Improving the Efficacy of Allogeneic Cell Therapies of Cancer

提高癌症同种异体细胞疗法的疗效

• 批准号: 10620375
• 负责人: Feiyan Mo
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620375
• 关键词: Address; Adoptive Cell Transfers; Adoptive Transfer; Affect; Allogenic; Antibodies; Autologous; Blood Circulation; CAR T cell therapy; CD19 gene; Cancer Patient; Cell Therapy; Cells; Clinical; Clinical Research; Complex; Development; Engineering; Evaluation; Genetic; Goals; Hematologic Neoplasms; Hematology; Immune; Immune Evasion; Immunosuppression; Impairment; Individual; Inflammation; Knowledge; Liquid substance; Lymphocyte; Malignant Neoplasms; Mediating; Mediator of activation protein; Modification; Molecular; Myeloid-derived suppressor cells; Natural Killer Cells; Neoplasm Metastasis; Neuroblastoma; OX40; Patients; Peptides; Performance; Phase; Pre-Clinical Model; Primary Neoplasm; Research; Research Project Grants; Resistance; Rest; Reverse engineering; Risk; Site; Solid; Solid Neoplasm; Study models; Surface; T cell therapy; T-Lymphocyte; TNFSF5 gene; Therapeutic; Treatment Efficacy; Treatment outcome; arm; cancer therapy; cellular targeting; chemokine; chimeric antigen receptor; chimeric antigen receptor T cells; clinical translation; cost; cytokine; exhaust; improved; inflammatory milieu; inhibitor; macrophage; mouse model; next generation; post-doctoral training; preclinical study; prevent; receptor; response; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY While chimeric antigen receptor (CAR) T-cells can be very effective in advanced hematological malignancies, autologous products often have variable potency and require complex and expensive manufacturing, limiting their scalability and accessibility. The long-term goal of this proposal is to develop a well-characterized, ‘off- the-shelf’ (OTS) therapeutic T-cell platform using banked T-cells pre-manufactured from healthy donors, thus offering immediate availability and high potency at a reduced cost. One major limitation of this approach is potential immune rejection of infused OTS T-cells by host T- and NK-cells, which would impair persistence and clinical benefit of the T-cell therapy. Therefore, my graduate dissertation project (Aim 1) focuses on engineering OTS therapeutic T-cells to resist host immune rejection. I have developed the ‘first-in-class’ chimeric alloimmune defense receptor (ADR) which enables allogeneic OTS CAR T-cells to defend themselves by selectively eliminating activated host alloreactive lymphocytes while sparing other resting non-alloreactive cells. T-cells co-expressing a 4-1BB-directed ADR and a CAR evade immune rejection and produce long-term anti- tumor activity in mouse models of OTS CAR T-cell therapy for both liquid and solid tumors. We are now optimizing the 4-1BB-specific ADR for clinical translation and will initiate a Phase I clinical study in our center. I am also exploring other potential ADR targets, including OX40 and CD40L, to maximize the anti-rejection activity. In addition to alloimmune rejection, activity of OTS T-cells in solid tumors can be inhibited by the immunosuppressive tumor microenvironment (TME). Mounting evidence suggests that the inflammatory milieu created by therapeutic T-cells may elicit reactive changes both locally (in the TME) and systemically (in circulation) that further inhibit anti-tumor activity of therapeutic T-cells and possibly promote tumor growth and metastasis. Examples include a surge of immunosuppressive M2-like macrophages in neuroblastoma patients receiving GD2 CAR T-cells and poor responses to CD19 CAR T-cell therapy in patients with high circulating myeloid-derived suppressor cells. In addition, preclinical studies indicate that treatment-induced inflammation enhances pre-metastatic niche (PMN) formation and increases the risk of metastasis. Therefore, during my post- doctoral training (Aim 2), I will first elucidate the reactive changes (both in TME and in circulation) caused by therapeutic T-cells and identify cellular/molecular mediators of enhanced immunosuppression at the primary tumor site. I will also investigate how T-cell therapies may affect PMN formation in solid tumors. I will then further modify therapeutic T-cells to counteract these unwanted responses by arming them with secreted factors (antibodies, peptide inhibitors) to block the responsible cytokines / chemokines, or by enabling them to selectively eliminate inhibitory cellular subsets in the TME. Successful completion of both Aims will ultimately improve the efficacy of OTS T-cell therapies of cancer.

项目摘要 虽然嵌合抗原受体（CAR）T细胞在晚期血液系统恶性肿瘤中可能非常有效，但 自动产品通常具有可变的效力，需要复杂且昂贵的制造，限制 它们的可伸缩性和可访问性。该提案的长期目标是开发一个特征良好的，“非” 使用由健康捐助者预先制造的库的T细胞的架子（OTS）治疗T细胞平台，因此 以降低的成本提供即时可用性和高效力。这种方法的一个主要局限性是 宿主T和NK细胞对受感染的OT T细胞的潜在免疫反应，这会损害持久性和 T细胞疗法的临床益处。因此，我的研究生论文项目（AIM 1）专注于工程 OTS治疗T细胞可抵抗宿主免疫排斥。我已经开发了“一流的”嵌合体 同种异体ots t-cells捍卫自己 选择性地消除活化的宿主同种异体淋巴细胞，同时保留其他静止的非异化性细胞。 T细胞共表达4-1BB定向的ADR和汽车逃避免疫注射，并产生长期的抗 液体和实体瘤的OTS CAR T细胞疗法的小鼠模型中的肿瘤活性。我们现在 优化4-1BB特异性ADR进行临床翻译，并将在我们中心进行I期临床研究。我 AM还探索包括OX40和CD40L在内的其他潜在ADR靶标，以最大程度地提高抗排斥活性。 除了同种免疫性排斥反应外，OTS T细胞在实体瘤中的活性可以抑制 免疫抑制肿瘤微环境（TME）。越来越多的证据表明炎症环境 由治疗性T细胞创建的可能会引起本地（在TME）和系统地引起反应性变化（在 循环）进一步抑制热T细胞的抗肿瘤活性，并可能促进肿瘤的生长和 转移。例子包括神经母细胞瘤患者的免疫抑制M2样巨噬细胞的激增 接受高循环的患者的GD2 CAR T细胞和对CD19 CAR T细胞治疗的反应不佳 髓样衍生的抑制细胞。此外，临床前研究表明治疗诱导的注射 增强了替代前生态位（PMN）的形成，并增加了转移的风险。因此，在我的职位中 - 博士培训（AIM 2），我首先阐明由 治疗性T细胞，并鉴定一级免疫抑制的细胞/分子介质 肿瘤部位。我还将研究T细胞疗法如何影响实体瘤的PMN形成。然后我会进一步 修改理论t细胞通过武装分泌因素来抵消这些不必要的反应 （抗体，胡椒抑制剂）阻止负责的细胞因子 /趋化因子或通过有选择性 消除TME中的抑制性细胞子集。 成功完成两个目标将最终提高OTS T细胞疗法的效率。