SIRPant Technology for anti-Cancer Immunity

SIRPant 抗癌免疫技术

• 批准号: 10325837
• 负责人: Nathanael McCurley
• 金额: $ 40万
• 依托单位: SIRPANT IMMUNOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325837
• 关键词: Acute; Antibodies; Antigen Presentation; Antigens; Atlases; Biodistribution; Biological Assay; Body Weight; Breast; Businesses; CD47 gene; Cancer Patient; Chronic; Clinical; Clinical Trials; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Detection; Development; Development Plans; Disease remission; Distal; Dose; Eating; Exhibits; FDA approved; Funding; Goals; Head; Hematology; Human; Human Pathology; ITIM; Immune; Immune Evasion; Immune checkpoint inhibitor; Immunity; Immunocompetent; Immunologic Memory; Immunologic Surveillance; Immunophenotyping; Immunotherapeutic agent; Immunotherapy; In Situ; Legal patent; Lesion; Liquid substance; Longevity; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Minority; Modality; Modeling; Mus; Neoplasm Metastasis; Organ; Patients; Peripheral Blood Mononuclear Cell; Phagocytes; Phagocytosis; Phase; Phase I Clinical Trials; Production; Protocols documentation; Radiation therapy; Reagent; Receptor Signaling; Recurrence; Relapse; Reproducibility; Research; Schedule; Skin; Small Business Technology Transfer Research; Solid Neoplasm; T memory cell; T-Cell Activation; T-Lymphocyte; Technology; Technology Transfer; Therapeutic; Toxic effect; Toxicology; Translations; Tumor Antigens; Tumor Immunity; Tumor stage; Validation; Work; Xenograft procedure; adaptive immune response; adaptive immunity; anti-cancer; base; cancer cell; cancer immunotherapy; cancer therapy; cancer vaccination; clinical application; clinical translation; commercialization; cytokine release syndrome; extracellular; immune checkpoint blockade; immune clearance; immunogenic; in situ vaccination; in vivo; lymphoid organ; macrophage; malignant breast neoplasm; melanoma; neoantigens; neoplasm immunotherapy; pre-clinical; preclinical efficacy; preempt; prevent; programs; response; therapeutic development; tumor

PROJECT SUMMARY Immune evasion is a hallmark of cancer. Various tumor immunotherapy treatments, such as immune checkpoint blockade and cancer vaccination, have been developed to overcome cancer’s ability to avoid immune detection and destruction; however, the result of these endeavors have not been satisfactory given a number of critical barriers. One of these barriers, and a prominent mechanism by which cancer evades immune surveillance and elimination, is through the cancer cell expressed CD47 to ligate SIRPα, an ITIMs-containing inhibitory signaling receptor expressed on macrophages, which serves as a negative regulator that inhibits macrophage phagocytosis, proinflammatory response and antigen presentation. In our studies, we discovered “Phago-Act”- a proprietary reagent that downregulates SIRPα expression and empowers SIRPα-deficient macrophages (SIRPαLow MØs) to be an initiator for triggering potent innate and adaptive anti-cancer immunity. Not only do they directly phagocytose cancer cells (“liquid”/non-adherent cancer in particular), but SIRPαLow MØs are also capable of conducting immunogenic antigen presentation to robustly activate tumor-specific cytotoxic T cells (Tc) with high tumoricidal activities, leading to rapid elimination of late-stage, large-size solid tumors with distal lesions (mimic metastases). The results of SIRPαLow MØs-initiated responses, which are especially effective in solid tumors, have been vetted extensively in various pre-clinical solid tumor models including cancers of pancreatic, colorectal, lung, breasts and skin (melanoma), all of which resist advanced anti-cancer therapies including immune checkpoint inhibitors and their combinations with RT and other modalities. Moreover, SIRPαLow MØs- induced tumor elimination also leads to long-lasting anti-cancer immunity that prevents recurrence. The goal of this fast-track STTR is to leverage these important research findings and to accelerate their translation to clinical implement of scalable SIRPαLow MØ-based immunotherapy – “SIRPant Technology” – to treat a broad spectrum of cancers and prevent relapse. Our current focus is Solid Tumors. In Phase I, we will extend current studies and establish reproducible protocols for producing human SIRPαLow MØ from PBMC (Aim I-1). Phase II is to fund specific IND-enabling CMC refinement (Aim II-1) and toxicology studies (Aim II-2) needed for a Phase I clinical trial, as well as patient applicable SIRPαLow MØs delivery strategies in combined with RT or/and immune checkpoint inhibitors (Aim II-3). (These discoveries and therapeutic developments are protected by our filed patents)

项目摘要 免疫逃避是癌症的标志。各种肿瘤免疫治疗，如免疫检查点 封锁和癌症疫苗，已经开发出克服癌症的能力，以避免免疫检测 和破坏;然而，考虑到一些关键问题，这些努力的结果并不令人满意 隔栏.这些障碍之一，也是癌症逃避免疫监视的一个重要机制， 消除，是通过癌细胞表达的CD 47连接SIRPα，一种含有ITIM的抑制性信号传导 巨噬细胞上表达的受体，其作为抑制巨噬细胞的负调节剂 吞噬作用、促炎反应和抗原呈递。在我们的研究中，我们发现了“Phago-Act”- 一种专有试剂，可下调SIRPα表达并增强SIRPα缺陷巨噬细胞 (SIRPα低MIBs）是引发有效的先天性和适应性抗癌免疫的引发剂。他们不仅 直接吞噬癌细胞（特别是“液体”/非粘附性癌），但SIRPα低水平MIBs也能够 进行免疫原性抗原呈递以稳健地激活肿瘤特异性细胞毒性T细胞（Tc）， 高杀肿瘤活性，导致晚期、大尺寸实体瘤和远端病变的快速消除 （模拟转移）。SIRPαLow Mass引发的反应的结果，在固体中特别有效， 肿瘤，已经在各种临床前实体瘤模型中进行了广泛的研究， 结直肠、肺、乳房和皮肤（黑色素瘤），所有这些都抵抗先进的抗癌治疗，包括 免疫检查点抑制剂及其与RT和其他方式的组合。此外，SIRPα低MIBs- 诱导的肿瘤消除还导致防止复发的持久抗癌免疫。的目标 这个快速通道STTR是为了利用这些重要的研究成果，并加速其转化为临床 实施可扩展SIRPα低分子量免疫疗法--“SIRPant技术”--治疗广谱 预防癌症复发。我们目前的重点是实体瘤。在第一阶段，我们将扩大目前的研究， 并建立了从PBMC中制备人SIRPαLow MRNA的可重复性方案（Aim I-1）。第二阶段是 为I期研究所需的特定IND支持CMC改进（目标II-1）和毒理学研究（目标II-2）提供资金 临床试验，以及患者适用的SIRPα低MRNA递送策略与RT或/和免疫 检查点抑制剂（Aim II-3）。（这些发现和治疗进展受我们的保护。 专利）