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Chimeric antigen receptor T cells produce robust responses in relapsed, refractory CLL
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CHICAGO — Autologous T cells genetically modified to express chimeric antigen receptors targeting CD19 induced strong, durable responses in patients with relapsed or refractory chronic lymphocytic leukemia, according to phase 2 study results presented at the ASCO Annual Meeting.
The researchers identified a dose of 5 x 108 as the optimal dose for this treatment regimen.
David Porter
The efficacy of CD19–targeted chimeric antigen receptor (CAR) T cells has been demonstrated in CLL and other malignancies; however, the optimal dose for treatment remained unknown.
“Typically, a patient will receive lympho-depleting chemotherapy appropriate for their underlying disease, and then receive an infusion of the modified T cells,” David Porter, MD, Jodi Fisher Horowitz professor in leukemia care excellence and director of blood and marrow transplantation at Penn Medicine’s Abramson Cancer Center, said during his presentation. “This can be done completely in the outpatient setting, assuming that the patient is stable enough. We concluded from our initial pilot study that [CAR T cells] can eradicate — and I do mean eradicate — relapsed and refractory CLL.”
Porter and colleagues sought to determine the optimal dosing for this regimen.
The first phase of the study included 28 patients, all of whom underwent more than two prior therapy lines, and relapsed or were refractory within 2 years of second-line therapy.
Porter and colleagues randomly assigned patients to a high-dose (5 x 108) or low-dose (5 x 107) CAR T-cell regimen.
Twenty-four patients were evaluable for response (high dose, n = 11; low dose, n = 13). Six patients treated on the high-dose regimen responded, compared with four patients on the low-dose regimen. Both arms had similar toxicity profiles.
Porter and colleagues proceeded to the second phase of the study with 5 x 108 chosen as the optimal dose.
A total of 17 patients have been treated at the optimal cell dose (median age, 59 years; range, 48-75; median prior therapies, n = 3). Forty-seven percent of patients had p53 deletion, and 35% progressed after treatment with ibrutinib (Imbruvica; Janssen, Pharmacyclics).
Median follow-up at the time of reporting was 9 months (range, 1-34).
The researchers have observed nine responses to date (complete, n = 6; partial, n = 3), for an overall response rate of 53%.
After a median follow-up of 26 months (range, 5-34), five patients remain in complete response; the other patient progressed.
Typical prognostic factors — including age, prior therapy or p53 mutation status — did not appear to influence response.
CAR T-cell expansion correlated with response. The researchers observed robust in-vivo expansion in all responding patients, with a median peak of 14.7% of CD3–positive cells. By contrast, the median peak was 0.35% among nonresponders.
The researchers evaluated all patients for response. Nineteen patients developed delayed cytokine release syndrome ( grade 3, n = 7). However, fifteen patients did not require intervention, and the remaining four patients were successfully reversed after treatment with tocilizumab (Actemra, Genentech).
Dose levels did not appear associated with development or severity of cytokine release syndrome.
“We have not identified a dose–toxicity relationship, and I think it has more to do with how many cells the patients end up with than how many cells we infuse,” Porter said. “CAR T cells induce sustained remissions for some patients with advanced CLL. It is a promising therapy and certainly deserves further study in the relapsed and refractory setting.” – by Cameron Kelsall
Reference:
Porter D, et al. Abstract 3009. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: Porter reports research funding and honoraria from and consultant roles with Novartis and Ocata Therapeutics. He also reports a patent agreement with Novartis, travel expenses from Immunovative Therapies, and that an immediate family member is employed by Genentech. Please see the abstract for a list of all other researchers’ relevant financial disclosures.