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.

项目摘要 该提案解决了过继性细胞治疗中的三个主要挑战：1）T细胞持久性; 2）肿瘤 免疫抗性和3）实体瘤的靶向表位鉴定，汇集了Dr. Yee在T细胞治疗中，Rai博士在表观遗传学中，Morelli博士在临床试验中。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产生记忆T细胞， (ETC)Yee实验室开创的疗法，使我们能够靶向HORMAD 1，一种广泛的癌症睾丸抗原， 在胃癌和食管癌中表达，其在晚期阶段代表显著未满足的需求。 通过应用合理设计的表观遗传调节剂的组合，我们计划优化复制基因。 HORMAD 1-特异性CTL（HMD-CTL）的容量和记忆特性， 有限的体内T细胞持久性的挑战（UG 3目的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，我们提出使用显性负性TGF-β受体通过以下方式螯合TGF-β： 使用逆转录病毒转导将TGFBDNR 2基因工程化表达为HORMAD 1特异性CTL 这一策略在细胞治疗制造中心（UG 3 Aim 2）中得到了很好的确立。最后，解决 针对胃癌和食管癌的挑战来自于正在进行的抗原发现管道 经过5年的发展，研究了从MHC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，我们已经经验性地验证了HLA-A2和HLA-A11 HORMAD 1的表位，证明了与使用ETC工作流程产生的CTL的高亲和力，并提出了 在这项试验中使用HORMAD 1特异性CTL，使我们能够覆盖超过25%的胃和食管癌患者， 考虑到这些肿瘤中HORMAD 1表达的流行率（> 40%）和HLA等位基因表达（> 40%）， 65%）。在完成本提案的UG 3部分后，我们将确定最佳表观遗传程序（目标1） 以及满足进行/不进行决定的度量的TGFBDNR 2转导工作流程（目标2）。在临床 试验组件（UH 3），这些策略将被组装，以使我们能够评价体内的安全性和持续时间 持久性，在两个细胞中比较HORMAD 1特异性CTL和TGFBDNR 2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平台提供了比其他ACT模式更大的灵活性，可以灵活地将特异性引导到 几乎任何所需的靶表位，证明了抗原扩散的证据，最小的毒性，并具有 已建立的记忆潜力在几个临床试验中被证明是持续的。我们预计， 增强的表观遗传记忆程序，并被赋予一种机制，以破坏至少一个特征， 肿瘤免疫抵抗，ETC疗法可以为推进过继细胞疗法提供一种载体， 以系统性和逐步的方式治疗实体肿瘤。