Author: By Laura Cowen, medwireNews Reporter
medwireNews: A chimeric antigen receptor (CAR)-T cell product targeting the tumour-specific antigen claudin-6 (CLDN6) was well tolerated when used as monotherapy or in combination with a CAR‑T cell-amplifying RNA Vaccine (CARVac) in a first-in-human trial involving people with solid tumours.
The treatment also showed “encouraging responses”, particularly in testicular cancer, reported John Haanen, from the Netherlands Cancer Institute in Amsterdam, at the 2022 AACR Annual Meeting in New Orleans, Louisiana, USA.
The multicentre, phase I BNT211 trial included eight patients with testicular cancer, four with ovarian cancer and one each with endometrial, fallopian tube and gastric cancer or sarcoma. All participants had CLDN6-positive relapsed or refractory advanced solid tumours with a median of four prior therapies and no further options for standard treatment.
They all underwent one course of lymphodepleting chemotherapy prior to CLDN6-targeted CAR-T cell infusion. In part 1 of the study, participants received CAR-T cell monotherapy at a dose of 1 x 107 cells (dose-level [DL]1; n=3) or 1 x 108 cells (DL2; n=6). In the absence of dose-limiting toxicity, the trial moved to part 2, in which additional participants received either DL1 (n=3) or DL2 (n=4 with recruitment ongoing) followed by CARVac every 3 weeks for five treatments then every 6 weeks thereafter.
John Haanen explained that CARVac is a CAR-T cell amplifying RNA vaccine encoding full-length CLDN6, which stimulates the expansion and persistence of CAR-T cells.
During the trial, two patients experienced a dose-limiting toxicity, both at DL2. One patient with testicular cancer had prolonged grade 4 pancytopenia after lymphodepletion.
Further analysis revealed pronounced cytopenia in a subgroup of patients with testicular cancer who had recently received high-dose chemotherapy and autologous stem cell transplantation. To address this, the researchers have recently opened a cohort with reduced lymphodepletion.
The second patient with dose-limiting toxicity had grade 4 haemophagocytic lymphohistiocytosis (HLH) prior to CARVac administration. This patient had ovarian cancer with Parvovirus B19 infection and recovered from HLH following treatment with intravenous immunoglobulin and steroids. In spite of this, their CAR-T cell count declined rapidly before the start of CARVac and could not be rescued but they still experienced clinical benefit.
There were 45 adverse events of grade 3 or worse in 15 participants, which John Haanen said were mainly caused by lymphodepletion or were asymptomatic transaminase and lipase elevations. Eight patients experienced asymptomatic cytokine release syndrome (all grade 1 or 2) that was associated with high interleukin-6 levels and managed with tocilizumab where necessary.
Preliminary efficacy data from 14 evaluable patients with at least 6 weeks of follow-up data showed that six patients had a partial response and six had stable disease, giving an objective response rate (ORR) of 43% and a disease control rate (DCR) of 86%. Five of the six patients with stable disease had a decrease in target lesion size that did not meet the criteria for partial response.
The response rate was particularly high among the five patients with testicular cancer, where at DL2, the ORR was 80%, including one complete response, and the DCR was 100%. Furthermore, some of these patients showed long-term (>150 days) CAR-T cell persistence and further deepening of responses following an initial partial response.
John Haanen concluded: “CLDN6 CAR-T cells [with or without] CARVac show an acceptable safety profile at doses tested and encouraging signs of clinical activity.”
Session discussant Vincent Lam, from Johns Hopkins Medicine in Baltimore, Maryland, USA, described the study as being an “important advanced in a rapidly growing field” that “validated” CLDN6 as a novel CAR-T target.
However, he noted that while CARVac “appears safe”, further research is required to determine the optimal setting, as well as dose, timing and duration of CARVac to achieve a persistent effect.
Haanen J, Mackensen A, Koenecke C, et al. BNT211: A Phase I trial to evaluate safety and efficacy of CLDN6 CAR-T cells and CARVac-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors. AACR Annual Meeting 2022; New Orleans, Louisiana, USA: 8–13 April.
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