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CAR T-cell therapy bb2121 shows promising efficacy for multiple myeloma
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ATLANTA — Anti-B-cell maturation antigen chimeric antigen receptor T-cell therapy bb2121 showed 94% overall response rates at high dose levels, according to multicenter phase 1 study results presented at the ASH Annual Meeting and Exposition.
“B-cell maturation antigen [BCMA] is a promising target for multiple myeloma, a disease that is essentially incurable and in need of new treatments desperately,” James N. Kochenderfer, MD, a physician-scientist at the Center for Cancer Research at the NCI, said during a press conference. “BCMA is a member of the TNF receptor superfamily and is express universally on multiple myeloma cells. Critically, expression is restricted to plasma cells and only a very small subset of B cells; most B cells do not express BCMA.”
A phase 1 proof-of-principle study conducted at the NCI showed the promise of anti-BCMA activity. Previous studies have evaluated T cell transduced with a gamma-retroviral vector encoding an anti-BCMA chimeric antigen receptor (CAR) with a CD28 costimulatory domain, but significant cytokine release syndrome occurred with this treatment among patients with a high disease burden.
In the current trial, Kochenderfer and colleagues evaluated bb2121 (Bluebird Bio), which utilizes a different CAR encoded by a lentiviral vector and contains the same single-chain Fv, a 4-1BB costimulatory domain, and a CD3-zeta T-cell activation domain.
“Lentiviruses seem to be better both in terms of persistence, and perhaps in the dangers that are involved. They tend to be less spread out in terms of where they integrate into the targets,” study author David Siegel, MD, chief of the division of myeloma at John Theurer Cancer Center at Hackensack Meridian Health, told HemOnc Today. “The construct includes a 4-1BB costimulatory domain and a CD3-zeta which, when turned on, make the T cell proliferate and kill cells. But you can’t have the T cells kill everything, so when it is connected to the monoclonal antibody it turns on only when it recognizes the BCMA target. This particular construct is very clean; it does not have a lot of background activation that would cause side effects.”
Researchers evaluated doses of bb2121 that escalated up in five dose levels from 50 x 106 cells to 1,200 x 106 cells; the latter group comprised an expansion cohort of 12 patients reported on separately.
Researchers collected cells from 24 patients, 21 (median age, 58 years; range, 37-74; 62% men) of whom were infused with the CAR T cells.
Forty-three percent of patients had high-risk cytogenetics.
“One very critical thing about this study was how heavily pretreated these patients were, with seven median prior lines of therapy, and a 100% rate of prior autologous stem cell transplant,” Kochenderfer said.
Prior treatments included bortezomib (Velcade, Takeda Oncology; 100% exposed; 67% refractory), carfilzomib (Kyprolis, Amgen; 91% exposed; 57% refractory), lenalidomide (Revlimid, Celgene; 100% exposed; 86% refractory), pomalidomide (Pomalyst, Celgene; 91% exposed; 71% refractory) and daratumumab (Darzalex, Janssen; 71% exposed; 48% refractory).
Medan follow-up was 35 weeks.
Seventy-one percent of patients experienced cytokine release syndrome, but only 10% were grade 3 or higher. Twenty-four percent of patients experienced neurotoxicity, but all were grade 1 or grade 2. Researchers observed no dose-limiting toxicities.
“Generally, this was a very well-tolerated product, especially in comparison with other protocols that I’ve participated in,” Kochenderfer said.
Five deaths occurred, three of which occurred due to disease progression on the lowest dose level. Two patients treated at higher doses died of cardiac arrest and myelodysplastic syndrome.
All patients at the lowest dose level experienced disease progression.
The other three dose levels — 150 x 106, 450 x 106 and 800 x 106, which researchers considered the active doses — showed more promising activity. Seventeen of 18 patients (94%) who received these active doses had an overall response, 10 of whom attained a complete remission.
The longest response currently ongoing is 68 weeks, with many other responses exceeding a year, Kochenderfer said.
Further, responses improved as late as 15 months following infusion, during which a patient transitioned from a very good partial response to complete response.
Median PFS had not been reached in the active-dose cohorts. PFS rates were 81% at 6 months and 71% at 9 months.
Median time to first response was 1.02 months (range, 0.5-3) and median time to best response was 3.74 months (range, 0.5-13.7).
“In general, these are very impressive responses compared with my previous experiences of treating multiple myeloma,” Kochenderfer said. “We have more mature data in the last 6 months that show a deepening of responses overtime.”
For instance, at analysis in May 2017, researchers observed a 27% complete response rate, 47% very good partial response rate, and a 27% partial response rate. By the data cutoff in October, these responses shifted primarily to complete responses (56%), whereas 33% had very good partial response and 6% had partial response.
“What we are seeing now is that for those patients who are responding, they are getting deeper responses as we follow them,” Siegel told HemOnc Today. “For the patients who achieve the deepest responses, a population that has been growing, fortunately we haven’t seen any of them relapsed to date.”
However, researchers can evaluate patients who have relapsed — all of whom have not had very deep responses — to identify causes for the loss of response as a predictor of benefit, such as the loss of the BCMA target.
“We haven’t yet explored this in depth, but it doesn’t seem it is universally the answer,” Siegel said. “It could be that the cells containing the virus have stopped proliferating, which we are starting to look at. Is it that they didn’t release cytokines emblematic of response? That also doesn’t seem to be uniform, so there is no signature yet for patients who have done poorly and relapsed. That will require more patients and a lot of studying.”
Due to this success and the approval of two other CAR T-cell products, it’s possible that CAR T cells will be commercially available for patients with myeloma within the next 2 years, Siegel said.
“We might be curing significant numbers of these patients, and this is the most exciting thing to come out for myeloma at this year’s ASH meeting,” he said. “But, it’s probably not the most important thing in the short term, because it’s not going to be applicable for a lot of patients. That’s the scariest thing about this — there are so many patients and doctors who are waiting for this therapy, but the reality is that it’s not going to be widely available any time in the near future.” – by Alexandra Todak
Reference:
Berdeja JG, et al. Abstract 740. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Kochenderfer reports research funding from Bluebird Bio and Kite Pharma, as well as multiple patents in the CAR field. Siegel reports consultant or speakers bureau roles with Amgen, Bristol-Myers Squibb, Celgene, Merck and Novartis. Please see the abstract for a list of all other authors’ relevant financial disclosures.
Perspective
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Renier J. Brentjens, MD, PhD
The excitement of CAR T-cell therapies to date has been limited to targeting CD19. The question to investigators in the field is, is CD19 the target that this technology will work with, or will the data that we’ve gleaned from CD19-targeted trials provide proof-of-principle that it can be expanded beyond B-cell leukemias and lymphomas to other acute hematologic malignancies, as well as hopefully in the future in solid tumor malignancies.
These less-mature data targeting BCMA in multiple myeloma are very exciting, suggesting that this is not just a proof of principle, but perhaps a more global approach to treating cancers, moving forward in the future.
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