HORMAD-specific TGF-beta resistant memory T cells for treatment of patients with Gastro-esophageal Cancer

HORMAD 特异性 TGF-β 耐药性记忆 T 细胞用于治疗胃食管癌患者

• 批准号: 10731407
• 负责人: Maria Pia Morelli
• 金额: $ 140.69万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731407
• 关键词: ATAC-seq; Address; Adoptive Cell Transfers; Adoptive Transfer; Advanced Malignant Neoplasm; Affinity; Algorithms; Alleles; Antigens; Blood Cells; Blood specimen; CD8-Positive T-Lymphocytes; CTAG1 gene; Cell Cycle Proteins; Cell Therapy; Cells; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; DNA Repair Gene; Disease; Dominant-Negative Mutation; Dose; EZH2 gene; Effectiveness; Effector Cell; Endowment; Engineering; Epigenetic Process; Epitope spreading; Epitopes; Esophagus; Family; Functional disorder; Gene Expression Profiling; Generations; Genes; HLA-A11; HLA-A2 Antigen; Immunologic Suppressor Factors; Immunology; Immunosuppression; In Vitro; Infusion procedures; Lung; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of pancreas; Malignant neoplasm of urinary bladder; Mediating; Memory; Modality; Outcome; Ovarian; Patients; Peptides; Phase; Phase Ib Clinical Trial; Phenotype; Population; Prevalence; Production; Proliferating; Property; Proteins; Protocols documentation; Regulatory T-Lymphocyte; Resistance; Safety; Sampling; Solid Neoplasm; Source; Specificity; Stomach; Surface; T cell differentiation; T cell therapy; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; TGFBR2 gene; Testis; Tissues; Toxic effect; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Tumor Antigens; Tumor Suppression; antigen-specific T cells; arm; cancer/testis antigen; cohort; cytokine; cytotoxicity; engineered T cells; epigenetic memory; epigenetic profiling; epigenomics; exhaustion; first-in-human; flexibility; gastroesophageal cancer; gp100 Antigen; immune resistance; immunogenic; immunogenicity; in silico; in vivo; inhibitor; interleukin-21; malignant stomach neoplasm; manufacture; melanocyte; mortality; novel; peripheral blood; pharmacologic; programs; protocol development; rational design; response; retroviral transduction; self-renewal; single-cell RNA sequencing; success; targeted treatment; transcriptomics; tumor; tumor microenvironment

Project Summary This proposal addresses three major challenges in adoptive cellular therapy: 1) T cell persistence; 2) Tumor immune resistance and 3) Target epitope identification for solid tumors, bringing together the expertise of Dr. Yee in T cell therapy, Dr. Rai in epigenetics and Dr. Morelli in clinical trials. We have established a strategy for generating memory T cells from peripheral blood of patients, via an ACT modality known as Endogenous T Cell (ETC) therapy pioneered in the Yee lab, allowing us to target HORMAD1, a cancer testis antigen broadly expressed in gastric and esophageal cancer, which in its advanced stages represents a significant unmet need. By applying rationally designed combinations of epigenetic modulators we plan to optimize the replicative capacity and memory properties of HORMAD1-specific CTL (HMD-CTL) generate ex vivo to address the challenge of limited in vivo T cell persistence (UG3 Aim 1). One of the dominant extrinsic factors mediating tumor immune resistance in gastric and esophageal cancer is the influence of TGF-β in the tumor microenvironment. In addressing this challenge, we propose the use of a dominant negative TGF-β receptor to sequester TGF-β by engineering expression of the TGFBDNR2 gene into HORMAD1-specific CTL using a retroviral transduction strategy that is well-established in the Cell Therapy Manufacturing Center (UG3 Aim 2). Finally, addressing the challenge of targeting gastric and esophageal cancers was borne out of an ongoing antigen discovery pipeline developed over 5 years examining the portfolio of tandem mass spectrometric defined epitopes eluted from MHC of over 30 tumor samples. From this pipeline we have empirically validated both an HLA-A2 and HLA-A11 epitopes of HORMAD1, demonstrated high affinity with CTL generated using the ETC workflow and propose the use of HORMAD1-specific CTL for this trial, allowing us to cover more than 25% of all gastric and esophageal patients given the prevalence of HORMAD1 expression in these tumors (> 40%) and HLA allele expression (> 65%). At completion of the UG3 portion of this proposal, we will identify an optimal epigenetic program (Aim 1) and TGFBDNR2 transduction workflow (Aim 2) that fulfills the metrics for a Go/ No-Go decision. In the clinical trial component (UH3) these strategies will be assembled to allow us to evaluate safety and duration of in vivo persistence, comparing HORMAD1-specific CTL and TGFBDNR2-engineered HORMAD-1-specitic CTL in two cohorts, while assessing for preliminary efficacy in an Expansion arm. The ETC platform provides greater flexibility than other ACT modalities in its agility to direct specificity to almost any desired target epitope, demonstrated evidence of antigen-spreading, minimal toxicities, and has an established memory potential proven to be sustained in several clinical trials. We anticipate, that with an enhanced epigenetic memory program and, endowed with a mechanism to undermine at least one feature of tumor immune resistance, ETC therapy can provide a vehicle for advancing adoptive cellular therapy for the treatment of solid tumors in a systematic and stepwise fashion.

