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Increasing the safety and efficacy of chimeric antigen receptor T cell therapy.

ABSTRACT: Chimeric antigen receptor (CAR) T cell therapy is a promising cancer treatment that has recently been undergoing rapid development. However, there are still some major challenges, including precise tumor targeting to avoid off-target or "on-target/off-tumor" toxicity, adequate T cell infiltration and migration to solid tumors and T cell proliferation and persistence across the physical and biochemical barriers of solid tumors. In this review, we focus on the primary challenges and strategies to design safe and effective CAR T cells, including using novel cutting-edge technologies for CAR and vector designs to increase both the safety and efficacy, further T cell modification to overcome the tumor-associated immune suppression, and using gene editing technologies to generate universal CAR T cells. All these efforts promote the development and evolution of CAR T cell therapy and move toward our ultimate goal-curing cancer with high safety, high efficacy, and low cost.

SUBMITTER: Li H

PROVIDER: S-EPMC5546931 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Increasing the safety and efficacy of chimeric antigen receptor T cell therapy.

Li Hua H Zhao Yangbing Y

Protein & cell 20170422 8

Chimeric antigen receptor (CAR) T cell therapy is a promising cancer treatment that has recently been undergoing rapid development. However, there are still some major challenges, including precise tumor targeting to avoid off-target or "on-target/off-tumor" toxicity, adequate T cell infiltration and migration to solid tumors and T cell proliferation and persistence across the physical and biochemical barriers of solid tumors. In this review, we focus on the primary challenges and strategies to ...[more]

PMID: 28434147

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Project description: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.

Dataset Information

Increasing the safety and efficacy of chimeric antigen receptor T cell therapy.

Publications

Increasing the safety and efficacy of chimeric antigen receptor T cell therapy.

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