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Signatures associated with highly functional CAR T cells (SJ-22-0008)
St. Jude Reference #SJ-22-0008
Description
Chimeric antigen receptor-modified (CAR) T cell therapy improved treatment of leukemia; however, despite standardized preparations, the CAR T cells have varied performance in individual patients, with problems in persistence and exhaustion. Researchers at St. Jude identified a unique signature, based on gene transcripts and surface markers in pre-infusion CAR T cells, to predict performance. Prior to CAR therapy, patients have received many treatments including chemotherapies that are toxic to highly proliferative immune cell populations and impact the biological condition of the endogenous T cells. Standard CAR treatment protocols involve generating autologous CAR T cell products and infusing into the patient without regard for the potential efficacy of those cells. This improves treatment by first determining if CAR T cells are suitable for infusion and then, enriching for CAR T cells that will give rise to potent effectors after infusion into the patient.
Researchers at St. Jude generated a comprehensive single-cell gene expression and T cell receptor (TCR) sequencing dataset using pre- and post-infusion CD19-CAR T cells from blood and bone marrow samples of pediatric patients with B cell acute lymphoblastic leukemia (B-ALL). They identified cytotoxic post-infusion cells with identical TCRs to a subset of pre-infusion CAR T cells. These effector precursor cells exhibited a unique transcriptional profile compared to other pre-infusion cells, corresponding to an unexpected surface phenotype (TIGIT+, CD62Llo, CD27-). Upon stimulation, these cells showed functional superiority and decreased expression of the exhaustion-associated transcription factor, TOX. Collectively, these results demonstrate diverse effector potentials within pre-infusion CAR T cell products, which can be exploited for therapeutic applications. Furthermore, they provide an integrative experimental and analytical framework for elucidating the mechanisms underlying effector development in CAR T cell products.
The use of the gene signature could be applied in the treatment of CD19+ B-ALL. There is a potential to develop a commercialized method or product to enrich for effector CAR T cells within the GMP product prior to infusion with certain combinations of the markers listed above. Beyond this application, treatment teams can use the classifier to assess the cytotoxic potential of a CAR T cell product prior to infusion. This program can be wielded as a diagnostic to determine if a patient’s autologous CAR T cells will be effective against B-ALL and delineate whether infusion of the product should occur in an effort to avoid the risks of CAR therapy or if another treatment protocol should be undertaken.
Keywords
Chimeric antigen receptor-modified (CAR), T cell therapy, leukemia, persistence, exhaustion, gene transcripts, surface markers, predict performance, comprehensive single-cell gene expression, T cell receptor (TCR) sequencing, CD19+ B-ALL, GMP
Granted Patents or Published Applications
Application filed, available under confidentiality.
Related Scientific References
Taylor L. Wilson, Hyunjin Kim, Ching-Heng Chou, Deanna Langfitt, Robert C. Mettelman, Anastasia A. Minervina, E. Kaitlynn Allen, Jean-Yves Metais, Mikhail V. Pogorelyy, Janice M. Riberdy, M. Paulina Velasquez, Pratibha Kottapalli, Sanchit Trivedi, Scott R. Olsen, Timothy Lockey, Catherine Willis, Michael M. Meagher, Brandon M. Triplett, Aimee C. Talleur, Stephen Gottschalk, Jeremy Chase Crawford, Paul G. Thomas; Common trajectories of highly effective CD19-specific CAR T cells identified by endogenous T cell receptor lineages. Cancer Discov 2022; candisc.1508.2021. https://doi.org/10.1158/2159-8290.CD-21-1508
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