Risk stratification may be possible with JCAR017
ATLANTA—Data suggest a therapeutic window may exist for chimeric antigen receptor (CAR) T-cell expansion with JCAR017, according to a preliminary model.
In a core set of 67 patients with diffuse large B-cell lymphoma (DLBCL) who had received JCAR017 in the TRANSCEND NHL 001 trial, investigators observed that baseline high tumor burden and inflammatory biomarkers were associated with high CAR T-cell expansion and increased rates of cytokine release syndrome (CRS) and neurotoxicity.
If the model holds up, researchers say they could potentially identify patients at risk for low or high T-cell expansion levels and develop a strategy to enhance or limit the expansion.
TRANSCEND NHL 001 (NCT02631044) is a multicenter, phase 1 trial in relapsed or refractory non-Hodgkin lymphoma evaluating 2 dose levels of JCAR017, also known as lisocabtagene maraleucel, or liso-cel for short.
Liso-cel is a CD19-directed 4-1BB CAR T cell administered at precise doses of CD4+ and CD8+ CAR T cells. It had previously demonstrated high complete remission (CR) rates and low incidences of CRS and neurotoxicity.
Tanya Saddiqi, MD, of City of Hope National Medical Center in Duarte, California, presented data from the dose-finding and expansion cohorts at the 2017 ASH Annual Meeting (abstract 193*).
Study design
Patients with DLBCL after 2 lines of prior therapy or mantle cell lymphoma after 1 prior line of therapy were eligible to enroll in TRANSCEND NHL 001.
Patients with de novo DLBCL, those who transformed from follicular lymphoma, or those with high-grade B-cell lymphoma made up the pivotal or core population. All DLBCL patients enrolled on the trial comprised the full population.
Patients were screened, enrolled, and underwent apheresis. Bridging therapy was permitted while their CAR T cells were being manufactured.
Patients then had a PET scan and lab tests prior to lymphodepletion.
“This is the time point of our interest,” Dr Saddiqi said, “to see if there are any patient characteristics or biomarkers that we can identify . . . that could help us figure out which patients are at higher risk of toxicity, potentially.”
Lymphodepletion consisted of fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2 for 3 days).
Patients received the JCAR017 infusion, and, at specific time points thereafter, cytokine, pharmacokinetic (PK), and clinical lab evaluations were conducted. PK evaluation and scans were performed every 3 months for the first year after JCAR017 infusion, and safety and viral vector follow-up for 15 years.
Dose levels were 5 x 107 cells as a single or double dose (DL1S) and 1 x 108 cells as a single dose (DL2S). Dose level 2 was chosen for further study, and double dosing was discontinued.
“Double dosing was actually not pursued further,” Dr Saddiqi explained, “because it did not seem to add any benefit over single dosing.”
At the time of the presentation, 91 total patients were treated, 67 of whom were the core population.
Results
Dr Saddiqi reported that patients treated with JCAR017 achieved a relatively high best overall response rate (ORR) and high durable CR rates.
“And this seems to be especially true for the core set of patients and particularly for patients at dose level 2,” she added.
At all dose levels, the core patients had a best ORR of 84% (41/49) and a CR rate of 61% (30/49).
At follow-up of 3 months or longer, the core group had an ORR of 65% (26/40) for all dose levels, 52% (11/21) for dose level 1, and 80% (12/15) for dose level 2.
