Dual target CAR T-cell therapy effective, durable, less toxic in lymphoma
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A novel CAR T-cell therapy targeting both CD19 and CD22 showed less toxicities than current CAR T-cell therapies while producing complete response with accepted regimens, according to a study presented at ASCO2020 Virtual Scientific Program.
“Although follow-up is short, this appears different from other CAR T-cell studies where there appears to be around a 25% relapse rate. This improved duration of response may be due to the dual targeting of CD19 and CD22 achieved with AUTO3 and the use of pembrolizumab to prevent early T-cell exhaustion,” Aravind Ramakrishnan, MD, from the Sarah Cannon Cell Therapy Program at St. David’s South Austin Medical Center, said in his recorded presentation.
Dual target: CD19/CD22
Ramakrishnan said while currently available CD19 CAR T cells are highly active in relapsed lymphoma, durable complete response only occurs in 29% to 37% of patients treated with them. He said PD-L1 upregulation and subsequent T-cell exhaustion as well as CD19 antigen loss stand as two potential mechanisms for this relapse. The ALEXANDER study looked at AUTO3 (Autolus Limited) CAR T cells, which targets both CD19 and CD22 simultaneously, used with pembrolizumab (Keytruda, Merck) in the pre-conditioning regimen to prevent CAR T-cell exhaustion.
“The manufacturing process for AUTO3 is closed, very robust and scalable with a 100% success rate,” Ramakrishnan said.
The phase 1/2 study used a rolling design, beginning dose escalation at 50 million CAR T cells with fludarabine and Cytoxan preconditioning. Patients received pembrolizumab starting at day 14 for three doses to test safety. Ramakrishnan said dose escalation completed at 450 million dose and the recommended dose in the phase 2 extension ranges from 150 to 450 million.
Phase 1 primary endpoints were incidence of grade 3 to 5 toxicity within 75 days of AUTO3 infusion and frequency of dose-limiting toxicities. Phase 2 primary endpoints were best overall response post-AUTO3 infusion and incidence of grade 3 to 5 toxicities within 75 days.
In this presentation, Ramakrishnan focused on the 23 patients who were at the evaluation point.
“The majority had advanced stage diffuse large B-cell lymphoma and this was a very high-risk population,” he said. “The majority of patients had high IPI scores, stage 4 disease and had at least three prior lines of therapy.”
Toxicities
Ramakrishnan reported that most toxicities greater than grade 3 were hematologic but there were no dose-limiting toxicities or AUTO3-related deaths reported. Most cytokine release syndrome (CRS) was grade 1 and “easily managed,” he said. Time-to-CRS was 7 days and median duration was 5 days.
“This suggests an excellent safety profile and, in our experience, appears better than the CRS rates seen with the currently approved CAR T-cell products.”
Of all the cohorts, there was one reported case of grade 3 neurotoxicity, which occurred in the 50-million cohort without pembrolizumab, he added.
“Importantly, at the 150- and 450-million cohorts and the cohorts including pembrolizumab, which is the recommended phase 2 dose range, there has been no evidence of neurotoxicity,” Ramakrishnan said. He proposed one reason for the low rates of CRS and neurotoxicity is the reported lower levels of cytokine production when compared with other trials.
Efficacy
Complete response has been seen in all doses tested, including the lowest dose, Ramakrishnan said.
The overall response rate at all dose levels is 65% with the complete response rate of 48%,” he said. “At doses greater than 150 million, the overall response rate is 69% with a complete response rate of 56%. For those patients who received the recommended phase 2 dose of greater than 150 million and pembrolizumab on day minus 1, the complete response rate is 63%, which appears very promising.”
Out of the 23 patients presented, 11 achieved complete remission, Ramakrishnan reported. All patients treated with pembrolizumab and all patients receiving at least 150 million cells remain in complete remission.
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Osborne W, et al. Abstract 8001. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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