Abstract
Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22+ malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3–4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.
Similar content being viewed by others
Data availability
For original deidentified patient data or the clinical trial protocol please contact LM (lmuffly@stanford.edu).
References
Boyd SD, Natkunam Y, Allen JR, Warnke RA. Selective immunophenoty** for diagnosis of B-cell neoplasms: immunohistochemistry and flow cytometry strategies and results. Appl Immunohistochem Mol Morphol. 2013;21:116–31.
Asnani M, Hayer KE, Naqvi AS, Zheng S, Yang SY, Oldridge D, et al. Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19. Leukemia. 2020;34:1202–7.
Haso W, Lee DW, Shah NN, Stetler-Stevenson M, Yuan CM, Pastan IH, et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood. 2013;121:1165–74.
Shah NN, Stevenson MS, Yuan CM, Richards K, Delbrook C, Kreitman RJ, et al. Characterization of CD22 expression in acute lymphoblastic leukemia. Pediatr Blood Cancer. 2015;62:964–9.
Majzner RG, Rietberg SP, Sotillo E, Dong R, Vachharajani VT, Labanieh L, et al. Tuning the antigen density requirement for CAR T-cell activity. Cancer Discov. 2020;10:702–23.
Shah NN, Highfill SL, Shalabi H, Yates B, ** J, Wolters PL, et al. CD4/CD8 T-cell selection affects chimeric antigen receptor (CAR) T-cell potency and toxicity: updated results from a Phase I Anti-CD22 CAR T-cell trial. J Clin Oncol. 2020;38:1938–50.
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T-cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.
Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48.
Mock U, Nickolay L, Philip B, Cheung GW, Zhan H, Johnston ICD, et al. Automated manufacturing of chimeric antigen receptor T cells for adoptive immunotherapy using CliniMACS Prodigy. Cytotherapy. 2016;18:1002–11.
Zhu F, Shah N, Xu H, Schneider D, Orentas R, Dropulic B, et al. Closed-system manufacturing of CD19 and dual-targeted CD20/19 chimeric antigen receptor T cells using the CliniMACS Prodigy device at an academic medical center. Cytotherapy. 2018;20:394–406.
Shah NN, Johnson BD, Schneider D, Zhu F, Szabo A, Keever-Taylor CA, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a Phase 1 dose escalation and expansion trial. Nat Med. 2020;26:1569–75.
Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24:20–28.
Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625–38.
Hines MR, Knight TE, McNerney KO, Leick MB, Jain T, Ahmed S, et al. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. Transpl Cell Ther. 2023;29:438.e1–438.e16.
Baird JH, Frank MJ, Craig J, Patel S, Spiegel JY, Sahaf B, et al. CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR-refractory large B-cell lymphoma. Blood. 2021;137:2321–5.
O’Leary MC, Lu X, Huang Y, Lin X, Mahmood I, Przepiorka D, et al. FDA Approval Summary: tisagenlecleucel for treatment of patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Clin Cancer Res. 2019;25:1142–6.
Bouchkouj N, Lin X, Wang X, Przepiorka D, Xu Z, Purohit-Sheth T, et al. FDA Approval Summary: brexucabtagene autoleucel for treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Oncologist. 2022;27:892–9.
Shah BD, Ghobadi A, Oluwole OO, Logan AC, Boissel N, Cassaday RD, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398:491–502.
Spiegel JY, Patel S, Muffly L, Hossain NM, Oak J, Baird JH, et al. CAR s with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med. 2021;27:1419–31.
Shalabi H, Qin H, Su A, Yates B, Wolters PL, Steinberg SM, et al. CD19/22 CAR T cells in children and young adults with B-ALL: phase 1 results and development of a novel bicistronic CAR. Blood. 2022;140:451–63.
Wang T, Tang Y, Cai J, Wan X, Hu S, Lu X, et al. Coadministration of CD19- and CD22-directed chimeric antigen receptor T-cell therapy in childhood B-cell acute lymphoblastic leukemia: a single-arm, multicenter, phase II trial. J Clin Oncol. 2023;41:1670–83.
Pan J, Tang K, Luo Y, Seery S, Tan Y, Deng B, et al. Sequential CD19 and CD22 chimeric antigen receptor T-cell therapy for childhood refractory or relapsed B-cell acute lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2023;24:1229–41.
Arnaudo L. On CAR-Ts, decentralized in-house models, and the hospital exception. Routes for sustainable access to innovative therapies. J Law Biosci. 2022;9:lsac027.
Fried S, Shouval R, Varda-Bloom N, Besser MJ, Yerushalmi R, Shem-Tov N, et al. Point-of-care CAR T-cell therapy as salvage strategy for out-of-specification tisagenlecleucel. Leuk Lymphoma. 2022;63:3385–93.
de Macedo Abdo L, Barros LRC, Saldanha Viegas M, Vieira Codeço Marques L, de Sousa Ferreira P, Chicaybam L, et al. Development of CAR- therapy for B-ALL using a point-of-care approach. Oncoimmunology. 2020;9:1752592.
Abou-El-Enein M, Elsallab M, Feldman SA, Fesnak AD, Heslop HE, Marks P, et al. Scalable manufacturing of CAR T cells for cancer immunotherapy. Blood Cancer Discov. 2021;2:408–22.
Acknowledgements
The authors would like to acknowledge Ted Gooley, Ph.D. of the Fred Hutchinson Cancer Research Center for his assistance with statistical analysis as well as Nirali Shah M.D., M.H.Sc. and the National Cancer Institute for providing additional viral vector to allow more patients to enroll on the CD22-CAR studies at Stanford.
Author information
Authors and Affiliations
Contributions
All authors were responsible for data collection and analysis, revision of the manuscript, and final approval. NJ, LS, LM, and SR were primarily responsible for manuscript writing.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Schultz, L.M., Jeyakumar, N., Kramer, A.M. et al. CD22 CAR T cells demonstrate high response rates and safety in pediatric and adult B-ALL: Phase 1b results. Leukemia 38, 963–968 (2024). https://doi.org/10.1038/s41375-024-02220-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41375-024-02220-y
- Springer Nature Limited