ASH: Very first shot across the bow for CAR T cells in numerous myeloma
Key clinical point: The very first clinical trial of a CAR targeting BCMA demonstrated strong antimyeloma activity in patients with at least three prior lines of myeloma therapy.
Major finding: Myeloma in plasma cells was diminished from 90% to 0% in one patient.
Data source: Phase I investigate in twelve patients with at least three prior lines of numerous myeloma therapy.
Disclosures: Dr. Kochenderfer reported consultancy with Bluebird Bio and off-label use of cyclophosphamide and fludarabine.
References
ORLANDO – Chimeric antigen receptor (CAR) T cells targeting BCMA eradicated myeloma cells in a patient with a mighty cargo of chemotherapy-resistant numerous myeloma.
The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just three months after autologous transplant.
CD138-positive plasma cells were entirely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation antigen (BCMA), and remain undetectable fourteen weeks after infusion.
“We have demonstrated for the very first time that CAR T cells can have powerful activity against measurable numerous myeloma,” Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Md., said at the annual meeting of the American Society of Hematology.
A 2nd patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells proceed to decrease six weeks after infusion.
The two ongoing responses, however, were associated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract probe (LBA-1), Dr. Kochenderfer said.
The accomplish responder experienced cytokine release toxicities including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for nine weeks after infusion and a baseline absolute neutrophil count of less than five hundred microliters remained at that level for forty days after infusion. All symptoms resolved within two weeks, he said.
The ongoing partial responder experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia and all downright resolved.
Both patients had much higher serum levels of interleukin-6 than the other patients, he noted.
Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to patients with less than 50% bone marrow plasma cells, Dr. Kochenderfer said.
Other responses among the twelve patients treated thus far include one transient very good partial response of 8-week duration, one transient partial response lasting two weeks, and eight responses of stable disease.
While three fresh drugs (elotuzumab, daratumumab, ixazomib) were approved for the treatment of numerous myeloma in the month of November alone, this is early days for CAR T-cell therapy in numerous myeloma.
“Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukemia, and chronic lymphocytic leukemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very titillating,” session comoderator Dr. David P. Steensmaryrqzsqczvczxc of the Dana-Farber Cancer Institute in Boston, said in an interview.
Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centers are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added.
BCMA is an suitable target for CAR T cell therapy for numerous reasons, Dr. Kochenderfer said. Numerous myeloma is still an incurable disease and BCMA, a member of the tumor necrosis factor superfamily, is uniformly voiced in 60% to 70% of cases.
Preclinical studies by the team also showcase that BCMA is not detectable in normal human tissues, but is selectively voiced only in bone marrow, lymphoid organs, and organs known to have plasma cells in their lamina propria and by plasma cells and a puny fraction of B cells.
The investigators genetically modified autologous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process taking nine days from embark to finish. T cells voicing this CAR recognize BCMA with excellent specificity, Dr. Kochenderfer observed.
The twelve patients received three hundred mg/m two of cyclophosphamide and thirty mg/m two of fludarabine (Fludara) daily for three days before a single infusion of anti-BCMA CAR at dose levels of 0.Three x ten 6 to nine x ten 6 T cells/kg. All patients had at least three prior therapies and normal organ function. Five had amyloid light chain only, four had immunoglobulin gamma disease, and four patients, including the finish responder, had immunoglobulin alpha disease.
It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr. Kochenderfer said at a press briefing.