Author: Biernacki, Melinda A. ; Bar, Merav ; Yeung, Cecilia C. S. ; Woodward, Kyle B. ; Furlan, Scott N. ; Till, Brian G. ; Cassaday, Ryan D. ; Bleakley, Marie ; Dahlberg, Ann ; Greenberg, Philip D. ; Brault, Michelle ; Vartanian, Nicole ; Kanaan, Sami B. ; Yeh, Albert C. ; Maloney, David G. ; Black, R. Graeme ; Summers, Corinne ; Newell, Evan W. ; Denker, Andrew E. ; Riddell, Stanley R. ; Cunningham, Tanya M. ; Gooley, Ted A. ; Krakow, Elizabeth F. ; Dossa, Robson G. ; Chapuis, Aude G.

AbstractRelapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective antileukemic effect post-HCT. We conducted a phase 1 clinical trial using a novel TCR-T product targeting the minor H antigen, HA-1, to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T after HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8 coreceptor were successfully manufactured from HA-1–disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to 9 HCT recipients who had developed disease recurrence after HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, 4 patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with 1 patient still in remission at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T-cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial was registered at ClinicalTrials.gov as #NCT03326921.

01 Jul 2024·MedComm

Liposome‐based in situ antigen‐modification strategy for “universal” T‐cell‐receptor engineered T cell in cancer immunotherapy

Article

Author: Xu, Ruihan ; Wang, Qin ; Peng, Rui ; Yu, Lixia ; Qi, Haoyue ; Du, Shiyao ; Liu, Fangcen ; Liu, Wanmin ; Li, Rutian ; Wei, Jia ; Meng, Fanyan

AbstractT‐cell receptor (TCR) engineered T‐cell therapy, unlike chimeric antigen receptor T‐cell therapy, relies on the inherent ability of TCRs to detect a wider variety of antigenic epitopes, such as protein fragments found internally or externally on cells. Hence, TCR‐T‐cell therapy offers broader possibilities for treating solid tumors. However, because of the complicated process of identifying specific antigenic peptides, their clinical application still encounters significant challenges. Thus, we aimed to establish a novel “universal” TCR‐T “artificial antigen expression” technique that involves the delivery of the antigen to tumor cells using DSPE‐PEG‐NY‐ESO‐1157‐165 liposomes (NY‐ESO‐1 Lips) to express TCR‐T‐cell‐specific recognition targets. In vitro as well as in vivo studies revealed that they could accumulate efficiently in the tumor area and deliver target antigens to activate the tumor‐specific cytotoxic T‐cell immune response. NY‐ESO‐1 TCR‐T therapy, when used in combination, dramatically curbed tumor progression and extended the longevity of mice. Additionally, PD‐1 blockage enhanced the therapeutic effect of the aforementioned therapy. In conclusion, NY‐ESO‐1 Lips “cursed” tumor cells by enabling antigenic target expression on their surface. This innovative technique presents a groundbreaking approach for the widespread utilization of TCR‐T in solid tumor treatment.

Cellular & Molecular Biology Letters

CRISPR–Cas9 applications in T cells and adoptive T cell therapies

Review

Author: Zhong, Shuhan ; Zhan, Yonghao ; Chen, Xiaoying ; Zhang, Xuepei

AbstractT cell immunity is central to contemporary cancer and autoimmune therapies, encompassing immune checkpoint blockade and adoptive T cell therapies. Their diverse characteristics can be reprogrammed by different immune challenges dependent on antigen stimulation levels, metabolic conditions, and the degree of inflammation. T cell-based therapeutic strategies are gaining widespread adoption in oncology and treating inflammatory conditions. Emerging researches reveal that clustered regularly interspaced palindromic repeats–associated protein 9 (CRISPR–Cas9) genome editing has enabled T cells to be more adaptable to specific microenvironments, opening the door to advanced T cell therapies in preclinical and clinical trials. CRISPR–Cas9 can edit both primary T cells and engineered T cells, including CAR-T and TCR-T, in vivo and in vitro to regulate T cell differentiation and activation states. This review first provides a comprehensive summary of the role of CRISPR–Cas9 in T cells and its applications in preclinical and clinical studies for T cell-based therapies. We also explore the application of CRISPR screen high-throughput technology in editing T cells and anticipate the current limitations of CRISPR–Cas9, including off-target effects and delivery challenges, and envisioned improvements in related technologies for disease screening, diagnosis, and treatment.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 2	-	PharmaEssentia Corp.	01 Apr 2024

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