Bispecific CAR-T Shows Promising Efficacy in Mantle Cell Lymphoma

LV20.19 CAR, an investigational bispecific chimeric antigen receptor T-cell therapy, has shown promising safety and efficacy in patients with relapsed/refractory (r/r) mantle cell lymphoma (MCL) who were treated in a phase 1/2 clinical trial (NCT04186520). The data were presented by Nirav N. Shah, MD, Medical College of Wisconsin, at the 2023 Tandem Meetings |Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held in Orlando, Florida, February 15-19, 2023.

LV20.19 CAR targets both CD19 and CD20. Among the 14 patients with r/r MCL who were treated with LV20.19 CAR in the trial, the overall response at 28 days post-treatment was 100%, with 10 patients achieving a complete response (CR) and 4 patients achieving a partial response (PR). Day 90 overall response data were available for 12 of the patients. Among these 12 patients, 11 had achieved a CR and 1 had achieved a PR. Furthermore, at day 28-65 post-treatment, 9 of 12 patients had achieved minimal residual disease negativity. It was noted that median overall survival and progression-free survival were not met.

In terms of safety, 13 of the 14 patients experienced cases of cytokine release syndrome, however all of these cases were grade 1-2. Three patients experienced cases of immune effector cell-associated neurotoxicity syndrome, with 1 of the cases being grade 1-2 and 2 of the cases being grade 3. Shah noted in his presentation that the grade 3 cases were treated with intrathecal steroids and chemotherapy and resolved. During treatment for 1 of the patients with grade3 ICANS, it was discovered that the patient had MCL-involvement in the cerebrospinal fluid, which would have been criteria for exclusion from participation if it had been known earlier. Hemophagocytic lymphohistiocytosis-like toxicities occurred in 3 patients, and 1 non-relapse mortality occurred at 46 days post-treatment due to gram-negative rod sepsis in a patient who had previously received allogeneic hemopoietic cell transplant (HCT). Shah pointed out that no patients required ICU care in the first 28 days after treatment. In terms of count recovery, the median absolute neutrophil count (ANC) at day 28 was 1.47 K/μl, the median ANC at day 90 was 1.71 K/μl, and Shah noted that platelet recovery was “basically normalized” by day 90 (median, 168 K/μl).

“Our program uses a CAR T-cell manufacturing which involves on-site production, and we use a flexible 8 day to 12 day manufacturing [platform],” Shah noted during his presentation. “So these patients were receiving CAR T-cells, the majority as a fresh product within 8 days of their apheresis, with lymphodepletion starting 4 days after leukapheresis.”

Shah noted that 11 patients received LV20.19 CAR that had been manufactured in 8 days, and 3 patients received LV20.19 CAR that had been manufactured in 12 days. Manufacturing was successful for 100% of patients, though 2 patients had to receive cryopreserved product. For 1 patient, this was due to a fungal sinus infection; the other patient had rapidly progressive disease and received a regimen of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) following apheresis.

The ages of the patients in the trial ranged from 50 to 74 years (median, 63) and the vast majority were male (93%). The patient population was heavily pre-treated, with patients having received 2 to 8 prior lines of therapy (median, 5). Six of the patients had previously received autologous HCT and 2 had previously received allogeneic HCT. Shah highlighted the fact that 11 of the patients had been treated with bendamustine, with 2 of these patients having received bendamustine within less than 1 year of treatment with LV20.19 CAR. He also noted that 93% of the patients were BTKi-exposed and 11 patients were BTKi-progressed.

“We do believe that these data are suggestive for further investigation,” Shah concluded his presentation. "We are developing a multicenter phase 2 study to really validate these findings beyond our single-center data. And really, I think these data sort of hypothesize that the dual-targeting of CD20, which is an important target in mantle cell lymphoma outside of CAR-T, may be additive in CD19 and improve CAR T-cell therapy outcomes for patients with relapsed/refractory mantle cell lymphoma.”

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REFERENCE

Shah NN, Fuqan F, Szabo A, et al. Results from a phase 1/2 study of tandem, bispecific anti-cd20/anti-cd19 (LV20.19) CAR t-cells for mantle cell lymphoma. Presented at: 2023 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR.February 15-19, 2023; Orlando, FL. Abstract 40