huCART19-IL8 Proves Safe and Elicits Durable Responses in CAR T–Pretreated R/R Lymphoma

Jakub Svoboda, MD

huCART19-IL8 had acceptable safety and induced durable responses in patients with lymphoma who were refractory or relapsed following second-generation CD19-targeted CAR T-cell therapies, according to data from a first-in-human phase 1 trial (NCT04684563) presented at the 17th International Conference on Malignant Lymphoma.¹

No study-related deaths occurred with the fourth-generation CAR T-cell therapy, and no new safety signals were observed with IL-18. huCART19-IL18 elicited an objective response rate of 82% (95% CI, 53%-97%) in this population (n = 11), which included a complete response rate of 55% and a partial response rate of 27%. Eighteen percent of patients experienced disease progression. The median duration of response was not yet reached (NR; range, 6.6-NR).

Moreover, the 12-month progression-free survival rate was 54% (95% CI, 15%-81%). At a median follow-up of 12 months (range, 3-20), the 12-month overall survival (OS) rate was 100%.

“The fourth-generation armored CAR T-cell therapy was feasible in [patients with] lymphoma with a manageable toxicity and adequate expansion,” Jakub Svoboda, MD, lead study author and associate professor of medicine at the Hospital of the University of Pennsylvania, said in a plenary presentation of the data. “We’ve seen some really durable responses in patients who were previously refractory to second-generation CAR T [products]. We have done multiple correlative studies. We’re interested in the impact of the prior CAR T on retreatment in general, which I think is important for this field.”

Significant progress has been made with CAR T-cell therapy in non-Hodgkin lymphoma (NHL) since axicabtagene ciloleucel (Yescarta) was first approved by the FDA for use in patients with large B-cell lymphoma in the third-line and beyond setting, Svoboda said. Three other products have also received regulatory approvals over the years spanning disease subsets and settings, including tisagenlecleucel (Kymriah; tisa-cel), lisocabtagene maraleucel (Breyanzi; liso-cel), and brexucabtagene autoleucel (Tecartus; brexu-cel).

“We also now have long-term follow-up on some of the patients from early trials, including the early trials [done] at Penn,” Svoboda noted. “We see consistently that there’s maybe 30% or 40% of patients who derive durable remissions, and possibly cures, but that leaves 70% or 60% of patients who will not be cured with this approach. Therefore, we need better treatments.”

It is known that those who progress on second-generation products tend to have poor outcomes. Several real-world studies, including the DESCAR-T analysis, have indicated that these patients have low response rates to subsequent therapy and a short median OS after first progression.² As such, several efforts are underway to improve this modality.

“Multiple groups are working on fourth-generation, or armored CAR Ts, which are really CAR T cells that have the specificity to target tumors through the chimeric antigen receptor, but they also have the ability to express transgenic protein and deliver it directly to the tumor site,” Svoboda explained.

huCART19-IL18 is an autologous CAR T, which has a 4-1BB co-stimulatory domain and its manufactured by transduction via a lentiviral vector to express from the same transcript the CD19 CAR and the human interleukin-18 (IL-18). Moreover, the single-chain variable fragment is humanized to reduce the risk of anti-murine immune responses. This product also has expedited 3-day manufacturing which could potentially result in stronger potency. In comparison, traditional CAR T-cell products take about 10 days to manufacture, according to Svoboda.

Svoboda explained that IL-18 was selected because the pro-inflammatory cytokine is known to stimulate interferon gamma production; it is also capable of strengthening the cytolytic potential of the T cells. “We felt it was fairly safe because there have been studies with recombinant human IL-18 done in various settings, including lymphoma,” he added. “We saw some responses, but the most important factor is that no maximum tolerated dose was defined.”

In mice models, huCART19-IL18 was found to have enhanced in vivo expansion and persistence vs huCART19, as well as better antitumor activity in the form of prolonged survival.

To enroll to the NHL cohort of the first-in-human trial, patients needed to be at least 18 years of age, have documented CD19 expression on malignant cells, an ECOG performance status of 0 or 1, and have received at least 2 previous therapies. They also must have relapsed after or been refractory to previous CAR T-cell therapy. Patients were excluded if they had central nervous system disease or active autoimmune disease in need of systemic immunosuppression.

The trial used a modified Bayesian optimal interval dose titration design. After the screening period, those enrolled to the trial underwent apheresis. Subsequent bridging therapy was permitted. After a safety visit, patients were assigned to their dose level.

“We started at a dose level of 3 x 106 CAR-positive cells without lymphodepleting chemotherapy [DL1A]. We were very cautious; we didn’t know what would happen to the patient who would get this product for the first time, and because he did well, we used lymphodepleting chemotherapy for subsequent dose levels,” Svoboda said.

