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Next-Generation Chimeric Antigen Receptor T-Cell Therapy: Going off the Shelf.

ABSTRACT: Autologous, patient-specific chimeric antigen receptor T-cell (CART) therapy has emerged as a powerful and potentially curative therapy for cancer, especially for CD19-positive hematological malignancies. Indeed, on August 30, 2017, the University of Pennsylvania-designed CD19-directed CART (CART-19) cell therapy (CTL019, tisagenlecleucel-t, Kymriah - Novartis) became the first CART therapy approved by the Food and Drug Administration (FDA) for acute lymphoblastic leukemia. However, the development of CART technology and its wider application is partly limited by the patient-specific nature of such a platform and by the time required for manufacturing. The efficacious generation of universal allogeneic CART cells would overcome these limitations and represent a major advance in the field. However, several obstacles in the generation of universal CART cells need to be overcome, namely the risk of CART rejection and the risk of graft-versus-host disease mediated by the allogeneic CART. In this review, we discuss the different strategies being employed to generate universal CART and provide our perspective on the successful development of a truly off-the-shelf CART product.

SUBMITTER: Ruella M

PROVIDER: S-EPMC5699508 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Next-Generation Chimeric Antigen Receptor T-Cell Therapy: Going off the Shelf.

Ruella Marco M Kenderian Saad S SS

BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 20171201 6

Autologous, patient-specific chimeric antigen receptor T-cell (CART) therapy has emerged as a powerful and potentially curative therapy for cancer, especially for CD19-positive hematological malignancies. Indeed, on August 30, 2017, the University of Pennsylvania-designed CD19-directed CART (CART-19) cell therapy (CTL019, tisagenlecleucel-t, Kymriah - Novartis) became the first CART therapy approved by the Food and Drug Administration (FDA) for acute lymphoblastic leukemia. However, the developm ...[more]

PMID: 29143249

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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

Next-Generation Chimeric Antigen Receptor T-Cell Therapy: Going off the Shelf.

Publications

Next-Generation Chimeric Antigen Receptor T-Cell Therapy: Going off the Shelf.

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