Bispecific CAR-T induces durable responses in advanced non-Hodgkin lymphoma
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Key findings:
- The investigational CAR-T conferred a 91% overall response rate among adults with advanced non-Hodgkin lymphoma.
- Efficacy appeared durable, with median OS in the phase 1 study not yet reached.
Ten of 11 patients with relapsed or refractory B-cell lymphoma achieved objective response to an investigational dual-target chimeric antigen receptor T-cell therapy, according to study results.
The novel cellular therapy exhibited a manageable safety profile, with no reports of high-grade cytokine release syndrome or neurotoxicity, findings presented at American Association for Cancer Research Annual Meeting showed.
Multiple patients have experienced durable remissions after receiving the experimental agent. Some have lasted more than 3 years, investigators noted.
“Our bispecific [CAR T] cells have shown robust activity and overall safety [among] patients with relapsed or refractory non-Hodgkin lymphoma,” Benjamin R. Puliafito, MD, hematology-oncology fellow at UCLA David Geffen School of Medicine, said during a presentation.
Background
Nearly 50% of patients with non-Hodgkin lymphoma treated with CD190directed CAR T cells will experience disease relapse. Antigen loss and lack of T-cell persistence are two primary contributors, Puliafito said.
To address antigen loss, researchers in the lab of Yvonne Y. Chen, PhD, at University of California, Los Angeles, developed an autologous bispecific CAR T-cell therapy that targets both CD19 and CD20 on the surface of cancer cells.
The novel CAR construct (CART19/20) is processed to modify the agent’s naive/memory T-cell population to enhance CAR T-cell performance and function.
“This bispecific CAR-T is designed to mitigate antigen loss as an escape mechanism. CART19/20 is also enriched in naive memory T cells, which can prolong in vivo persistence of the T cells and increase activity,” Puliafito said. “This makes [CART19/20] ideal for achieving the goal of long-term CAR T-cell persistence and disease control.”
Methodology
Puliafito and colleagues conducted a first-in-human phase 1 dose-escalation trial to assess the safety, efficacy and persistence of CART19/20 among adults with advanced non-Hodgkin lymphoma.
The study included 11 adults with relapsed or refractory diffuse large B-cell lymphoma (n = 5) or primary mediastinal B-cell lymphoma (n = 1) who received two or more previous lines of therapy, or those with mantle cell lymphoma (n = 1) or follicular lymphoma (n = 4) who received three or more lines of therapy.
Investigators excluded individuals who received previous CAR-T.
Study participants underwent preconditioning lymphodepletion followed by infusion with CART19/20 at one of two dose levels — 50 × 106 CAR T cells, or 200 × 106 CAR T cells.
Safety — measured by incidence of treatment-related adverse events and dose-limiting toxicities within 28 days of infusion — served as the primary endpoint.
Secondary endpoints included clinical efficacy based on objective response rate, duration of response, PFS, OS and CAR T-cell persistence.
Key findings
Median follow-up was 20.7 months.
Six (60%) of 10 patients eligible for the safety analysis developed CRS. No cases of grade 2 or higher CRS occurred.
CRS onset occurred at a median 8 days (range, 5-11) after CART19/20 infusion, with a median duration of 2.5 days (range, 0-3).
Investigators observed no neurotoxicity or immune effector cell-associated neurotoxicity syndrome after treatment.
The most frequently reported treatment-related adverse events included anemia (100%), neutropenia (90%) and thrombocytopenia (90%).
Three deaths occurred during the study — one each attributed to disease progression, COVID-19 after disease progression, and hypocellular marrow.
Ten of 11 patients (91%) achieved objective response to treatment, including seven (86%) treated at the lower dose and all three patients (100%) treated at the higher dose.
Eight participants (73%) achieved complete response to therapy, including all three patients treated at the higher dose.
An additional patient with follicular lymphoma experienced disease relapse 18 months after initial CAR-T infusion. The patient received a second infusion of CART19/20 that induced a complete response that had lasted more than 6 months as of data cutoff.
Researchers reported median PFS of 18.2 months (2.6 to not estimable). Median OS had not been reached (5.7 to not estimable).
Two patients remained disease free for more than 3 years after infusion, and both still had CAR T cells in their circulating blood as of their last follow-up, Puliafito said.
Clinical implications
The results suggest that the bispecific targeting strategy employed by CART19/20 can result in high response rates while limiting incidence of high-grade treatment-related toxicities, Puliafito said.
The treatment appears to be durable, especially given the length of responses observed among patients who treated at the higher dose level, he added.
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Puliafito BR, et al. Abstract CT023. Presented at: American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando.
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