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 该提案解决了自适应细胞疗法的三个主要挑战：1）T细胞持久性； 2）肿瘤 免疫抵抗力和3）实体瘤的靶向表位鉴定，将博士的专业知识汇总在一起 YEE在T细胞疗法中，RAI的表观遗传学博士和临床试验中的Morelli博士。我们已经建立了一个策略 通过称为内源性T细胞的ACT模态从患者的外周血产生记忆T细胞 （etc）在YEE实验室中率先进行的治疗，使我们能够广泛靶向Hormad1，这是一种癌症抗原 在胃癌和食管癌中表达，在其晚期阶段，这代表了一个重要的未满足需求。 通过应用理性设计的表观遗传调节剂组合，我们计划优化复制品 Hormad1特异性CTL（HMD-CTL）的容量和内存属性生成离体以解决该问题 挑战有限的体内T细胞持久性（UG3 AIM 1）。介导肿瘤的主要外部因素之一 胃癌和食管癌的免疫耐药性是TGF-β在肿瘤微环境中的影响。 在应对这一挑战时，我们提出使用主要的阴性TGF-β受体来隔离TGF-β TGFBDNR2基因的工程表达使用逆转录病毒转换 在细胞疗法制造中心（UG3 AIM 2）建立了良好的策略。最后，解决 靶向胃癌和食管癌的挑战是源于正在进行的抗原发现管道的挑战 开发了5年以上，研究了从MHC洗脱的串联质谱定义表位的投资组合 超过30个肿瘤样品。从这条管道中，我们在经验上验证了HLA-A2和HLA-A11 Hormad1的表位表现出与使用ETC工作流和建议产生的CTL的高亲和力 在此试验中使用Hormad1特异性CTL，使我们覆盖了所有胃和食管的25％以上 鉴于在这些肿瘤（> 40％）和HLA等位基因表达（> 65％）。完成本提案的UG3部分时，我们将确定一个最佳表观遗传学计划（AIM 1） 和TGFBDNR2传输工作流（AIM 2），可满足GO/ No-Go决定的指标。在临床上 试验部分（UH3）将组装这些策略，以使我们能够评估体内的安全性和持续时间 持久性，比较hormad1特异性的CTL和TGFBDNR2工程的hormad-1特异性CTL 同时在评估扩展组中的初步效率时。 ETC平台比其敏捷性的其他ACT方式更大的灵活性，以直接特异性 几乎所有所需的目标表位，证明了抗原膨胀，最小毒性的证据，并且具有 确定的记忆潜力被证明是在多项临床试验中持续的。我们期待的是， 增强的表观遗传记忆程序，并具有一种机制，以破坏至少一个特征 肿瘤免疫耐药性等疗法可以为推进适应性细胞疗法的工具提供 以系统和逐步的方式处理实体瘤。