CAR T-Cell Therapy Plus Amplifying Vaccine Shows Initial Safety, Efficacy in Solid Tumors


Three patients dosed had tumors shrinkages of 18%, 21%, and 27%.

BNT211, a CLDN6 chimeric antigen receptor (CAR) T-cell candidate, has shown signs of efficacy in solid tumors with a favorable safety profile, both alone and in combination with a CAR-T cell amplifying RNA vaccine (CARVac).1

"CAR T-cell therapy is already well established with patients with hematologic malignancies. However, clinical success is still lacking in patients with solid tumors, most likely due to impaired CAR T-cell persistence. CLDN6, a membrane protein involved in tight junction formation, is a well-suited target for CAR T-cell therapy in solid tumors," Andreas Mackensen, MD, director, department of hematology/oncology, University Hospital of Erlangen, Germany, said during his presentation of the data.1

Mackensen presented initial data from a phase 1/2 trial (NCT04503278) assessing BNT211 at the 36th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), November 10-14, 2021.

“Preclinical studies demonstrated that combining these engineered cells with a CARVac leads to in vivo expansion of adoptively transferred CAR-T cells, resulting in their improved persistence and functionality,” Mackensen and colleagues wrote.1

The open-label, multi-center phase 1/2 trial is evaluating dose escalations of BNT211 monotherapy and combination therapy with CARVac in 3 dose levels. CARVac is applied every 3 weeks starting at 4 days after transplantation, following a 1-step, intra-patient dose escalation in part 2 of the trial.

READ MORE: TCR T-Cell Therapy Shows Efficacy Across Solid Tumor Types

The trial is primarily assessing safety as measured by treatment-emergent adverse events (AEs) and dose-limiting toxicities (DLTs). Secondary outcome measures include safety biomarkers, objective response rate, disease control rate, and duration of response. The trial is currently enrolling patients with CLDN6-positive relapsed/refractory solid tumors that have exhausted standard treatment options and have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.

"Our goal is to leverage our understanding of immunology and tumor biology together with our advanced technologies to provide cancer patients with novel treatments," Özlem Türeci, MD, co-founder and chief medical officer, BioNTech, said in a statement.2 "Claudin-6 is a new target that we believe is well-suited for CAR-T therapy and presents a differentiated avenue for the treatment of solid tumors."

Eight patients have been treated as of July 23, 2021. Dose level 1 and part of dose level 2 have been completed as per part 1 of the trial. Dose level 1 as per part 2 is ongoing. Seven patients had underlying testicular, ovarian, and endometrial cancers as well as soft-tissue sarcoma. One patient had cancer of unknown primary and was treated with a dose lower than dose level 1 with CARVac.

In terms of safety, no DLTs or serious AEs related to therapy have been observed. Manageable, grade 1-2 cytokine release syndrome without neurotoxicity occurred in both patients in dose level 2. Other patients had transient, moderate elevations of IL-6 and C-Reactive Protein serum levels. Specifically, CARVac administration yielded transient flu-like symptoms; these resolved within 24 hours.

Investigators observed robust engraftment of CAR T-cells in peripheral blood but this declined after day 17. Two patients with liver metastases experienced further expansion accompanied by alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Total bilirubin was unaffected.

Initial efficacy data revealed that 6 weeks after transplantation, 4 participants had stable disease (3 transitioned to progressive disease after another 6-18 weeks) and 1 had progressive disease out of the evaluable patients. Initial tumors shrunk in 3 patients according to RECIST1.1 by 18%, 21%, and 27%.

"CLDN6 CAR T-cells were well-tolerated at dose level 1. Liver metastases seem to support CAR T-cell engraftment and we achieved first signs of clinical activity. The same dose level in combination with CARVac was also well-tolerated. We observed the first CRS and all patients had robust CAR T frequency. At dose level 2, all patients had CRS starting at day 5to day 7, which was manageable, and all patients had CAR T frequency that translated to anti-tumor activity," Mackensen said during his presentation.1 "Not a single dose-limiting toxicity in any of the cohorts has been reported so far, but patients with a history of high-dose chemo appear to be at risk for thrombocytopenia, so we have opened a cohort without lymphodepletion."

For more coverage of SITC 2021, click here.

1. Mackensen A, Koenecke C, Haanen J, et al. BNT211: a phase I/II trial to evaluate safety and efficacy of CLDN6 CAR-T cells and vaccine-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors. Presented at Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington, DC. Abstract 958
2. BioNTech to present new clinical data from first-in-class CAR-T program BNT211 in late-breaking session at 36th SITC Annual Meeting. News release. BioNTech. November 1, 2021.
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