CAR T cell therapy for T cell leukemia and lymphoma: latest updates from 2022 ASH Annual Meeting
Journal of Hematology & Oncology volume 16, Article number: 18 (2023)
Due to the concern of fratricide, clinical development of CAR T cells for the therapy of T cell malignancies lags behind that for B cell malignancies. Attempts are being made to revise T cell biomarkers so that the re-engineered CAR T cells can target T cell malignancies. CD3 and CD7 are the two pan-T cell surface biomarkers that have been either knocked out or knocked down through genome base- editing technology or by protein expression blockers so that the re-engineered T cells can target T cells without fratricide. We summarized several latest reports on the CAR T cells for the therapy of T cell leukemia /lymphoma from the 2022 ASH Annual Meeting, with latest updates on clinical trials of TvT CAR7, RD-13-01, and CD7 CART.
To the editor
Attempts are being made to revise T cell biomarkers so that the re-engineered CAR T cells can target T cell malignancies without fratricide . CD3 and CD7 are the two pan-T cell surface biomarkers that have been either knocked out or knocked down through genome base- editing technology or by protein expression blockers so that the re-engineered T cells can target T cells without fratricide [2, 3]. We summarized several latest reports on the CAR T cells for the therapy of T cell leukemia /lymphoma (TCLL) from the 2022 ASH Annual Meeting (ASH2022).
CD7 targeted CAR T cells by genome editing
The abstract 2001 reported a targeted base- editing (BE) technology that can mediate precise C → U → T conversion using CRISPR guided cytidine deamination  (Table 1). The BE-edited allogeneic CAR T cells have disruptions of TCR, CD7 and CD52 (BE-CAR7). Early data from the clinical trial, TvT CAR7 study, were reported at ASH2022 . This phase I study was planned for children with relapsed /refractory (R/R) CD7 + T-ALL. The BE-CAR7 cells were used to induce negative measurable residual disease (MRD) prior to allogeneic hematopoietic stem cell transplant (alloHSCT) at day + 28 (Table 2). The first highly refractory T ALL subject treated had grade 2 cytokine release syndrome (CRS), grade I immune effector cell-associated neurotoxicity syndrome (ICANS). The patient (pt) successfully achieved MRD negativity, had no graft-vs-host disease (GVHD), and received alloHSCT.
Another study reported data on a different CD7- genome edited alloCAR T cell product, RD13-01, in 10 patients with R/R TCLL . On day 28, 8 pts reached complete remission (CR), and 7 of them had negative MRD. 6 patients in CR (including 1 MRD + CR) proceeded to alloHSCT. Among the 10 subjects, 4 had durable CR, 4 died, 2 had no response. Nine of the 10 pts had grade I and 1 with grade 3 CRS, 1 had ICANS. GVHD was not reported.
CD7 targeted CAR T cells by protein expression blocking
By employing an IntraBlock technology that can retain CD7 intracellularly, thereby leading to downregulation of surface CD7 expression, CD7-targeted CAR T cells from either stem cell donors or new donors were engineered and infused to patients with R/R TCLL . In a recent report of phase 2 data with a 11 -month median follow-up , the objective response rate (ORR) remained at 90% 3 months post-infusion for the 20 enrolled pts. The rate for one-year progressive-free survival was 62.3%, and overall survival rate at 1 year was 60.0% (95% CI, 38.5–81.5). There was 10% grade 3 or higher CRS. Grade 1–2 GVHD was at 40%.
CD7 protein expression blocker (PEBL) binds and anchors CD7 in the ER and Golgi apparatus, resulting in CD7 degradation, thus leading to downregulation of surface CD7 expression. One group constructed a dual CD3/CD7 PEBL to block both CD3 and CD7 expression, together with anti-CD7 CAR, the CAR T cells, PCART7, specifically targeted CD7 + T cells in vitro and in vivo . Due to lack of TCR activation secondary to CD3 downregulation, GVHD was not observed. This approach avoids genome editing, though clinical trials are needed to verify the applicability in human.
CD3 targeted CAR T cells by protein expression blocking
By using the CD3 PEBL mentioned above, anti-CD3 PEBL-CAR T cells were generated that have been shown to have potent and specific cytotoxicity against CD3 + target cells in both in vitro and in vivo models . Again, GVHD was much reduced in the mouse model treated with the anti-CD3 PEBL-CAR T cells. These features make this novel anti-CD3 CAR-T cells suitable for the treatment of TCLL.
