1. Simoneaux, Richard

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ORLANDO-Among B-cell based malignancies, the use of CD19 targeting chimeric antigen receptor T (CAR-T) cells have shown clinical efficacy. As a result, approvals were granted by the FDA for two of these therapies: tisagenlecleucel, which is approved for patients with aggressive non-Hodgkin lymphoma or acute lymphoblastic leukemia; and axicabtagene ciloleucel for patients having aggressive non-Hodgkin lymphomas.

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The use of B-cell maturation agent (BCMA)-targeted CAR-T bb2121 has been utilized in multiple myeloma, as that protein is frequently expressed on malignant and normal plasma cells (N Engl J Med 2019;380:1726-1737). Although this immunotherapy has produced high initial response rates, the responses obtained are often not durable, with many patients undergoing a relapse within a year.


As a result of these shortcomings, a phase I clinical trial was initiated that evaluated the co-administration of a gamma secretase inhibitor JSMD194 (also known as LY3039478) with BCMA-targeting CAR-T cells. One participating clinician on this study was Andrew Cowan, MD, an assistant member of Fred Hutchinson Cancer Research Center and physician at the Seattle Cancer Care Alliance. "It was encouraging to see the levels of response that we did, given the low dosage level of CAR-T cells given to these patients." He gave an update at the 2019 ASH Annual Meeting (Abstract 204).


BCMA-Targeted CAR-T Therapy

"Although BCMA CAR T-cell therapy has shown some efficacy in patients with multiple myeloma, a significant proportion of patients relapse," Cowan stated. "One potential means by which malignant cells can evade this immunotherapy involves loss of the BCMA protein on the cellular surface, which has been observed after CAR T-cell therapy. However, further studies clearly need to be done to better understand the mechanism by which multiple myeloma relapse occurs."


Cell surface levels of BCMA are thought to be altered by gamma secretase, a protease that catalyzes the cleavage of the antigen from those surfaces. This results in the release of soluble BCMA (Nat Commun 2015;6:7333). "It is thought that gamma secretase-mediated cleavage of BCMA from malignant plasma cells may limit efficacy of BCMA-directed CAR-T cells in two ways: first, by lowering target antigen density and, second, by providing a soluble decoy which could effectively bind to the CAR-T cells present," Cowan explained.


In preclinical studies performed using a mouse model, at 42 days post-dosing, all mice treated solely with BCMA CAR-T cells displayed progressive tumors. However, mice receiving BCMA CAR-T cells in combination with the gamma secretase inhibitor JSMD194 had their tumors completely cleared and remained tumor-free (Blood 2019;134(19):1585-1597). Summarizing their findings in these preclinical studies, Cowan stated, "Our data suggest that combining CAR-T cells targeting BCMA with a gamma secretase inhibitor may be a promising approach to improve tumor cell elimination in multiple myeloma."


Participation in this study was limited to patients with relapsed or refractory multiple myeloma and had 10 percent or more plasma cells in the bone marrow (as confirmed by CD138-based immunohistochemical analyses). Prior to receiving their ex vivo-modified CAR-T cells, patients received cyclophosphamide- and fludarabine-based myeloablative therapy.


"First, we wanted to evaluate the safety of BCMA-targeted CAR-T cells in combination with the gamma secretase inhibitor JSMD194 in patients with relapsed or treatment-refractory multiple myeloma. Secondly, we also sought to determine the recommended phase II dose of BCMA CAR-T cells administered in combination with JSMD194 in patients with measurable tumor burden prior to T-cell transfer," Cowan noted.


Study Results

A total of eight patients were screened for participation, (median age-64.5 years; range-50-70 years) who had a median of 10 prior regimens (range, 4-23); of these, seven subsequently underwent treatment. In prior therapies, one patient did not show a response to an earlier treatment with BCMA-targeted CAR-T cells of a different construct, while another showed progression during a clinical trial involving a BCMA-based bispecific antibody. At enrollment, the median bone marrow plasma cell involvement was 32.5 percent, with values ranging from 10 percent to 80 percent.


"It was of interest to note," Cowan added, "that roughly 75 percent of patients had high-risk features in their disease." In addition, at screening, the median monoclonal protein was level was 2.55 g/dL, with a range of 0.1-5.1 g/dL.


Two important analytics with the use of the gamma secretase inhibitor in this study are the level of BCMA expression and the soluble BCMA levels before and after treatment with JSMD194. Pre-treatment, BCMA expression levels on plasma cells ranged from 7.6 percent to 98 percent; however, after the three-dose (oral) run-in of JSMD194, the levels were 75-100 percent. Conversely, after three oral doses of the gamma secretase inhibitor, soluble BCMA levels were decreased by approximately two-fold (range 1.6-2.6-fold). In addition, post-treatment, the BCMA antigen-binding capacity increased by a median of 20-fold (range: 7.55-fold to 156.68-fold).


The overall response rate for the six assessable patients was 100 percent, with five patients showing a very good partial response and one showing a partial response. Flow cytometry showed that five of six patients were minimal residual disease-negative.


As of the data cutoff date, at a median follow-up of 5 months (range: 1-11 months), no patient had undergone a relapse. "Unfortunately," Cowan stated, "one patient died 33 days post-CAR-T therapy exhibiting cytokine release syndrome (CRS) and concurrent fungal infection."


In terms of safety outcomes, the most frequently observed non-hematologic adverse event of grade 3 or greater was neutropenic fever (70%). Although CRS was present in all patients, these were typically primarily grade 1 or 2 (using Lee criteria).


"In this study, we showed that inhibition of gamma secretase with JSMD194 routinely increased BCMA surface expression on myeloma cells in treated patients and reduced the soluble BCMA," Cowan noted. "The combination of a gamma secretase inhibitor with BCMA CAR-T cells produced rapid responses, including patients who had failed previous BCMA-targeted therapies. The responses that were obtained were achieved using low CAR-T cell doses (50 x 106 cells); however, longer follow-up is clearly necessary to determine if the response durability is actually improved," Cowan noted.


Richard Simoneaux is a contributing writer.