BNT211 showed encouraging responses in testicular cancer but less encouraging responses in ovarian cancer.
BNT211, a combination chimeric antigen receptor (CAR) T-cell receptor and CAR T-cell-amplifying RNA vaccine (CARVac) therapy, has demonstrated a manageable safety profile with promising signs of clinical activity in patients with claudin 6 (CLDN6)-positive testicular cancer.1
“CLDN6 CAR T cells as a monotherapy or combined with CARVac were well tolerated at evaluated dose levels... We observed that dose-dependent expansion of CAR Tc cells could be achieved in all patients translating into clinical activity,” presenter Prof. Dr. Andreas Mackensen, Director, Department of Medicine 5 – Hematology and Oncology, Universitätsklinikum Erlangen, Germany, said during his presentation at the European Society for Medical Oncology (ESMO) 2022 Congress, September 9-13, in Paris, France.1
The 2-part therapy is designed to improve in-vivo expansion and persistence of CAR T-cells and is being evaluated in a first-in-human, phase 1/2 trial (NCT04503278). The therapy’s CAR T-cell therapy component is CLDN6-targeted and the CARVac component encodes for CLDN6.
The trial is enrolling up to 96 patients with CLDN6-positive relapsed/refractory solid tumors, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no further standard treatment options. In the first part of the trial, after lymphodepletion, participants are evaluated in a 3+3 dose escalation of the CAR T-cell therapy followed by repeated CARVac treatments with 1 intra-patient dose escalation from 25 to 50 μg.
The trial is primarily evaluating treatment-related adverse events (AEs) and dose-limiting toxicities (DLTs) while secondary endpoints will start to preliminarily evaluate efficacy via change from baseline in the levels of soluble immune factors measured by cytokine multiplex assay, overall response rate, disease control rate, and duration of response.
Twenty-two patients, 13 with testicular and 4 with ovarian cancers, have been treated in the study as of June 15, 2022, at dose level (DL) 1 (107 CAR T cells; n = 6) or 2 (108 CAR T cells; n = 13). One patient was treated with less cells than DL1 and in DL2, 1 patient received 50% of the lymphodepletion regimen and 2 received no lymphodepletion.
“I wanted to point out how heavily-pretreated these patients are, particularly in the testicular cancer space where it hasn’t seen a lot of advances and we often don’t think about because it has such a high cure rate up front but for patients who don’t achieve that upfront cure there hasn’t been a recent advancement in therapies,” David A. Braun, MD, PhD, assistant professor of medicine and Lousi Goodman and Alfred Gilman Yale Scholar, Yale School of Medicine, said during an invited discussion.2
BNT211’s safety profile was manageable, with 2 patients experiencing DLTs (pancytopenia in 1 patient receiving DL2 CAR T monotherapy and hemophagocytic lymphohistiocytosis in 1 patient receiving DL2 BNT211 combination therapy).1 Over grade 2 treatment-emergent AEs were mostly related to lymphodepletion or asymptomatic transaminase/lipase elevations. Cytokine release syndrome occurred in 45% of patients with 1 case above grade 3. There was 1 case of grade 1 immune effector cell-associated neurotoxicity syndrome that quickly resolved.
Preliminary efficacy analyses revealed that 6 patients had a partial response, 7 had stable disease (5 with target lesion shrinkage), and 7 had progressive disease (including 2 deaths). Overall response rate (ORR) was 33% and disease control rate was 67%.Patients with testicular cancer showed the best responses and impressive tumor shrinkage, Mackensen noted. Out of these 11 patients, ORR was 45% and 57% for those in DL2. The patient with testicular cancer that had a CR had undergone 6 lines of prior treatment.
“If we look at ovarian cancer, it’s a slightly different story. There are responses here, we see 2 PRs, which is encouraging for ovarian cancer, but none of these are durable... this is not what we’re looking for with immunotherapy and that’s in contrast to the testicular cancer results which are incredibly encouraging,” Braun said.2
Investigators observed a dose-dependent CAR-T expansion, with a strong persistence of CAR T observed for over 100 days. A few patients exhibited CAR-T persistence for over 200 days.1
“The goal of the CARVac mRNA vaccine is to keep the CAR T-cells at this persistent level within a therapeutic window... [In terms of its effect], it’s too early to tell... I’m not seeing a big difference... we are seeing some persistence so that’s something we need to keep an eye on. Is the CARVac part really helping or is this driven by the CLDN6 CAR T-cell itself,” Braun said.2
“The process of generation of CLDN6 CAR T-cells has been switched to an automated process and dose escalation is ongoing. The recommended phase 2 dose will be identified for the final product,” Mackensen said.1