以及保护 肿瘤重新挑战。但是，在小鼠的存在下存在相同但未处理的第二肿瘤（2°） 相反的侧面抑制了这种治疗的作用，防止了用 EBRT + IT mab-il2。在这种情况下，未处理的2°肿瘤会导致肿瘤特异性免疫无反应性 EBRT + IT mAb-il2在1°肿瘤下。我们将其称为伴随的免疫耐受性（CIT）。我们可以克服 CIT并通过将其mab-il2与1°肿瘤和1°和2°肿瘤一起消除两个肿瘤来消除两个肿瘤。 向2°肿瘤输送至2-5 Gy RT可以克服CIT。但是，将系统性EBRT提供给 由于EBRT的全身免疫抑制，处理许多转移的位点是有问题的。但这可以 使用分子靶向放射性疗法（TRT），可以有效地实现无免疫抑制。 131i-MIBG是神经母细胞瘤（NBL）的常见TRT。我们的威斯康星大学P01团队领导 使用烷基磷酸 - 胆碱（APCH）类似物对新型TRT进行临床前/临床测试，这些类似物有选择地传递 放射线对体内的癌症。这些显示在NBL异种移植物中的131i-MiBG上> 10倍摄取，但与MIBG不同， 在NBL和几乎所有测试的肿瘤中显示出类似的摄取。我们的Lead-Candidate形式的TRT，90Y-NM600具有 超过131i-mibg的许多概念和临床优势，包括无需的潜在门诊治疗 用于患者隔离。在我们的小鼠模型中，我们已经证明了与90Y-NM600和IMMRX的潜在协同作用。 该项目扩大了几个协作项目和核心的持续协作进展 该P01的建议是系统地发展将TRT与我们的组合IMMRX相结合的效力。我们将 在冷NBL和肉瘤的免疫能力小鼠模型中追求这种协同作用。我们的体内目标是能力 使用TRT来帮助在两个单独部位的宏观肿瘤和宏观肿瘤的小鼠中进行放射座位 传播微焦点。我们将仔细分析组织学处的肿瘤和免疫参数 治疗和对照小鼠的细胞和分子水平以及固化的小鼠与显示的小鼠的小鼠 进步或救济。此外，我们将集成到测试新的新向量中，以交付TRT。 这里开发的见解/方案应能够快速转化为冷临床癌。