James N. Kochenderfer, MD

Genetically engineered T cells eradicated multiple myeloma cells in a patient with advanced disease, suggesting the potential to cure the condition, a National Cancer Institute (NCI) investigator reported at the 2015 ASH Annual Meeting.

The patient initially had more than 90% multiple myeloma cells in his bone marrow that was reduced to 0% one month after an infusion of allogeneic T cells modified by an anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR), according to lead investigator James N. Kochenderfer, MD.

Although he cautioned that the research is in its early stages, the findings show the promise that gene therapy holds for patients with the malignancy.

“This is the first example of CAR T-cells, any kind of T-cell therapy, completely eradicating or decreasing measurable multiple myeloma,” said Kochenderfer, of the NCI’s Experimental Transplantation and Immunology Branch. “For the first time, we have demonstrated that CAR T cells can eradicate large burdens of multiple myeloma.”

“We saw the patient just this week, and he is still in complete stringent remission, which is ongoing for 14 weeks,” noted Kochenderfer. “This treatment can work in at least one patient who had chemorefractory myeloma.”

The patient was among 12 people treated with the CAR-BCMA therapy. Of the other participants, 1 achieved a very good partial response, 2 others had partial responses, and the remaining 8 had stable disease.

Kochenderfer’s study comes at a time of rapid expansion of therapeutic options for patients with multiple myeloma. The FDA approved 3 new therapies during a 15-day period in November including elotuzumab and daratumumab, the first monoclonal antibodies ever available for the disease, and ixazomib, the first oral proteasome inhibitor.

In remarks during a press briefing, Kochenderfer said there remains a need for therapies that would result in durable remissions. Currently, no cure exists for myeloma.

“My goal for the CAR T cells for myeloma is to have something that will give stringent complete remissions that last long term,” he said. “It would be something that would be given after many other treatments are administered. It’s not a frontline therapy in the near future. It hopefully would be more efficacious than monoclonal antibodies.”

Kochenderfer said his goal also is to try to reduce the toxicity of CAR therapy without reducing its efficacy.

The patient who had the best response to the CAR-BCMA therapy also experienced the most toxicities. He initially had severe cytokine release syndrome following infusion of the therapy. The patient remained platelet-transfusion dependent for 9 weeks before attaining an ongoing stringent complete remission.

The toxicities that preceded the stringent complete response included fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. Each of the symptoms/signs resolved within 2 weeks, said Kochenderfer. The patient had an absolute neutrophil count less than 500 microliters at the time of CAR-BCMA infusion and remained at that level for 40 days after infusion.

Despite the toxicities, the response to the therapy was rapid and dramatic. The patient had highly elevated IgA (>3000 mg/dL) prior to treatment. The level dropped by more than 30% within a few days after infusion and reached undetectable levels by day 20.

“His serum and urine immunofixation tests have remained negative,” Kochenderfer said. “His flow cytometry assessment of myeloma became negative and remains negative 3 months after treatment.”

Analysis of bone marrow before and after treatment showed disappearance of CD138-positive cells following infusion of the CAR-BCMA T cells.

“After treatment, the CD138-positive plasma cells were completely absent. I think that was the most important finding of this study,” said Kochenderfer. “We completely eradicated the malignant plasma cells in this patient, and they continue to be absent 14 weeks after treatment.”

“Why did the treatment eradicate malignant cells in this patient?” he asked. “That’s what we would like to know, and we are still conducting studies to see whether we can find the answer.”

The patients treated thus far included 5 with amyloid light chain only, 3 patients with IgA disease, and 4 with IgG disease. They received CAR-BCMA doses of 0.3 x 10(6) to 9 x 10(6) T-cells/kg.

The patient who achieved the stringent complete response was one of two who received the highest dose. The other patient achieved a partial response.

The rationale for using BCMA as part of the CAR therapy stems from its role as a member of the tumor necrosis factor superfamily that is expressed in 60% to 70% of multiple myeloma cases, said Kochenderfer.

Studies involving quantitative PCR have shown BCMA only in bone marrow, lymphoid organs, and tissue known to have plasma cells in the lamina propria. Immunohistochemical studies have shown that BCMA is expressed only by plasma cells and a small fraction of B cells, Kochenderfer continued.

Given the current understanding of BCMA, investigators sought to develop a therapeutic approach to myeloma, synthesizing DNA that encodes an anti-BCMA CAR, ligating it into a replication-incompetent retrovirus, and transduced it into T-cells. Tests showed that T cells expressing the CAR have high specificity for recognizing BCMA.

Ali SA, Shi V, Wang M, et al. Remissions of Multiple Myeloma during a First-in-Humans Clinical Trial of T Cells Expressing an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. LBA-1.

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