In summary, by genome knockout or by blocking protein expression of surface CD3 and /or CD7, it is feasible to avoid fratricide and target T cell malignancies through CAR T cells.
Availability of data and materials
The material supporting the conclusion of this study has been included within the article.
American Society of Hematology
Acute lymphoblastic leukemia
Chimeric antigen receptor
Cytokine release syndrome
Immune effector cell-associated neurotoxicity syndrome
Graft vs host disease
Overall response rate
Progression free survival
Hou J-Z, Ye JC, Pu JJ, Liu H, Ding W, Zheng H, Liu D. Novel agents and regimens for hematological malignancies: recent updates from 2020 ASH annual meeting. J Hematol Oncol. 2021;14(1):66.
Kamiya T, Wong D, Png YT, Campana D. A novel method to generate T-cell receptor–deficient chimeric antigen receptor T cells. Blood Adv. 2018;2(5):517–28.
Pan J, Tan Y, Wang G, Deng B, Ling Z, Song W, Seery S, Zhang Y, Peng S, Xu J, Duan J, Wang Z, Yu X, Zheng Q, Xu X, Yuan Y, Yan F, Tian Z, Tang K, Zhang J, Chang AH, Feng X. Donor-derived CD7 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia: first-in-human. Phase I Trial J Clin Oncol. 2021;39(30):3340–51.
Chiesa R, Georgiadis C, Ottaviano G, Syed F, Braybrook T, Etuk A, Zhan H, Gkazi SA, Preece R, Adams S, Thomas R, Awuah A, Gilmour K, Mhaldien L, Chu J, Pinner D, Kubat A, Veys P, Rao K, Lucchini G, O’Connor D, Vora A, Qasim W. Tvt CAR7: phase 1 clinical trial of base-edited "universal” CAR7 T cells for paediatric relapsed/refractory T-ALL. Blood. 2022;140(Supplement 1):4579–80.
Zhang X, Zhou Y, Yang J, Li J, Qiu L, Ge W, Pei B, Chen J, Han L, Ren J, Lu P. A novel universal CD7-targeted CAR-T cell therapy for relapsed or refractory T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Blood. 2022;140(Supplement 1):4566–7.
Tan Y, Pan J, Deng B, Ling Z, Weiliang S, Tian Z, Cao M, Xu J, Duan J, Wang Z, Wang K, Li C. Efficacy and safety of donor-derived CD7 CAR T cells for r/r T-cell acute lymphoblastic leukemia/lymphoma: interim analysis from a phase 2 trial. Blood. 2022;140(Supplement 1):4602–3.
Wong XFA, Ng J, Zheng S, Ismail R, Qian H, Campana D, Tan YX. Development of an off-the-shelf chimeric antigen receptor (CAR)-T cell therapy for T-cell acute lymphoblastic leukemia (T-ALL) without gene editing. Blood. 2022;140(Supplement 1):2358–9.
Qian H, Gay FPH, Pang JWL, Lee Y, Ang J, Tan HC, Lek ES, Campana D, Tan YX. Development of anti-CD3 chimeric antigen receptor (CAR)-T cells for allogeneic cell therapy of peripheral T-cell lymphoma (PTCL). Blood. 2022;140(Supplement 1):4510–1.
DL is the editor-in-chief of the Journal of Hematology & Oncology.
The study is partly supported by the National Key Research and Development Program of China (No. 2021YFC2500304), Key Program of National Natural Science Foundation of China (No. 82230004, 81730004), National Natural Science Foundation of China (No. 82200136, No. 81970113), and the Capital Health Research and Development of Special Fund (No. 2022-1-4082).
Ethics approval and consent to participate
This is not applicable for this summary.
Consent for publication
This is not applicable for this summary.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Huang, Q., Zhang, Xh. & Liu, D. CAR T cell therapy for T cell leukemia and lymphoma: latest updates from 2022 ASH Annual Meeting. J Hematol Oncol 16, 18 (2023). https://doi.org/10.1186/s13045-023-01406-8
- CAR T
- T cell leukemia