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BCMA-Targeted CAR T-cell Therapy plus Radiotherapy for the Treatment of Refractory Myeloma Reveals Potential Synergy.

ABSTRACT: We present a case of a patient with multiply relapsed, refractory myeloma whose clinical course showed evidence of a synergistic abscopal-like response to chimeric antigen receptor (CAR) T-cell therapy and localized radiotherapy (XRT). Shortly after receiving B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy, the patient required urgent high-dose steroids and XRT for spinal cord compression. Despite the steroids, the patient had a durable systemic response that could not be attributed to XRT alone. Post-XRT findings included a second wave of fever and increased CRP and IL6, beginning 21 days after CAR T cells, which is late for cytokine-release syndrome from CAR T-cell therapy alone on this trial. Given this response, which resembled cytokine-release syndrome, immediately following XRT, we investigated changes in the patient's T-cell receptor (TCR) repertoire over 10 serial time points. Comparing T-cell diversity via Morisita's overlap indices (CD ), we discovered that, although the diversity was initially stable after CAR T-cell therapy compared with baseline (CD = 0.89-0.97, baseline vs. 4 time points after CAR T cells), T-cell diversity changed after the conclusion of XRT, with >30% newly expanded TCRs (CD = 0.56-0.69, baseline vs. 4 time points after XRT). These findings suggest potential synergy between radiation and CAR T-cell therapies resulting in an abscopal-like response.

SUBMITTER: Smith EL

PROVIDER: S-EPMC6606365 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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BCMA-Targeted CAR T-cell Therapy plus Radiotherapy for the Treatment of Refractory Myeloma Reveals Potential Synergy.

Smith Eric L EL Mailankody Sham S Staehr Mette M Wang Xiuyan X Senechal Brigitte B Purdon Terence J TJ Daniyan Anthony F AF Geyer Mark B MB Goldberg Aaron D AD Mead Elena E Santomasso Bianca D BD Landa Jonathan J Rimner Andreas A Riviere Isabelle I Landgren Ola O Brentjens Renier J RJ

Cancer immunology research 20190521 7

We present a case of a patient with multiply relapsed, refractory myeloma whose clinical course showed evidence of a synergistic abscopal-like response to chimeric antigen receptor (CAR) T-cell therapy and localized radiotherapy (XRT). Shortly after receiving B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy, the patient required urgent high-dose steroids and XRT for spinal cord compression. Despite the steroids, the patient had a durable systemic response that could not be attributed ...[more]

PMID: 31113804

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Project description:The present study aimed to study the efficacy and adverse effects of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy in relapsed or refractory multiple myeloma. Patients were divided into three dose groups based on cell therapy concentration. After CAR-T cell therapy for 10 patients with recurrent or refractory multiple myeloma, the patients were monitored and evaluated regularly to observe the efficacy and adverse reactions of CAR-T cell therapy. At a median follow-up of 337 (253-504) days, one patient succumbed 24 days due to rapidly progressing disease. The overall response rate of nine patients was 88.9%, including 77.8% (7/9) with minimal residual disease negative complete remission (CR) and 11.1% (1/9) with partial remission. A total of three patients were maintained in remission state for more than a year and eight were maintained for more than six months. Among the three patients with extramedullary invasion, two extramedullary lesions disappeared and one was stable. The highest copy number of CAR-T cells in seven patients with CR was >1x105 copies/µl gDNA, and the best therapeutic effect can be achieved within 30 (7-30) days after the copy number of CAR-T cells reached 1x105 copies/µl genomic DNA. The median onset time in the nine patients was 43 (22-169) days, and the median progression-free survival was 337 (253-504). Among the 10 patients, nine (90%) had cytokine release syndrome, all of which were below grade II. There were nine (90%) patients with hematological adverse reactions, six (60%) patients with severe anemia, five (50%) patients with grade III and above leukopenia, five (50%) patients with granulocytopenia, four (40%) patients with grade III and above thrombocytopenia, and three (30%) patients with grade III and above pancytopenia. It was concluded that anti-BCMA CAR-T cell therapy is a promising treatment method for relapsed or refractory multiple myeloma and extramedullary invasion, with stable efficacy and controllable adverse effects.

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.).

Project description:BackgroundB-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy has obtained promising results in relapsed or refractory multiple myeloma (R/R MM), while some patients do not response, or relapse in short term after treatment. Combining with anti-CD38 might solve the problem of targeting BCMA alone. We aimed to assess the efficacy and safety of BCMA and CD38 (BCMA-CD38) bispecific CAR-T cells in R/R MM patients.MethodsWe did a single-center, single-arm clinical study at the Second Affiliated Hospital of Yangtze University in China. Patients meeting with the inclusion criteria were administered with fludarabine and cyclophosphamide before CAR-T cells infusion. Response and adverse events were assessed after infusion. This study was registered with the Chinese Clinical Trial Registration Center (ChiCTR1900026286).ResultsFirst, we found BCMA-CD38 CAR-T cells exhibited enhanced killing effect on BCMA+CD38+ cells in vitro, compared to BCMA CAR-T and CD38 CAR-T cells. We further demonstrated its anti-tumor activity in vivo. Then, we enrolled 16 R/R MM patients for safety and efficacy analyses. Of the 16 evaluable patients, 14 (87.5%) respond to the treatment, including 13 stringent complete response (sCR) and one partial response (PR), while two patients did not respond. At a median follow-up of 11.5 months, of the 13 patients who achieved sCR, 76.9% (10/13) did not relapse or progress during follow-up. Relapse occurred in 3 patients (Patient 2, 3 and 4) after achieving sCR. In sum, four patients died, of which one died of hemophagocytic lymphohistiocytosis syndrome secondary to severe cytokine release syndrome (CRS) and three died of disease progression or relapse. The 1-year progression-free survival rates was 68.8%. The 1-year overall survival rate was 75.0%. Extramedullary lesions were eliminated in 62.5% (5/8) patients. The most common symptoms after CAR-T infusion were cytopenia (16, 100%), fever (10, 62.5%), fatigue (8, 50.0%) and myalgias (8, 50.0%). Twelve patients (75.0%) were observed with various grades of CRS, of which five patients (31.3%) got serious CRS (Grade ≥ 3). The CAR+ cell expansion levels were associated with the severity of CRS. Transient clonal isotype switch was observed after CAR-T infusion.ConclusionOur results confirm that BCMA-CD38 CAR-T cells therapy is feasible in treating R/R MM patients, with high response rate, low recurrence rate and manageable CRS, which will be a promising treatment option for R/R MM.Trial registrationChiCTR1900026286, registered on September 29, 2019, retrospectively registered, URL: https://www.chictr.org.cn/showproj.aspx?proj=43805.

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BCMA-Targeted CAR T-cell Therapy plus Radiotherapy for the Treatment of Refractory Myeloma Reveals Potential Synergy.

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BCMA-Targeted CAR T-cell Therapy plus Radiotherapy for the Treatment of Refractory Myeloma Reveals Potential Synergy.

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