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Anti–B-cell maturation antigen CAR T cells show promise for advanced multiple myeloma
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ORLANDO, Fla. — T cells genetically modified to express a chimeric antigen receptor targeting B-cell maturation antigens demonstrated strong clinical activity in patients with heavily pretreated multiple myeloma, according to study results presented at the ASH Annual Meeting and Exposition.
B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells, according to study background. James N. Kochenderfer, MD, investigator in the experimental transplantation and immunology branch of the NCI’s Center for Cancer Research, and colleagues conducted a first-in-humans clinical trial using autologous T cells modified with a gamma-retroviral vector to express an anti-BCMA chimeric antigen receptor (CAR).
James N. Kochenderfer
“B-cell maturation antigen is expressed in many cases of multiple myeloma,” Kochenderfer told HemOnc Today. “The CAR gives the T cells the ability to recognize a specific target on malignant cells.”
The study included data from 12 patients with advanced multiple myeloma (median prior therapy lines, 7).
Patients received a chemotherapy regimen of cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) for 3 days, followed by a single infusion of CAR-modified T cells at one of four dose levels (0.3x106, 1x106, 3x106 or 9x106 CAR-positive T cells/kg of body weight).
Six patients received the lowest two dose levels. The researchers reported a transient partial remission in one patient, lasting 2 weeks. The other five patients achieved stable disease.
Among three patients assigned to the third dose level, two achieved stable disease. The other patient obtained a very good partial remission, with complete elimination of myeloma bone disease confirmed by PET scan, normalization of serum free light chains and clearance of bone marrow plasma cells.
Toxicities associated with these dose levels appeared mild and included cytopenia, fever and cytokine release syndrome, including tachycardia. One of these patients had hypotension.
Two patients received the highest dose level.
The first patient had multiple myeloma that comprised greater than 90% of total bone marrow cells prior to treatment. Beginning 4 hours following infusion, the patient experienced cytokine release syndrome. He had a neutrophil count below 500/μL before CAR T-cell infusion, which persisted for 40 days after infusion prior to recovery.
According to the researchers, this patient’s myeloma was rapidly eliminated following infusion, with bone marrow plasma cells decreasing to 0% 1 month after treatment. The patient’s serum M-protein was undetectable 2 months after treatment, with serum and urine immunofixation electrophoresis tests negative after 2 months. The patient is currently in stringent complete remission.
“The elimination of multiple myeloma was quite impressive, given the advanced status of this patient’s disease,” Kochenderfer said in an interview.
The second patient treated with the highest dose had multiple myeloma with 80% bone marrow plasma cells prior to treatment and also experienced cytokine release syndrome. The patient’s M-protein decreased from 3.6 g/dL before treatment to 0.8 g/dL 4 weeks after treatment.
Further, the patient’s serum lambda free light chain decreased from 95.9 mg/dL prior to treatment to 0.15 mg/dL 4 weeks after treatments. Bone marrow plasma cells were undetectable 4 weeks after infusion.
Researchers detected T cells containing the CAR-BCMA gene in the blood of all evaluable patients (n = 10), with peak levels ranging from 0.04% to 18.2% of blood mononuclear cells. Blood levels of interleukin-6 and other inflammatory cytokines appeared highest in patients with clinical signs of cytokine release syndrome. Further, the three patients with the highest serum levels of interleukin-6 achieved the most impressive anti-myeloma responses, according to the researchers.
The mean serum BCMA level of treated patients was 243 ng/mL prior to treatment; following treatment, levels decreased in responding patients.
The researchers reported that toxicities appeared similar to those seen in patients with leukemia treated with anti-CD19 CAR T cells.
“We are constantly working to improve anti–B-cell maturation antigen CAR T cells," Kochenderfer said. “A multicenter clinical trial will open within the next 2 months.” – by Cameron Kelsall
Reference:
Ali SA, et al. Abstract LBA-1. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
For more information:
James N. Kochenderfer, MD, can be reached at the NCI’s Center for Cancer Research, Building 10–CRC–Room 3-3888, Bethesda, MD 20892; email: kochendj@mail.nih.gov.
Disclosure: Kochenderfer reports research funding from Bluebird Bio Inc. One other study researcher reports research funding from Celgene. The other researchers report no relevant financial disclosures.
Perspective
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Noopur Raje, MD
We are all very excited in the myeloma setting, because in the last few weeks we have had three drugs approved, including immuno-oncology drugs and an oral proteasome inhibitor. These include elotuzumab (Empliciti, Bristol-Myers Squibb), daratumumab (Darzalex, Janssen) and now ixazomib (Ninlaro, Takeda/Millennium).However, monoclonal antibodies — which do work with the immune system — are not the only area of excitement. Cellular therapies have been another area of research. Presented at the ASH Annual Meeting as a late-breaker was a study that evaluated CAR T cells directed against a cell surface protein called BCMA. We know that BCMA is quite significantly expressed on all myeloma cells and all plasma cells in general. Kochenderfer and colleagues at the NIH used CAR T cells against BCMA, and although the data are fairly preliminary, we are beginning to see there are responses at the dose levels that the NIH team has been able to get to. We have long awaited to look at these data and see whether these are sustainable responses, and to see what toxicities are associated with this regimen.
A couple of other approaches also were discussed at this meeting that are important to mention. There were data on bispecific monoclonal antibodies, which are still in preclinical development and are designed to act with the CD3 T cells. We look forward to seeing whether they pan out in the clinic. Others such as checkpoint inhibitors against PD-1 have been used in consort with the immunomodulatory drugs and are already showing activity in patients.
Overall, there is a lot of exciting research that will come down the pike in the very near future in addition to everything we have had approved, and we will have to wait and see how sustainable these remissions are going to be.
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Saad Z. Usmani, MD
There has been a lot of excitement generated over the past 3 years based on the technology of chimeric antigen receptor (CAR) T-cell therapy. These T cells are engineered to target specific antigens, and antigens that are relevant to a specific hematologic malignancy. We’ve seen data published in acute lymphoblastic leukemia and chronic lymphocytic leukemia, as well as in B-cell lymphomas, in the past. There have been data presented at ASH previously with different constructs targeting multiple myeloma.This exciting paper that we saw this year evaluated a BCMA-targeted T cell, presented by Syed Abbas Ali, MD, and colleagues from the NCI. They reported on 12 patients in an early phase 1 experience, where patients had a median of seven prior lines of therapy. The investigators saw some very robust responses, including very good partial responses or better, in those patients who had a high burden of disease — or, per the report, over 90% of bone marrow plasmacytosis.
Overall, these results are quite encouraging. In terms of safety, a cytokine storm may occur in these patients. Once we have figured out how best to move this technology forward, it will be an excellent option for relapsed/refractory disease, or even earlier lines of therapy and newly diagnosed patients. We still have to figure out what antigens and targets we may use in CAR T cells for patients with multiple myeloma, but this is definitely a good start.
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