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JCAR015 Experience Informs Future CAR-T Studies

Silas Inman @silasinman
Published: Friday, Nov 10, 2017

Mark J. Gilbert, MD
Mark J. Gilbert, MD
The high rates of cerebral edema seen with JCAR015 in the phase II ROCKET trial were attributed to early and rapid chimeric antigen receptor (CAR)-modified T-cell expansion and a rise in interleukin (IL)-15 levels, a finding that could help inform future CAR T-cell usage, according to a presentation at the 32nd Annual SITC Meeting.1

Although not directly associated with the rates of cerebral edema, the CD28 costimulatory domain used for the JCAR015 construct has been associated with faster T-cell expansion compared with the 4-1BB costimulatory domain, noted Gilbert.

“There’s no evidence in the work we’ve done to say that the CAR construct contributed significantly,” he said. “We do know that if the primary issue is rapid expansion, in our hands at least, CD28 CAR T-cells do seem to expand faster than the 4-1BB versions that we’ve been studying.”

In addition to the posthoc assessment of toxicity, clinical findings from the ROCKET trial were presented in a poster session at the SITC meeting.2 Overall, the trial enrolled 38 adult patients with B-cell acute lymphoblastic leukemia at a median age of 39 years, of which 32 had morphological disease. Forty-two percent of patients were <30 years old and the median number of prior therapies was 2 (range, 1-7), with half receiving prior blinatumomab.

In those with morphological disease at baseline, the complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 47% (95% CI, 29%-65%; P <.0001). At day 28 specifically, which was the primary endpoint, the CR/CRi rate was 59% (95% CI, 41%-76%; P <.0001). For responders (n = 18), 89% tested negative for minimal residual disease. After a median follow-up of 12.9 months, the median overall survival was 8.1 months (95% CI, 5.2-not reached). The median relapse-free survival was 4.4 months (95% CI, 2.1-9.4). The median time to first CR/CRi following JCAR015 was 48 days (range, 28-88).

Severe cytokine release syndrome was experienced by 22% of patients treated with JCAR015 and severe neurotoxicity was observed in 56% of patients in the trial. The posthoc analysis showed a correlation between early peak CAR T-cell expansion and fatal neurotoxicity. Cerebral edema was not associated with prior CNS irradiation, prior intrathecal chemotherapy, prior CNS disease, prior allogeneic transplant, higher ECOG performance status, or prior blinatumomab.

References

  1. Gilbert MJ. Severe neurotoxicity in the phase 2 trial of JCAR015 in adult B-ALL (ROCKET Study): analysis of patient, protocol and product attributes. Presented at: 32nd Annual SITC Meeting, National Harbor, MD, November 8-12.
  2. DeAngelo DJ, Ghobadi A, Park JH, et al. Clinical outcomes for the phase 2, single-arm, multicenter trial of JCAR015 in adult B-ALL (ROCKET Study). Presented at: 32nd Annual SITC Meeting, National Harbor, MD, November 8-12. Poster P217.

 



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