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: 10686219
• 负责人: Feiyan Mo
• 金额: $ 7.78万
• 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/10686219
• 关键词: Ablation; Acceleration; Address; Adoptive Cell Transfers; Adoptive Transfer; Affect; Allogenic; Antibodies; Autologous; CAR T cell therapy; CD19 gene; Cancer Patient; Cell Therapy; Cells; Circulation; Clinical; Clinical Research; Complex; Development; Dose; Engineering; Evaluation; Genetic; Goals; Hematologic Neoplasms; Hematology; Immune; Immune Evasion; Immune system; Immunosuppression; Impairment; Inflammation; Knowledge; Liquid substance; Lymphocyte; Macrophage; Malignant Neoplasms; Mediating; Mediator; Modification; Molecular; Myeloid-derived suppressor cells; Natural Killer Cells; Neoplasm Metastasis; Neuroblastoma; OX40; Patients; Peptides; Performance; Phase; Postdoctoral Fellow; 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; Tumor Promotion; arm; cancer therapy; chemokine; chimeric antigen receptor; chimeric antigen receptor T cells; clinical translation; cost; cytokine; engineered T cells; exhaust; improved; individual patient; inflammatory milieu; inhibitor; manufacture; 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细胞在晚期恶性血液病中非常有效， 自体产物通常具有可变的效力，并且需要复杂且昂贵的制造， 可扩展性和可访问性。该提案的长期目标是制定一个特征鲜明的"小康“， 使用从健康供体预制造的库T细胞的“货架”（OTS）治疗性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是 宿主T细胞和NK细胞对输注的OTS T细胞的潜在免疫排斥，这将损害持久性， T细胞疗法的临床益处。因此，我的研究生论文项目（目标1）侧重于工程 OTS治疗性T细胞抵抗宿主免疫排斥。我开发了一种“一流”的嵌合体 同种免疫防御受体（ADR），其使同种异体OTS CAR T细胞能够通过以下方式来保护自己： 选择性地消除活化的宿主同种异体反应性淋巴细胞，同时保留其它静息的非同种异体反应性细胞。 共表达4- 1BB导向的ADR和CAR的T细胞逃避免疫排斥并产生长期的抗- OTS CAR T细胞治疗液体肿瘤和实体肿瘤的小鼠模型中的肿瘤活性。我们现在 优化4- 1BB特异性ADR的临床转化，并将在我中心启动I期临床研究。我 我还在探索其他潜在的ADR靶点，包括OX 40和CD 40 L，以最大限度地提高抗排斥反应活性。 除了同种免疫排斥外，实体瘤中OTS T细胞的活性可被免疫抑制剂抑制。 免疫抑制肿瘤微环境（TME）。越来越多的证据表明， 由治疗性T细胞产生的免疫应答可能引起局部（在TME中）和全身（在TME中）的反应性变化。 循环），其进一步抑制治疗性T细胞的抗肿瘤活性并可能促进肿瘤生长， 转移例子包括神经母细胞瘤患者中免疫抑制性M2样巨噬细胞的激增 接受GD 2 CAR T细胞和对CD 19 CAR T细胞治疗反应差的高循环免疫缺陷患者 骨髓来源的抑制细胞。此外，临床前研究表明，治疗诱导的炎症 增强转移前小生境（PMN）形成并增加转移的风险。因此，在我任职期间- 博士培训（目标2），我将首先阐明反应性变化（在TME和循环）所造成的 治疗性T细胞，并鉴定原发性免疫抑制增强的细胞/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中PMN的形成。我将进一步 通过用分泌的因子武装治疗性T细胞以抵消这些不需要的反应 （抗体，肽抑制剂）来阻断负责的细胞因子/趋化因子，或通过使它们能够选择性地 消除TME中的抑制性细胞亚群。 这两个目标的成功完成将最终提高癌症的OTS T细胞疗法的疗效。