huCART19-IL18 Is Tolerable, Induces Responses in CAR T-Cell–Pretreated R/R Lymphoma

Jakub Svoboda, MD

Treatment with armored huCART19-IL18 was feasible, well tolerated, and elicited durable responses in patients with relapsed/refractory lymphomas who had progressed after CD19-directed CAR T-cell therapy, according to findings from a first-in-human phase 1 trial (NCT04684563) presented at the 2024 ASCO Annual Meeting.¹

The most common adverse effects (AEs) seen in over 10% of patients were decreased neutrophil counts, decreased white blood cell levels, cytokine release syndrome (CRS), decreased platelet counts, hypoalbuminemia, hypocalcemia, anemia, fatigue, increased aspartate aminotransferase (AST), hypotension, hypophosphatemia, increased alanine aminotransferase, COVID-19, hypoxia, decreased fibrinogen, hyponatremia, hypokalemia, weight loss, increased international normalized ratio, increased creatinine, increased alkaline phosphatase, other nervous system disorders, pain in extremity, dehydration, immune system disorders, nausea, constipation, abdominal pain, and atrial fibrillation. Treatment-related nonhematologic AEs of grade 3 or higher included hypotension (24%), CRS (14%), COVID-19 (14%), hypoxia (14%), increased AST (5%), decreased fibrinogen (5%), and pulmonary edema (5%).

No unexpected toxicities or study-related deaths occurred. One patient reported a dose-limiting toxicity (transient grade 3 pulmonary edema at dose level 3), and 12 patients experienced severe AEs.

“When used in lymphoma, like in our project, targeting CD19 again after patients progressed following prior anti-CD19 CAR T-cell therapies can be a feasible and effective strategy, and we’ve seen durable remissions now going for 2-plus years in patients who were clearly refractory to the currently available second-generation CAR T-cell therapies,” Jakub Svoboda, MD, said in the presentation.

Dr Svoboda is an associate professor of medicine (hematology-oncology) at the Hospital of the University of Pennsylvania in Philadelphia.

Patients who progress after treatment with currently available CD19-directed CAR T-cell therapies typically experience poor outcomes. For instance, in a cohort of 135 patients with large B-cell lymphoma (LBCL) who received subsequent anticancer therapy following progression on CD19-targeted CAR T-cell therapy, the median overall survival (OS) was 8.5 months (95% CI, 5.6-11.0).²

“This particular study…had this unique cohort of 55 patients or so who had biopsies following CD19[-directed CAR T-cell therapy progression], and [over] 94% were positive for CD19, so the target is there,” Svoboda noted.¹

huCART19-IL18 is an autologous, fourth-generation, 4-1BB–based CAR T-cell therapy targeting CD19. This therapy is a humanized version of scFv and has an expedited 3-day manufacturing period. Moreover, huCART19-IL18 is armored with the capacity to secrete interleukin 18 (IL18), which has been shown to enhance cytolytic potential, modulate the tumor microenvironment, and have an anti-lymphoma effect in preclinical studies.

The non-Hodgkin lymphoma cohort of this trial enrolled patients at least 18 years of age with documented CD19-positive disease who had received at least 2 prior lines of therapy, had relapsed on or were refractory to prior CAR T-cell therapy, and had an ECOG performance status of 0 or 1. Patients were excluded from the study if they had active central nervous system disease or active autoimmune disease.

On day 0, huCART19-IL18 infusion was administered at 1 of 7 dose levels. At dose levels –1 (7 x 105 cells) and 1A (3 x 106 cells), which was determined to be the starting dose, patients did not receive lymphodepleting chemotherapy. At dose levels 1B, 2, 3, 4, and 5, patients received huCART19-IL18 at 3 x 106, 7 x 106, 3 x 107, 7 x 107, and 3 x 108 cells, respectively. These patients received lymphodepleting chemotherapy prior to CAR T-cell infusion, which consisted of cyclophosphamide at 250 mg/m2 plus fludarabine at 25 mg/m2 for 3 days or bendamustine at 90 mg/m2 for 2 days. The last lymphodepletion dose occurred on day –2.

The primary objective of the trial was safety. Secondary objectives included manufacturing feasibility, preliminary efficacy, and findings from correlative studies.

Twenty-eight patients consented to treatment, 22 of whom were eligible for treatment and 21 of whom received huCART19-IL18 infusion. Retreatment was permitted in patients who did not achieve an initial complete response (CR) with huCART19-IL18. Five patients received retreatment.

At the time of infusion, patients had a median age of 64 years (range, 59-68), and most (76%) were male. Thirty-eight percent, 29%, 14%, 9.5%, 4.8%, and 4.8% of patients had diffuse LBCL (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), transformed FL, high-grade B-cell lymphoma, and T-cell/histiocyte-rich B-cell lymphoma, respectively. Patients had received a median of 7 prior lines of therapy (interquartile range [IQR], 6-9).

