A novel “armored” chimeric antigen receptor (CAR) T cell appears to be feasible for retreatment of patients with non-Hodgkin lymphoma (NHL) who fail to respond to standard CAR T-cell therapy, according to preliminary results of a phase I trial presented at the 2024 ASCO Annual Meeting.1 The unique feature of this new CAR T cell is that it is “armored” to secrete the proinflammatory cytokine interleukin 18 (IL-18), which has been shown to enhance CAR T-cell activity in preclinical studies.
In 20 patients with NHL who previously failed to respond to standard CAR T-cell therapy and were treated with the investigational huCART19-1L18, the product was found to be safe. It yielded a 3-month overall response rate of 80%.
“While the standard anti-CD19 CAR T-cell therapies have been a great advancement for our lymphoma patients, they do not work for everyone. By the time we treat someone with commercially available, FDA-approved CAR T-cell therapies, they have already received at least one front-line treatment, and they are hopeful the CAR T-cell therapy will result in long-term remission. If the standard CAR T-cell therapy doesn’t work for them, it’s incredibly disappointing. This is the first study using armored CAR T-cell–secreting IL-18. Although it is still early, it’s gratifying to see so many patients with lymphoma responding to the novel CAR T-cell product developed here at Penn,” said lead author Jakub Svoboda, MD, of Penn Medicine’s Abramson Cancer Center.
“Another attractive feature of this new product is that manufacturing has been expedited to 3 days to limit T-cell exhaustion and shorten the time from apheresis to treatment,” he explained.
Carl June, MD
The investigational huCART19-1L18 was developed by the senior author of this abstract, Carl June, MD, a pioneer in the development of standard CAR T-cell therapy. Dr. June is the Richard W. Vague Professor in Immunotherapy in the Perelman School of Medicine at the University of Pennsylvania. “We’ve likened this CAR [huCAR19-1L18] to an armored truck or tank,” he stated in a Penn Medicine press release. The release of IL-18 benefits CAR T-cell proliferation and cytotoxicity.
Study Details and Results
“To enroll in the trial, patients [had to have relapsed or refractory disease after] prior anti-CD19 CAR T cells if indicated by FDA label. A single intravenous infusion is given following lymphodepleting chemotherapy. Bridging therapy is optional,” Dr. Svoboda explained.
As of January 2024, 20 patients with documented relapsed or refractory CD19 NHL to at least two prior lines of therapy including CAR T cells received one infusion of huCART19-1L18. Median patient age was 64; 76% were male. The median number of prior therapies was seven. The study explored five dose levels of huCART19-IL18 ranging from 3 to 300 million CAR-positive cells. A total of 10 patients received prior CD28-based CAR T-cell products (axicabtagene ciloleucel, brexucabtagene autoleucel), and 10 were given 4-1BB products (tisagenlecleucel, lisocabtagene maraleucel).
There were no study deaths reported. Adverse events were comparable to those associated with standard CAR T-cell therapy, including cytopenias and infections. Cytokine-release syndrome was reported in 62%, and immune effector cell–associated neurotoxicity syndrome was observed in 14%. About one-third of these patients received the immunosuppressive agent tocilizumab.
At 3 months, complete response was seen in 52%, and partial response was achieved in 29%. Median progression-free survival was 8.7 months. There were no obvious outcome differences based on the dose level of infused CAR T cells.
“The key takeaways are that treatment with armored CAR T cells that have the capacity to secrete a transgenic protein is feasible without unexpected toxicities. Targeting CD19 again after prior anti-CD19 CAR T-cell failure can be an effective strategy resulting in durable responses. Preliminary correlative studies suggest that IL-18 enhances CAR T-cell efficacy through intrinsic and extrinsic processes,” Dr. Svoboda told listeners.
Expert Point of View
Invited discussant of this novel chimeric antigen receptor (CAR) T-cell therapy, Peter Riedell, MD, of the University of Chicago, was optimistic about huCART19-1L18 based on this early study. From this trial, we see that “retreatment after CAR T-cell therapy failure is feasible and associated with high response rates. Importantly, CD19 remains a viable target in patients with prior CD19 CAR T exposure. This product has a manageable safety profile with durable responses to date,” he commented.
Dr. Riedell continued: “CAR T’s curative potential has transformed the treatment landscape for relapsed or refractory diffuse large B-cell lymphoma [DLBCL]. However, 60% of patients do not achieve a durable treatment response with currently available therapies. Therefore, strategies are needed to improve on the therapeutic efficacy of CAR T.”
“The huCART19-1L18 construct has unique features,” he added. “It targets CD19, incorporates rapid manufacturing, and secretes interleukin 18 (a proinflammatory cytokine) to enhance CAR T proliferation and cytotoxicity. Treatment is largely feasible though one-third of patients needed a lower dose level because of manufacturing challenges. The toxicities of cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome are in line with those of commercial products and manageable with supportive care.” However, repeat CAR T-cell infusions may not be feasible for all patients, and the appropriate selection of patients needs to be defined.
DISCLOSURE: Dr. Svoboda has served as a consultant or advisor to Adaptive Biotechnologies, AstraZeneca, Atara Biotherapeutics, Bristol Myers Squibb, CRISPR Therapeutics, Pharmacyclics, and Seagen; and has received institutional research funding from Adaptive Biotechnologies, AstraZeneca, Bristol Myers Squibb, Incyte, Kite, Merck, Pharmacyclics, Seagen, and TG Therapeutics. Dr. Riedell has served as a consultant or advisor to AbbVie, ADC Therapeutics, BeiGene, Bristol Myers Squibb/Celgene, CVS, Genentech/Roche, Genmab, Intellia Therapeutics, Kite, Nektar, Novartis, Pharmacyclics/Janssen, and Sana Biotechnology; has received travel support from Adaptive Biotechnologies; and has received institutional research funding from Bristol Myers Squibb/Celgene, Calibr, Cellectis, CRISPR Therapeutics, Fate Therapeutics, Genentech/Roche, Kite, Novartis, Tessa Therapeutics, and Xencor.
REFERENCE
1. Svoboda J, et al: Safety and efficacy of armored huCART19-IL18 in patients with relapsed/refractory lymphomas that progressed after anti-CD19 CAR T cells. 2024 ASCO Annual Meeting. Abstract 7004. Presented June 1, 2024.