项目概要 该提案解决了过继性细胞疗法中的三个主要挑战：1）T 细胞持久性； 2) 肿瘤 免疫抵抗和 3) 实体瘤的靶表位识别，汇集了 Dr. 的专业知识。 Yee 博士负责 T 细胞治疗，Rai 博士负责表观遗传学，Morelli 博士负责临床试验。我们制定了一项战略 通过称为内源性 T 细胞的 ACT 模式，从患者的外周血中生成记忆 T 细胞 Yee 实验室首创的 (ETC) 疗法使我们能够广泛靶向 HORMAD1（一种癌症睾丸抗原） 在胃癌和食道癌中表达，在晚期阶段代表着显着的未满足的需求。 通过应用合理设计的表观遗传调节剂组合，我们计划优化复制 HORMAD1 特异性 CTL (HMD-CTL) 的容量和记忆特性在体外生成以解决 有限体内 T 细胞持久性的挑战（UG3 目标 1）。介导肿瘤的主要外在因素之一 胃癌和食管癌的免疫抵抗是肿瘤微环境中TGF-β的影响。 为了应对这一挑战，我们建议使用显性失活 TGF-β 受体通过以下方式隔离 TGF-β： 使用逆转录病毒转导将 TGFBDNR2 基因工程表达到 HORMAD1 特异性 CTL 中 细胞疗法制造中心已确立的战略（UG3 目标 2）。最后，针对 针对胃癌和食道癌的挑战源于持续的抗原发现管道 经过 5 年多的开发，检查了从 MHC 中洗脱的串联质谱确定的表位组合 超过30个肿瘤样本。从这个管道中，我们凭经验验证了 HLA-A2 和 HLA-A11 HORMAD1 的表位，证明与使用 ETC 工作流程生成的 CTL 具有高亲和力，并提出 在本试验中使用 HORMAD1 特异性 CTL，使我们能够覆盖所有胃和食管的 25% 以上 给予患者这些肿瘤中 HORMAD1 表达的患病率 (> 40%) 和 HLA 等位基因表达的患病率 (> 65%）。完成本提案的 UG3 部分后，我们将确定最佳表观遗传计划（目标 1） TGFBDNR2 转导工作流程（目标 2）满足 Go/No-Go 决策的指标。在临床上 试验部分（UH3）将组合这些策略，以便我们评估体内的安全性和持续时间 持久性，比较 HORMAD1 特异性 CTL 和 TGFBDNR2 工程化的 HORMAD-1 特异性 CTL 队列，同时评估扩展组的初步疗效。 ETC 平台比其他 ACT 模式提供更大的灵活性，能够灵活地指导特异性 几乎任何所需的目标表位，已证明抗原扩散的证据，毒性最小，并且具有 已建立的记忆潜力在多项临床试验中被证明可以持续。我们预计，随着 增强的表观遗传记忆程序，并具有破坏至少一个特征的机制 肿瘤免疫抵抗，ETC 疗法可以为推进过继性细胞疗法提供工具 以系统和逐步的方式治疗实体瘤。