TY - JOUR
T1 - CD19/22 CAR T cells in children and young adults with B-ALL
T2 - phase 1 results and development of a novel bicistronic CAR
AU - Shalabi, Haneen
AU - Qin, Haiying
AU - Su, Angela
AU - Yates, Bonnie
AU - Wolters, Pamela L.
AU - Steinberg, Seth M.
AU - Ligon, John A.
AU - Silbert, Sara
AU - DéDé, Kniya
AU - Benzaoui, Mehdi
AU - Goldberg, Sophia
AU - Achar, Sooraj
AU - Schneider, Dina
AU - Shahani, Shilpa A.
AU - Little, Lauren
AU - Foley, Toni
AU - Molina, John C.
AU - Panch, Sandhya
AU - Mackall, Crystal L.
AU - Lee, Daniel W.
AU - Chien, Christopher D.
AU - Pouzolles, Marie
AU - Ahlman, Mark
AU - Yuan, Constance M.
AU - Wang, Hao Wei
AU - Wang, Yanyu
AU - Inglefield, Jon
AU - Toledo-Tamula, Mary Anne
AU - Martin, Staci
AU - Highfill, Steven L.
AU - Altan-Bonnet, Gregoire
AU - Stroncek, David
AU - Fry, Terry J.
AU - Taylor, Naomi
AU - Shah, Nirali N.
N1 - Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/8/4
Y1 - 2022/8/4
N2 - 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).
AB - 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).
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U2 - 10.1182/blood.2022015795
DO - 10.1182/blood.2022015795
M3 - Article
C2 - 35605184
AN - SCOPUS:85133230401
SN - 0006-4971
VL - 140
SP - 451
EP - 463
JO - Blood
JF - Blood
IS - 5
ER -