Sending CAR T Cells After Multiple Myeloma

Preliminary results from an ongoing phase I clinical trial in China suggest that chimeric antigen receptor (CAR) T cells engineered to home in on a protein called BCMA may be a potent therapeutic option for multiple myeloma. The data were presented by Wanhong Zhao, MD, PhD, of Xi'an Jiaotong University, during the 2017 American Society of Clinical Oncology Annual Meeting in Chicago, IL.

BCMA is widely expressed on plasma cells that accumulate in the bone marrow of patients with multiple myeloma. Its role in the progression of this disease—by promoting tumor cell proliferation—was uncovered in 2004, Zhao noted, and the Chinese study evaluating LCAR-B38M (Nanjing Legend Biotech) is one of the first clinical trials of CAR T cells that target this particular biomarker.

Frank Fan, MD, PhD, Legend's chief scientific officer, pointed out that LCAR-B38M is designed to “collaboratively bind to two epitopes on BCMA instead of just one, so the target is firmly locked in and it's more difficult for the myeloma cells to escape.” Otherwise, because BCMA is sizeable, having the CAR T cells latch on via a single binding domain would be akin to “trying to hold a basketball with one hand—it's better if you use both hands,” he said.

To date, the study investigators have enrolled and treated 35 patients with relapsed/refractory multiple myeloma. Zhao highlighted 19 patients who have been followed for more than 4 months, the recommended time for full efficacy assessment by the International Myeloma Working Group. The objective response rate to LCAR-B38M was 100%: 14 patients met the criteria for a stringent complete response (sCR), 4 achieved very good partial remission (VgPR), and one had a partial response.

The sCR and VgPR benchmarks are unique to multiple myeloma, respectively defined as no detectable tumor cells in the bone marrow and no M protein—used to estimate the extent of disease—in the serum or urine, or decreases in both by more than 90%. Meanwhile, patients whose bone marrow tumor cells and M protein levels drop by about 50% are considered partial responders, Fan explained.

Zhao reported that “so far, there hasn't been a single relapse” among the patients who achieved sCR—in fact, five patients have been tracked for more than a year now and remain disease-free.

Although cytokine release syndrome (CRS) was a common side effect of treatment, it was largely transient, Zhao said, with fever and low blood pressure being the main, manageable, symptoms. Two patients whose CRS was more severe recovered after receiving the inflammation-reducing therapy tocilizumab (Actemra; Genentech). Neurologic side effects such as cerebral edema, another common complication of CAR T-cell therapy, were not observed.

Marcela Maus, MD, PhD, director of cellular immunotherapy at Massachusetts General Hospital Cancer Center in Boston, described these early results as “impressive.” She encouraged the investigators to make further details on LCAR-B38M readily accessible, noting that “before giving this [therapy] to my patients, I'd want to know more about the CAR construct, as well as the preclinical and translational data.”

To Michael Sabel, MD, of the University of Michigan in Ann Arbor, studies like this one are “moving us in a different direction from immune checkpoint inhibitors, which are fascinating but relatively nonspecific—asking one's own T cells to recognize and destroy tumor cells won't work for every cancer and in every case.” The “revolutionary science” behind genetically engineered CAR T cells allows for precision immunotherapy that should increase the number of patients who benefit, he added.

Zhao, Fan, and their colleagues will continue to evaluate LCAR-B38M; they plan to enroll a total of 100 patients from four participating hospitals in China. They also hope to launch a similar trial in the United States in 2018. –Alissa Poh