CD19/22 CAR T cells in children and young adults with B-ALL: phase 1 results and development of a novel bicistronic CAR

Author:

Shalabi Haneen1ORCID,Qin Haiying1,Su Angela1,Yates Bonnie1,Wolters Pamela L.1,Steinberg Seth M.2,Ligon John A.13ORCID,Silbert Sara14,DéDé Kniya1,Benzaoui Mehdi15ORCID,Goldberg Sophia1ORCID,Achar Sooraj6ORCID,Schneider Dina7ORCID,Shahani Shilpa A.18,Little Lauren1,Foley Toni1,Molina John C.1ORCID,Panch Sandhya910,Mackall Crystal L.1111213ORCID,Lee Daniel W.11415ORCID,Chien Christopher D.1,Pouzolles Marie1,Ahlman Mark16,Yuan Constance M.17ORCID,Wang Hao-Wei17ORCID,Wang Yanyu18,Inglefield Jon18,Toledo-Tamula Mary Anne19,Martin Staci1,Highfill Steven L.9,Altan-Bonnet Gregoire6ORCID,Stroncek David9,Fry Terry J.120ORCID,Taylor Naomi15ORCID,Shah Nirali N.1ORCID

Affiliation:

1. 1Pediatric Oncology Branch and

2. 2Biostatistics and Data Management Section, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD;

3. 3Division of Hematology/Oncology, Department of Pediatrics, University of Florida, Gainesville, FL;

4. 4Center for Cancer and Blood Disorders, Children’s National Hospital, Washington, DC;

5. 5Université Montpellier, Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France;

6. 6Laboratory of Integrative Cancer Immunology, CCR, NCI, NIH, Bethesda, MD;

7. 7Lentigen, a Miltenyi Biotec Company, Gaithersburg, MD;

8. 8Department of Pediatrics, City of Hope, Duarte, CA;

9. 9Center for Cellular Engineering, Department of Transfusion Medicine, NIH Clinical Center, Bethesda, MD;

10. 10Department of Hematology, Seattle Cancer Care Alliance, University of Washington, Seattle, WA;

11. 11Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford, CA;

12. 12Department of Pediatrics and

13. 13Department of Medicine, Stanford University, Stanford, CA;

14. 14Department of Pediatric Hematology/Oncology, Department of Pediatrics, University of Virginia, Charlottesville, VA;

15. 15University of Virginia Cancer Center, Charlottesville, VA;

16. 16Radiology and Imaging Sciences, NIH Clinical Center, Bethesda, MD;

17. 17Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD;

18. 18Applied Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD;

19. 19Clinical Research Directorate, Frederick National Laboratory for Cancer Research, NCI, Frederick MD; and

20. 20University of Colorado Anschutz Medical Campus and Center for Cancer and Blood Disorders, Children’s Hospital of Colorado, Aurora, CO

Abstract

Abstract Remission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on our phase 1 dose-escalation study of a novel murine stem cell virus (MSCV)-CD19/CD22-4-1BB bivalent CAR T-cell (CD19.22.BBζ) for children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives included laboratory investigations, CAR T-cell expansion and cytokine profiling. Twenty patients, ages 5.4 to 34.6 years, with B-ALL received CD19.22.BBζ. The complete response (CR) rate was 60% (12 of 20) in the full cohort and 71.4% (10 of 14) in CAR-naïve patients. Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having ≥ grade 3 CRS and only 1 experiencing neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80.8% (95% confidence interval [CI]: 42.4%-94.9%) and 57.7% (95% CI: 22.1%-81.9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19.22.BBζ compared with EF1α-CD22.BBζ prompted laboratory investigations comparing EF1α vs MSCV promoters, which did not reveal major differences. Limited CD22 targeting with CD19.22.BBζ, as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19.28ζ/CD22.BBζ construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19.22.BBζ in a heavily pretreated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations (www.clinicaltrials.gov #NCT03448393).

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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