Fully human BCMA CAR T treatment effective, persistent in myeloma
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ORLANDO – A novel CAR T-cell treatment derived from human components showed 100% overall response and enduring activity in a small study presented at the ASH Annual Meeting and Exposition.
“Results of the CT103 are very promising. It is a safe and highly effective therapy for heavily pretreated refractory or relapsed multiple myeloma patients. Toxicity was general manageable, and no neurotoxicity observed,” Jue Wang, MD, of the department of hematology at Tongji Hospital of Tongji Medical College in China, said during his presentation. “It has an impressive efficacy with an overall response rate of 100% and over 70% of evaluated patients achieved the best response of [complete response] or [stringent complete response] and the rapid response of one-third of patients achieving [complete response] or [stringent complete response] within 2 weeks post infusion.”
Wang presented data on CT103A, a second-generation CAR design with a unique fully human scFv sequence and a 4-1BB costimulatory and CD3-zeta domain encoded within the lentiviral vector, tested in 18 study participants.
The participants underwent a three-plus-three dose escalation treatment after standard lymphodepletion. They included people refractory to proteasome inhibitor, who failed at least three lines of prior therapy, had an ECOG score less than 2 and were BCMA-positive, Wang said. Four of the participants previously received a murine-based CAR T-cell therapy but continued to progress.
Because the primary objective was safety and tolerability, Wang reported that while 94% of the participants experienced cytokine release syndrome, there was no neurological toxicity observed and all adverse events were typical and managed with traditional methods.
“We did experience a grade 4 CRS at dose level 6 and we consider it a dose-limiting toxicity event,” Wang said.
All 18 patients responded to CT103A with 88.2% achieving very good partial response or better and 70% achieving stringent complete response or complete response. Of the four who previously underwent CAR T-cell therapy, three achieved stringent complete response and one achieved very good partial response.
Wang said all evaluated patients tested negative for measurable residual disease at some point within the 100 days post-infusion and a third had stringent complete response within 2 weeks.
“In 10 of 14 patients with a follow up time of greater than 100 days, current results show that CT103A remains at significant levels indicating that the cells have a strong persistence in vivo,” he said. “In the remaining 4 patients, copies dropped below the threshold. Two patients relapsed from their best response achieved.”
With the one dose-limiting activity and stratification of analysis by dose level, Wang also presented data to show that the lowest dose given remains effective.
“At the lowest dosage of CAR T cells, we can still see a similar pattern of expansion and persistence. By comparing the CRS and response rate between 1 million cells and the higher dosage groups, it is obvious there are less severe CRS at the lowest level, but the effect seems comparable. Among these 9 patients, CT103A appears to remain effective with an improved safety profile,” he said. “What may be the most compelling are the results of the lowest dosage level with CT103A remaining active and effective in these patients with minimal side effects.”
In the four patients who previously received a murine CAR T-cell therapy, Wang showed there was little residual effect, suggesting the CT103A dosing was the most impactful.
“BCMA is an ideal target for multiple myeloma. However, even with the encouraging results and high response rates of previous anti-BCMA CAR T trials, more than half of the patients treated with this therapy will have their disease come back within a year,” Wang said. “This raises the big question: What are the mechanisms of relapse and how can we overcome this? There may be several answers to that question, but we chose to focus on the topic of host anti-CAR immunity because there are lines of evidence that non-human scFvs may induce cellular and humoral immune responses which may result in the inability of certain CAR T cells to survive in vivo. Utilizing a fully human BCMA CAR T may be the correct answer.” – by Katrina Altersitz
Reference: Wang J, et al. Abstract 582. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosure: Wang reports no relevant financial disclosures.