Abstract
Central memory CD8 T cells exhibit marked veto activity enhancing engraftment in several mouse models of T cell-depleted bone marrow (TDBM) allografting. Graft-versus-host disease (GVHD) can be prevented by stimulation of mouse or human memory CD8 T cells against their cognate antigens under cytokine deprivation, in the early phase of culture followed by further expansion with IL21, IL15, and IL7. Thus, human anti-viral CD8 central memory veto T cells generated from CMV and EBV-positive donors are currently evaluated in a clinical trial at MD Anderson Cancer Centre (MDACC). Results in 15 patients indicate a low risk of GVHD. Considering that these cells could offer an attractive platform for CAR cell therapy, we evaluated methodologies for their effective transduction with 2 retroviral vectors. Initially, a vector directed against Her2 was tested and optimal transduction was attained at day 5 of culture. The transduced cells were expanded for an additional 7 days and exhibited marked anti-tumor reactivity ex-vivo while retaining their veto activity. Transduction with a vector directed at CD19 was effectively attained at days 4-5 allowing for substantial harvest of transduced cells at day 12 of culture. These Veto-CD19CAR central memory CD8 T cells exhibited marked anti-tumor reactivity in-vitro and in-vivo without GVHD, measured following transplantation into immune-deficient mice. These results strongly suggest that Veto-CAR T cells offer an attractive platform for CAR T cell therapy without gene editing for addressing the risk of GVHD or graft rejection.
| Original language | English |
|---|---|
| Article number | szaf020 |
| Journal | Stem Cells Translational Medicine |
| Volume | 14 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 1 Jun 2025 |
Funding
This research was supported in part by the following Core facilities: The Advanced Cytometry & Sorting Core Facility supported by NCI P30CA016672. Small Animal Imaging Core Facility supported by P30CA016672. Retrovirus-packed CAR construct was produced by The ATC Gene Vector Core at Baylor College of Medicine. Wei-Hsin Liu, Anat Globerson Levin, Assaf Lask, and Esther Bachar Lustig designed, performed, and organized most of the experiments, analyzed and interpreted the data, and co-wrote the manuscript. Galit Horn, Tova Waks, Bar Nathansohn Levi, Irit Milman Krentsis, Xiaohua Su, Einav Shoshan, assisted in performing experiments and participated in discussions. Maksim Mamonkin provided the CD19CAR vectors and assisted in the design of the transduction protocol. Richard E. Champlin participated in editing the manuscript, Yair Reisner arranged financial support, designed, coordinated, and conducted the study, including analysis and interpretation of data, co-wrote the manuscript and provided final approval of the manuscript. This work was supported in part by Cell Source Inc, by the Cancer Prevention and Research Institute of Texas (CPRITRR170008) and a staff appreciation and recognition reward (STARs award from the University of Texas system). This work was supported in part by Cell Source Inc, by the Cancer Prevention and Research Institute of Texas (CPRITRR170008) and a staff appreciation and recognition reward (STARs award from the University of Texas system). This research was supported in part by the following Core facilities: The Advanced Cytometry & Sorting Core Facility supported by NCI P30CA016672. Small Animal Imaging Core Facility supported by P30CA016672. Retrovirus-packed CAR construct was produced by The ATC Gene Vector Core at Baylor College of Medicine.
All Science Journal Classification (ASJC) codes
- Developmental Biology
- Cell Biology