Mixed Safety Data Reported With JCAR021 in Relapsed/Refractory LBCL

Nicolas Gazeau, MD

JCAR021, a fully-human scFv CD19-targeted chimeric antigen receptor (CAR) T-cell therapy, showed durable responses in patients with relapsed or refractory large B-cell lymphoma (LBCL). However, there was a high rate of neurotoxicity when administered at a dose of 7 x 106 cells/kg, according to data from a phase 1/2 trial (NCT03103971) presented during the 2023 Transplantation & Cellular Therapy Meetings.¹

In those who received this highest dose (n = 15), JCAR021 elicited an overall response rate (ORR) of 87%, which comprised a complete response (CR) rate of 67% and a partial response (PR) rate of 20%. In this group, the 12-month progression-free survival (PFS) rate was 47%, and the 12-month overall survival (OS) rate was 86%. Notably, in those who achieved a CR with JCAR021, the 12-month PFS rate was 63%; in those who did not have a CR, this rate was 33%.

In the dose-limiting toxicity (DLT)–evaluable set (n = 22), the rate of any-grade cytokine release syndrome (CRS) was 77%; these effects were grade 3 or higher in 4% of patients. Any-grade neurotoxicity was experienced by 72% of patients, and 45% had effects that were grade 3 or higher. All but one case of neurotoxicity fully resolved at day 28. The case that did not resolve was a DLT that occurred in a patient who received JCAR021 at the highest dose and they had grade 4 neurotoxicity with spinal cord edema and paraplegia.

“We are now investigating JCAR021 in patients already treated with CD19[-targeted] CAR T-cell [therapy],” said lead study author Nicolas Gazeau, MD, of CHRU Lille, Lille, France, and Fred Hutchinson Cancer Center, in Seattle, Washington, in a presentation of the data. “We need to now improve management of toxicity and neurotoxicity for patients treated with CD19[-targeted] CAR T cells, and it’s another objective.”

CD19-targeted CAR T-cell therapies have been found to have substantial efficacy in patients with relapsed or refractory B-cell malignancies. However, most patients are unable to achieve a complete and durable remission, according to Gazeau. Prior data with another CD19-targeted CAR T-cell therapy, JCAR014, indicated that after a second cycle of lymphodepletion and CAR T infusion, there was a lack of CD19 CAR T-cell expansion and persistence in the blood.

“We observed that the murine scFv of the CAR T cell was responsible [for the] CD8-mediated rejection,” Gazeau explained. “[As such,] trying to avoid immunogenicity as much as possible can maybe improve persistence and improve response. That’s why we created a fully human CAR T cell with a fully human binding domain.”

The phase 1/2 study enrolled patients who were at least 18 years of age who had relapsed or refractory B-cell non-Hodgkin lymphoma (NHL), which could be diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), high-grade B-cell lymphoma with MYC and BCL2 and/or BL6 rearrangements, transformed LBCL, or primary mediastinal LBCL. They were required to have detectable PET-positive disease via Lugano criteria, and they must have received prior anthracycline and rituximab (Rituxan) or another CD20-targeted antibody.

They also needed to meet at least 1 of the following criteria: having refractory disease following first-line chemoimmunotherapy, having relapsed or refractory disease following at least 2 lines of treatment or after autologous hematopoietic stem cell transplant (HSCT), having relapsed or refractory disease after allogeneic HSCT, or not being candidates to receive autologous HSCT.

If patients previously received a CD19-targeted CAR T-cell therapy, they were excluded. They also could not have a history or presence of clinically relevant central nervous system pathology that is determined to be a contraindication to lymphodepletion or JCAR021 infusion via principal investigator assessment.

Patients first underwent screening and apheresis, followed by restaging. They were then given a lymphodepletion regimen comprised of cyclophosphamide at 300 mg/m2 on fludarabine at 30 mg/m2 on days -5, -4, and -3. On day 0, patients were infused with JCAR021 with a 1:1 CD4/CD8 ratio. The CAR T-cell therapy was examined at 3 different dose levels (DL): 7 x 105 (DL1; n = 4), 2 x 106 (DL2; n = 4), and 7 x 106 (DL3; n = 15). On day 28, patients had a new PET/CT for re-evaluation of response.

The primary objective of the research is to examine the preliminary safety of lymphodepletion and JCAR021 in this patient population. Secondary objectives include characterizing the pharmacokinetic profile of the CAR T-cell therapy and assessing its antitumor activity. Investigators also wanted to estimate the PFS and OS in those infused with JCAR021.

Among the 23 total patients, the median age was 62 years (range, 35-78) and most (68%) were male. Moreover, the majority (61%) of patients had DLBCL NOS; 31% had transformed LBCL from an indolent histology and 8% had double- or triple-hit high-grade B-cell lymphoma.

These patients were heavily pretreated, according to Gazeau, having received a median of 3 prior lines of therapy (range, 2-7). “Some of them had very severe disease, with a very high lactate dehydrogenase, extranodal disease [83%], or bulky disease [48%],” he said.

In the entire cohort, JCAR021 induced an ORR of 74%, which comprised a CR rate of 52% and a PR rate of 22%. The 12-month PFS rate in all patients who were infused with the CAR T-cell therapy was 44%, and the 12-month OS rate was 86%.

He added that “with a lot of limitation,” his team set out to compare some patients with LBCL treated with the highest dose of JCAR021 (n = 15) vs those with high-risk relapsed/refractory NHL who received JCAR014 on protocol (NCT01865617) at the highest dose (n = 17), which was 2 x 106 CAR T cells/kg. “We tried to match them to let them have the same lymphodepletion,” Gazeau noted.

When JCAR021 was administered at the highest dose, a higher ORR and CR rate was observed, at 87% and 67%, respectively, than that observed with JCAR014, at 59% and 53%, respectively. The 12-month PFS rate was also higher with JCAR021 vs JCAR014, at 63% and 33%, respectively.

“But coming with better efficacy, we also had a higher toxicity,” Gazeau said. Any-grade CRS was observed in 93% of patients who received JCAR021 vs 29% of those who received JCAR014. Any-grade neurotoxicity was experienced by 80% of those who received JCAR021 compared with 29% of those who were administered JCAR014.

Investigators also tried to compare the peak and the persistence of the CAR T cells for JCAR021 and JCAR014. “We showed that JCAR021 had a higher peak [of CAR transgene expansion] than JCAR014 at the highest dose, and probably a comparable rate of decay,” Gazeau concluded.

Reference

Gazeau N, Fiorenza S, Kimble E, et al. Fully human CD19-targeted CAR T-cell therapy for relapsed or refractory large B-cell lymphoma: results of a first-in-human phase I/II study. Presented at: 2023 Transplantation & Cellular Therapy Meetings; February 15-19, 2023; Orlando, FL. Abstract 15.