Armored cells may form ‘an effective strategy’ in lymphoma after CAR-T fails
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Key takeaways:
- Eighty percent of heavily pretreated patients had an objective response to therapy.
- No new safety signals observed using the novel CAR-T construct.
CHICAGO — Treatment of with an investigational chimeric antigen receptor T-cell therapy showed an acceptable safety profile and produced durable remissions among certain patients with non-Hodgin lymphoma.
Results from the first-in-human trial, presented at ASCO Annual Meeting, could end up influencing the expansion and effectiveness of huCART19-IL18, according to researchers.
“When using armored [chimeric antigen receptor T cells in patients with lymphoma], targeting CD19 again after prior anti-CD19 CAR failure can be an effective strategy, resulting in durable responses,” Jakub Svoboda, MD, an associate professor of medicine at Abramson Cancer Center at University of Pennsylvania, said during a presentation. “Preliminary correlative studies suggest that [interleukin-18] enhances CAR T-cell therapy efficacy through intrinsic/extrinsic mechanisms.”
Background and methodology
A percentage of patients with relapsed or refractory non-Hodgin lymphomas do not receive long-term benefit from existing anti-CD19 CAR T cells.
Researchers attempted to enhance therapeutic efficacy by engineering huCART19-IL18 — a fourth generation 4-1BB anti-CD19 construct — armored with the ability to secrete the proinflammatory cytokine interleukin-18 (IL-18).
This study served as a first-in-human trial using huCART19-IL18 for CD19-positive B-cell malignancies. Eligible patients for the non-Hodgkin lymphoma cohort included those who experienced disease relapse after treatment with CD19-directed CAR-T or those who are refractory to CD19-directed CAR T-cell therapy.
As of Jan. 20, 2024, data cutoff date, 21 patients (median age, 64 years; range, 47-74; 76% men) with CD19-positive NHL received huCART19-IL18 infusions. The heavily pretreated study population — 38% of whom had diffuse large B-cell lymphoma — received a median 7 prior lines of therapy.
Safety served as the study’s primary endpoint, with secondary endpoints that included manufacturing feasibility and efficacy measurements.
Results, next steps
Of 21 study-evaluable patients, 18 (86%) received bridging therapy.
Researchers noted manufacturing of dose level 5 (3 × 108) as not being feasible due to an inability to achieve the target dose in four of six (67%) patients assigned to that dose level.
Researchers observed no study-related deaths in 21 patients eligible for safety evaluation.
Cytokine release syndrome occurred in 13 patients (62%): grade 1 for seven (33%), grade 2 for three (14%) and grade 3 for three (14%). Additionally, immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in three patients: grade 1 for two (10%) and grade 2 for one (5%).
Researchers evaluated efficacy in 20 patients with a median follow-up of 15 months (range, 3-31); they observed a 3-month overall response rate of 81% (90% CI, 60-93), with 52% complete remission (90% CI, 30-70) and 29% partial remission (90% CI, 14-51).
Researchers also observed a median duration of response of 10 months and median PFS of 8.7 months. Median OS has not been reached.
The most common grade 3 adverse events that could possibly be attributed to huCART19-IL18 included fatigue (38%), hypotension (29%) and low fibrinogen (23%).
Study investigators did not observe a correlation between cell dose and outcome; however, both response rates and mean expansion appeared higher in patients previously exposed to CD28 CAR than among patients who had prior 4-1BB CAR.
“To our knowledge, this is the first study using an armored CAR-T product secreting IL18,” Svoboda said.
“Peak huCART19-IL18 expansion and responses could be affected by prior CAR type,” he added. “We recommend expansion of dose level 1 and dose level 2.”
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Svoboda J, et al. Abstract 7004. Presented at: ASCO Annual Meeting; May 30 – June 4, 2024; Chicago.
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