Chimeric Antigen Receptor T Cells as Salvage Therapy for Post-Chimeric Antigen Receptor T Cell Failure

Elizabeth M. Holland, Bonnie Yates, Seth M. Steinberg, Constance M. Yuan, Hao Wei Wang, Colleen Annesley, Haneen Shalabi, David Stroncek, Terry J. Fry, Joerg Krueger, Elad Jacoby, Emily Hsieh, Deepa Bhojwani, Rebecca A. Gardner, Shannon L. Maude, Nirali N. Shah*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Outcomes for post-chimeric antigen receptor (CAR) T cell therapy (CART) relapse are poor. The utilization of a unique CAR T cell construct for post-CART failure is increasing, but this approach is not well described. In this study, with CART-A the first unique CAR T cell construct received and CART-B the second, the primary objective was to characterize outcomes following CART-B. Secondary objectives included evaluating safety and toxicity with sequential CART infusions; investigating the impact of potential factors, such as antigen modulation and interval therapy, on CART-B response; and characterizing long-term outcomes in patients receiving multiple CARTs. This was a retrospective review (NCT03827343) of children and young adults with B cell acute lymphoblastic leukemia (B-ALL) undergoing CART therapy who received at least 2 unique CART constructs, excluding interim CART reinfusions of the same product. Of 135 patients, 61 (45.1%) received 2 unique CART constructs, including 13 who received >2 CARTs over time. Patients included in this analysis received 14 distinct CARTs targeting CD19 and/or CD22. The median age at CART-A was 12.6 years (range, 3.3 to 30.4 years). The median time from CART-A to CART-B was 302 days (range, 53 to 1183 days). CART-B targeted a different antigen than CART-A in 48 patients (78.7%), owing primarily to loss of CART-A antigen target. The rate of complete remission (CR) was lower with CART-B (65.5%; 40 of 61) than with CART-A (88.5%; 54 of 61; P = .0043); 35 of 40 (87.5%) CART-B responders had CART-B targeting a different antigen than CART-A. Among the 21 patients with a partial response or nonresponse to CART-B, 8 (38.1%) received CART-B with the same antigen target as CART-A. Of 40 patients with CART-B complete response (CR), 29 (72.5%) relapsed. For the 21 patients with evaluable data, the relapse immunophenotype was antigennegative in 3 (14.3%), antigendim in 7 (33.3%), antigenpositive in 10 (47.6%), and lineage switch in 1 (4.8%). The median relapse-free survival following CART-B CR was 9.4 months (95% confidence interval [CI], 6.1 to 13.2 months), and overall survival was 15.0 months (95% CI, 13.0 to 22.7 months). Given the limited salvage options for post-CART relapse, identifying optimizing strategies for CART-B is critical. We raise awareness about the emerging use of CART for post-CART failure and highlight clinical implications accompanying this paradigm shift.

Original languageEnglish
Pages (from-to)574.e1-574.e10
JournalTransplantation and Cellular Therapy
Volume29
Issue number9
DOIs
StatePublished - Sep 2023

Funding

FundersFunder number
CRISPR Therapeutics
Magnuson Clinical CenterZIA BC 011823
National Institutes of Health
U.S. Department of Health and Human Services
National Cancer Institute
Novartis
Coins for Alzheimer's Research Trust
Government of South Australia

    Keywords

    • Acute lymphoblastic leukemia
    • Chimeric antigen receptor T cells
    • Immunotherapy
    • Relapse
    • Salvage therapy

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