Lymphodepletion chemotherapy was comprised of cyclophosphamide at 250 mg/m2 and fludarabine at 25 mg/m2 for 3 days or bendamustine (Bendeka) at 90 mg/m2 for 2 days. Patients then received a single intravenous infusion of huCART19-IL18. Examined dose levels include level 1B (DL1B) at 3 x 106 cells, level 2 (DL2) at 7 x 106 cells, and level 3 (DL3) at 3 x 107 cells.

“Currently, we are on dose level 4 of 7 x 107 CAR-positive cells.” Dose level 5 is 3 x 108 cells.

Safety served as the primary end point of the trial, and key secondary end points included feasibility, early efficacy, and correlative analysis.

At the data cutoff date of March 3, 2023, 18 patients underwent apheresis, and 16 patients were enrolled to the study. Manufacturing was completed for 15 patients and 13 patients were infused with the CAR T-cell product. Eleven patients were evaluable for efficacy and 12 were evaluable for safety.

In the 13 patients who were infused with huCART18-IL18, the median age was 65 years (range, 53-74). Most patients (38%) had diffuse large B-cell lymphoma, followed by follicular lymphoma (31%), mantle cell lymphoma (15%), T-cell/histiocyte-rich large B-cell lymphoma (8%), and high-grade B-cell lymphoma (8%). Patients received a median of 8 prior lines of therapy, with a range of 4 to 14 lines.

Most patients (92%) previously received a CD19-targeted CAR T-cell therapy; 6 patients received axi-cel, 5 received tisa-cel, 1 received liso-cel, and 1 received brexu-cel. Thirty-three percent of patients were primary refractory. Twenty-three percent of patients received a bispecific antibody, and just under half (42%) of patients had tumors harboring a P53 mutation.

Eighty-five percent of the 13 patients received bridging therapy, most with either polatuzumab vedotin-piiq (Polivy)–based therapy or BTK inhibitors. All patients except for the first patient received lymphodepleting chemotherapy, “and as usual, at Penn, we used bendamustine in the majority of patients,” Svoboda noted. One patient received DL1A, 2 received DL1B, 2 received DL2, 6 received DL3, and 1 received DL4. Two DL3 and 1 DL4 products did not meet the target dose but exceeded minimum infusible dose.

Regarding safety, the most common adverse effects (AEs) thought to be potentially related to the treatment included cytokine release syndrome (CRS; n = 7), followed by fatigue (n = 6), myalgia (n = 4), hypotension (n = 3), infections and infestations beyond COVID-19 (n = 3), increased alanine aminotransferase (n = 3), increased aspartate aminotransferase (n = 3), decreased neutrophil count (n = 3), decreased white blood cell count (n = 3), hypoalbuminemia (n = 2), headache (n = 2), nervous system disorders (n = 2), hypoxia (n = 2), hypogammaglobinemia (n = 2), decreased fibrinogen (n = 2), and increased INR (n = 2).

Other potential related AEs included anorexia, hyponatremia, generalized muscle weakness, pulmonary edema, atrial fibrillation, chills, increased alkaline phosphatase, increased creatinine, decreased platelet count, and weight loss (n = 1 each).

Rates of CRS and immune effector cell–associated neurotoxicity syndrome (ICANS) were comparable to what has been reported with second-generation CAR T-cell products, according to Svoboda.

Any-grade CRS was observed in 58% of patients; 33% had grade 1 CRS, 17% had grade 2 CRS, and 8% had grade 3 CRS. Seventeen percent of patients had any-grade ICANS, with 8% of patients having a grade 1 event and 8% having a grade 2 event.

Non-hematologic toxicities that were related to treatment and were grade 3 or higher included infections (17%), hypotension (17%), hypoxia (17%), and pulmonary edema (8%).

“We feel that the product is expanding well. We’ve seen high peak huCART19-IL18 expansion, even at the low cell dose levels infused. We see long-term persistence. Some of the early patients continue to have detectable product in their blood,” Svoboda noted. “Interestingly, we haven’t seen any clear correlation of expansion and cell dose so we’re thinking about that. One of the things that stood out to us is that patients who had prior CD28-based products, like brexu-cel, had a much better expansion compared to the patients who had 4-1BB products previously.”

Svoboda added that numbers are small so additional analysis is needed.

Enrollment to 3 cohorts—NHL, chronic lymphocytic leukemia, and acute lymphoblastic leukemia—is ongoing.

Editor’s Note: Dr Svoboda disclosed serving in a consultancy role for Seagen, Pharmacyclics, Incyte, Genmab, Bristol Myers Squibb, Atara, AstraZeneca, Adaptive, and ADCT. Research funding was received by TG, Seagen, Pharmacyclics, Merck, Incyte, Bristol Myers Squibb, AstraZeneca, and Adaptive.

Reference

Svoboda J, Landsburg DL, Chong EA, et al. Fourth generation huCART19-IL18 produces durable responses in lymphoma patients previously relapsed/refractory to anti-CD19 CAR T-cell therapy. Hematol Oncol. 2023;41(suppl 2):35-37. doi:10.1002/hon.3163_6