Bispecific CAR T-cell therapy safe, effective for advanced multiple myeloma
Click Here to Manage Email Alerts
ORLANDO — More than 90% of patients with relapsed or refractory multiple myeloma responded to therapy with a bispecific chimeric antigen receptor T-cell therapy that targets both CD38 protein and B-cell maturation antigen, according to results of a phase 1 dose-escalation trial presented at ASH Annual Meeting and Exposition.
The dual-target CAR T-cell therapy also exhibited a manageable safety profile, with no reported cases of treatment-related neurotoxicity.
“Although anti-BCMA CAR T cells have shown promising results in relapsed or refractory multiple myeloma, short-term relapse due to low expression of BCMA is a major problem that needs to be solved,” researcher Yu Hu, MD, professor of hematology at Tongji Medical College at Huazhong University of Science and Technology in Hubei, China, told Healio.
Hu and colleagues aimed to design dual-target BM38 CAR T cells that target both BCMA and CD38 to help improve outcomes for this patient population.
“CD38 is also expressed on suppressor cells,” he said. “BM38 CAR T cells have the potential to overcome an immunosuppressive microenvironment, thus enhancing the effect in patients with extramedullary tumors.”
Hu said his team’s CAR construct is unique compared with current commercially available therapies because BM38 CAR T cells are the first dual-target CAR T cells that contain anti-BCMA and anti-CD38 in tandem and the 4-1BB costimulatory domain for the treatment of multiple myeloma.
“Our product can bind to both BCMA and CD38 antigens on myeloma cell membranes simultaneously or individually, thus reducing the off-target effect,” Hu said. “They can also be used for patients with low BCMA expression or single-target recurrence.”
Researchers enrolled 22 patients (median age, 59 years; range, 49-72; 50% men) with relapsed or refractory multiple myeloma in the trial. Nine patients (41%) had extramedullary disease
All patients had received a minimum two prior lines of therapy that included at least one proteasome inhibitor and an immunomodulatory agent. Fourteen patients (64%) had received at least three prior lines of therapy.
Patients underwent lymphodepletion chemotherapy with cyclophosphamide and fludarabine before CAR T-cell infusion. At least two patients received one of the escalating dose levels of CAR T cells, which included five dose levels ranging from 0.5 × 106 cells/kg to 4 × 106 cells/kg.
Investigators used 016 International Uniform Response Criteria for Multiple Myeloma to evaluate treatment efficacy, and they used Common Terminology Criteria for Adverse Events version 5.0 to grade toxicity.
At median follow-up of 68 weeks, 20 patients achieved response, equating to an overall response rate of 90.9%. These included 12 (54.5%) serum complete responses, two (9%) very good partial responses and five (22.7%) partial responses. Eighteen patients (81.8%) achieved bone marrow minimal residual disease-negative status.
Median PFS had not been reached, but researchers reported a 78.9% PFS rate at 9 months.
Results at 68 weeks also showed that extramedullary lesions were eliminated among eight of nine patients after BM38 CAR T-cell therapy.
CAR T cells in peripheral blood peaked from day 7 to day 15 after infusion among patients who had a serum complete response, and between days 14 and 30 for those who did not. BM38 CAR T cells can be found in peripheral blood up to 450 days after infusion using qualitative polymerase chain reaction.
Investigators selected 4 × 106 CAR T cells as the optimal dose for further study because of its superior response rate and acceptable toxicity profile.
Twenty patients (90.9%) had cytokine release syndrome (CRS) after BM38 CAR T-cell infusion. This included five cases (23%) of grade 3 or higher CRS. Patients who developed CRS had their symptoms resolved with tocilizumab (Actemra, Genentech) and supportive care.
Researchers reported no cases of treatment-related neurotoxicity; however, nearly all patients had some form of hematological toxicity. Three patients (14%) developed treatment-related hepatoxicity.
“Our study demonstrates an improved efficacy with the bivalent BM38 CAR T therapy for patients with relapsed or refractory multiple myeloma,” Hu told Healio.
He cited the study’s high overall response rate, longer duration of serum complete responses, and “effective elimination for extramedullary lesions” as examples of the bispecific CAR’s efficacy.
“Our ORR of 90.9% and stringent complete response rate of 54.5% is higher than any other current CAR T-cell therapy used to treat in myeloma,” Hu said. “More encouragingly, extramedullary lesions were partially or completely eliminated in eight of nine patients, which is the best result yet seen for extramedullary myeloma. Our humanized dual-target BM38 CAR T cells provide hope for patients with relapsed or refractory multiple myeloma with low expression of BCMA or single-target disease recurrence and extramedullary lesions.” – by Drew Amorosi
Reference:
Li C, et al. Abstract 930. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: The authors report no relevant financial disclosures.
Perspective
Back to Top
Ruben Niesvizky, MD
This study uses a CD38 dual-target CAR and it’s a second-generation form of CAR, whereas first-generation CARs used only a single target. Very high response rates have been obtained with first-generation single-target CARs; however, the responses have been very short-lived and led to disease relapse with early-generation products.
The approach being used to overcome this limitation is dual-target CAR T cells that can obviate the issue surrounding the downregulation of targets and make the treatment more potent.
Here we see the results of the phase 1 dose-escalation portion of the trial. The patient characteristics are typical of a population with advanced, high-risk disease. The prognosis for these patients would have been 6 months of PFS before first-generation CAR T-cells, and that has been extended to approximately 10 to 11 months.
It’s too early to conclude that this second-generation dual-target CAR will lead to improved survival, but the 50% serum complete response rate is on target with previous studies. Bone marrow minimal residual disease-negative status is higher in this study, but the results do not indicate how many of the patients with serum complete responses are minimal residual disease-negative.
Although this is a phase 1 study, it does show improvement in treating this population with advanced multiple myeloma, and these data are very promising.
Click Here to Manage Email Alerts