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CAR T-cell therapy: is it prime time in myeloma?

ABSTRACT: Chimeric antigen receptor (CAR) T cells have shown promising activity in hematological malignancies and are being studied for the treatment of multiple myeloma, as well. B-cell maturation antigen, which is widely and almost exclusively expressed on plasma cells and B cells, is a promising target. Other targets being evaluated include CD19, CD38, CD138, signaling lymphocyte activation molecule or CS1, light chain, GPRC5D, and NKG2D. Early clinical studies have shown promising response rates in heavily pretreated patients, but relapses have occurred. Cytokine release syndrome and neurotoxicity have been observed in the majority of patients but are mostly grades 1 and 2. Relapse may be mediated by antigen escape and the limited persistence of CAR T cells. CAR T-cell constructs that target multiple antigens/epitopes or constructs with longer persistence due to a higher proportion of memory phenotype T cells may decrease the rates of relapse. Allogeneic CAR T cells that offer "off-the-shelf" options are also being developed. The challenges in integrating CAR T cells in myeloma therapy include disease relapse, adverse effects, cost, and identifying the right patient population. Longer-term data on efficacy and toxicity are needed before CAR T cells are ready for prime time in myeloma.

SUBMITTER: Sidana S

PROVIDER: S-EPMC6855102 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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CAR T-cell therapy: is it prime time in myeloma?

Sidana Surbhi S Shah Nina N

Blood advances 20191101 21

Chimeric antigen receptor (CAR) T cells have shown promising activity in hematological malignancies and are being studied for the treatment of multiple myeloma, as well. B-cell maturation antigen, which is widely and almost exclusively expressed on plasma cells and B cells, is a promising target. Other targets being evaluated include CD19, CD38, CD138, signaling lymphocyte activation molecule or CS1, light chain, GPRC5D, and NKG2D. Early clinical studies have shown promising response rates in he ...[more]

PMID: 31714964

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Project description:Multiple myeloma (MM) remains an incurable disease regardless of recent advances in the field. Therefore, a substantial unmet need exists to treat patients with relapsed/refractory myeloma. The use of novel agents such as daratumumab, elotuzumab, carfilzomib, or pomalidomide, among others, usually cannot completely eradicate myeloma cells. Although these new drugs have had a significant impact on the prognosis of MM patients, the vast majority ultimately become refractory or can no longer be treated due to toxicity of prior treatment, and thus succumb to the disease. Cellular therapies represent a novel approach with a unique mechanism of action against myeloma with the potential to defeat drug resistance and achieve long-term remissions. Genetic modification of cells to express a novel receptor with tumor antigen specificity is currently being explored in myeloma. Chimeric antigen receptor gene-modified T-cells (CAR T-cells) have shown to be the most promising approach so far. CAR T-cells have shown to induce durable complete remissions in other advanced hematologic malignancies like acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). With this background, significant efforts are underway to develop CAR-based therapies for MM. Currently, several antigen targets, including CD138, CD19, immunoglobulin kappa (Ig-Kappa) and B-cell maturation antigen (BCMA), are being used in clinical trials to treat myeloma patients. Some of these trials have shown promising results, especially in terms of response rates. However, the absence of a plateau is observed in most studies which correlates with the absence of durable remissions. Therefore, several potential limitations such as lack of effectiveness, off-tumor toxicities, and antigen loss or interference with soluble proteins could hamper the efficacy of CAR T-cells in myeloma. In this review, we will focus on clinical outcomes reported with CAR T-cells in myeloma, as well as on CAR T-cell limitations and how to overcome them with next generation of CAR T-cells.

Project description:BackgroundPreclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma.MethodsIn this phase 1 study involving patients with relapsed or refractory multiple myeloma, we administered bb2121 as a single infusion at doses of 50×106, 150×106, 450×106, or 800×106 CAR-positive (CAR+) T cells in the dose-escalation phase and 150×106 to 450×106 CAR+ T cells in the expansion phase. Patients had received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were refractory to both drug classes. The primary end point was safety.ResultsResults for the first 33 consecutive patients who received a bb2121 infusion are reported. The data-cutoff date was 6.2 months after the last infusion date. Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 85% of the patients), leukopenia (in 58%), anemia (in 45%), and thrombocytopenia (in 45%). A total of 25 patients (76%) had cytokine release syndrome, which was of grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects occurred in 14 patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient (3%) had a reversible grade 4 neurologic toxic effect. The objective response rate was 85%, including 15 patients (45%) with complete responses. Six of the 15 patients who had a complete response have had a relapse. The median progression-free survival was 11.8 months (95% confidence interval, 6.2 to 17.8). All 16 patients who had a response (partial response or better) and who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10-4 nucleated cells). CAR T-cell expansion was associated with responses, and CAR T cells persisted up to 1 year after the infusion.ConclusionsWe report the initial toxicity profile of a BCMA-directed cellular immunotherapy for patients with relapsed or refractory multiple myeloma. Antitumor activity was documented. (Funded by Bluebird Bio and Celgene; CRB-401 ClinicalTrials.gov number, NCT02658929.).

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CAR T-cell therapy: is it prime time in myeloma?

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CAR T-cell therapy: is it prime time in myeloma?

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