One patient did not receive a prior second-generation CAR T-cell therapy because commercial product manufacturing failed twice. Among the 20 patients who received prior CAR T-cell therapy, 50% received a CD28-based product (axicabtagene ciloleucel [Yescarta], 38%; brexucabtagene autoleucel [Tecartus], 9.5%), and 50% received a 4-1BB–based product (tisagenlecleucel [Kymriah], 38%; lisocabtagene maraleucel [Breyanzi], 9.5%). Thirty-five percent of patients had progressive disease as their best response to prior CAR T-cell therapy, and 20% of patients had CRS with prior second-generation CAR T-cell therapy. The median time from prior CAR T-cell therapy to apheresis was 16 months (range, 3-56).

In total, 3, 1, 7, 5, and 6 patients were assigned to dose levels 1, 2, 3, 4, and 5, respectively; 3, 4, 6, 5, and 2 patients were infused at those respective dose levels. Higher dose levels corresponded with an increasing number of patients who did not meet the target dose. A total of 8 patients did not meet the target dose, 7 of whom underwent infusion at lower doses. The median time from apheresis to huCART19-IL18 infusion was 67 days (range, 26-137).

Regarding toxicities of special interest, any-grade CRS occurred in 62% of patients (grade 1, 33%; grade 2, 14%; grade 3, 14%). The median onset to CRS was 4 days (range, 1-11), and the median duration was 7 days (range, 3-12). Any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 14% of patients (grade 1, 10%; grade 2, 5%; grade 3, 0%). The median onset to ICANS was 8 days (range, 7-20), and the median duration was 7 days (range, 3-7). In total, 33% and 24% of patients received tocilizumab (Actemra) and steroids, respectively, as supportive care; 10% received supportive care in the intensive care unit.

At 3 months, the overall response rate was 81% (90% CI, 62%-93%), including a CR rate of 52% (90% CI, 33%-71%) and a partial response (PR) rate of 29% (90% CI, 13%-49%). At a median follow-up of 17.5 months (range, 3-34), the median duration of response was 9.6 months (90% CI, 5.5-not reached [NR]). Among patients with DLBCL/transformed FL, 30%, 20%, and 50% had progressive metabolic disease, partial metabolic response, and complete metabolic response, respectively. Among patients with FL and MCL, the partial and complete metabolic response rates were 33% and 67%, respectively.

The median progression-free survival was 8.7 months (90% CI, 5.4-NR), and the median OS was NR (90% CI, NR-NR).

Investigators observed no clear association between efficacy and safety outcomes and huCART19-IL18 dose level. At dose levels 1, 2, 3, 4, and 5, the respective CR rates were 66%, 50%, 50%, 60%, and 50%. PR rates were 34%, 25%, 16%, 20%, and 50%, respectively.

However, prior receipt of CAR T-cell therapy was shown to affect huCART19-IL18 expansion and outcomes. Patients who received 4-1BB–based agents had a median peak expansion of 314 cells (IQR, 223-2693), whereas those who received CD28–based agents had a median peak expansion of 13,692 cells (IQR, 3270-25,398; P = .011). Among patients who received 4-1BB–based agents, the respective CR and PR rates were 30% and 30%. Among patients who received CD28–based agents, these respective rates were 80% and 20%.

“What’s still not ready for prime time but very exciting is that we have access to day 14 biopsies and a lot of correlative samples. We hope that we’ll be able to show how the IL18 may be affecting and enhancing the CAR T [cells], and these types of studies may actually allow us to use some of these findings in other settings, maybe perhaps in even solid tumors,” Svoboda emphasized.

The investigators recommend huCART19-IL18 dose levels of 3 x 106 or 7 x 106 for dose expansion.

Disclosures: Dr Svoboda reports consulting or advisory roles with Adaptive Biotechnologies, AstraZeneca, Atara Biotherapeutics, Bristol-Myers Squibb, CRISP Therapeutics, Pharmacyclics, and Seagen; he has received institutional research funding from Adaptive Biotechnologies, AstraZeneca, Bristol-Myers Squibb, Incyte, Kite, Merck, Pharmacyclics, Seagen, and TG Therapeutics.

References

1. Svoboda J, Landsburg DJ, Nasta SD, et al. Safety and efficacy of armored huCART19-IL18 in patients with relapsed/refractory lymphomas that progressed after anti-CD19 CAR T cells. J Clin Oncol. 2024;42(suppl 16):7004. doi:10.1200/JCO.2024.41.16_supple.7004
2. Alarcon Tomas A, Fein JA, et al. Outcomes of first therapy after CD19-CAR-T treatment failure in large B-cell lymphoma. Leukemia. 2023;37(1):154-163. doi:10.1038/s41375-022-01739-2