BioNTech's Cancer Vaccine Begins to Show Promise in Human Trials: Initial Results Are Positive

The Turkish scientists who became known to almost everyone worldwide through mRNA Covid-19 vaccines are Uğur Şahin and Özlem Türeci. Their biotechnology firm BioNTech is now attracting attention with a new cancer treatment.

A new chimeric antigen receptor (CAR) T-cell therapy developed by BioNTech, evaluated in a phase I clinical trial showed an acceptable safety profile and also demonstrated efficacy as a single treatment or in combination with an amplifying RNA vaccine (CARVac). This study concerns the phase 1 BNT211-01 trial of the safety and feasibility of CLDN6-specific CAR T cells and CARVac in relapsed or treatment-resistant solid (organ/tissue-derived) tumors.

Preliminary results from the BNT211-01 study involving 16 patients were presented at the Association for Cancer Research (AACR) 2022 Meeting. In a new development, on 23 October 2023, Nature Medicine published the study's scientific article with data from 22 patients who received this experimental treatment.

Let us immediately answer one of the first questions that comes to mind on this subject:

How Does BioNTech's Cancer Vaccine Differ from Conventional CAR T-Cell Therapy?

What distinguishes BioNTech's cancer vaccine from conventional CAR T-cell therapy is the use of the developed CAR-T cells in combination with an mRNA vaccine (CARVac). CARVac enables CAR-T cells to multiply more effectively in the patient's body and recognize target tumor cells more accurately. In addition, by targeting an antigen specific to solid tumors, such as CLDN6, this therapy aims to overcome the challenges faced by conventional CAR-T therapies in treating solid tumors.

What Is CLDN6?

CLDN6 stands for Claudin-6, and this protein molecule acts as an oncofetal antigen. This protein forms tight junction structures that connect cells and contribute to cell membrane integrity. CLDN6 is a protein expressed at high levels and specifically in many solid tumors, and is therefore considered a potential therapeutic target. Oncofetal antigens are proteins generally produced during fetal life and silenced in adult tissues, but reactivated in cancer cells. High expression of CLDN6 in these tumors provides a specific target for immunotherapies such as CAR T-cell therapies, making it easier to distinguish healthy cells from tumor cells and thereby provide more effective treatment.

Uğur Şahin and colleagues, focusing on the widely expressed antigen in various solid tumors, CLDN6, a tumor-specific antigen, conducted the first open-label, multicenter human trial (phase I/II clinical trial) to evaluate the safety and preliminary efficacy of a previously developed CAR T-cell product targeting it.

This approach was tested in preclinical models in combination with a CLDN6-encoding mRNA vaccine (CARVac) that supports CAR T-cell multiplication in the patient's body and more accurate target recognition. BNT211 is the name given to this combination treatment, which resulted in the expansion and greater persistence in the blood of transferred CAR T cells, improving tumor-cell killing.

Details of the Cancer Vaccine Study

To test CLDN6 CAR T-cell therapy alone and in combination with CARVac, the researchers recruited patients with relapsed or treatment-resistant, CLDN6-positive advanced solid tumors into the study.

BNT211 combination treatment consists of patient-specific CAR T cells and mass-produced CARVac that is not patient-specific. CARVac is an RNA vaccine developed to amplify a specific CAR T-cell response, and this property enables mass production. Rather than making each component of the therapy patient-specific, this approach aims to provide a treatment applicable to a broad patient population.

Initially, 180 patients were screened for the study; 126 could not enter because they were CLDN6-negative. Overall, 22 patients had been treated at the time of this report.

The clinical trial consisted of two groups receiving increasing doses of CLDN6-targeted CAR T cells as monotherapy (group 1) or in combination with CARVac (group 2).

In group 2, CARVac was administered every 2 or 3 weeks until 100 days after CAR T-cell transfer, and one patient received a maintenance cancer vaccine every 6 weeks. 

Results

Approximately 40% of patients developed manageable cytokine release syndrome without any signs of neurotoxicity. Other adverse events included cytopenia (low blood cell counts) and abnormal immune responses, all of which were manageable. CARVac administration resulted in transient flu-like symptoms lasting up to 24 hours.

Efficacy was evaluable in 21 patients:

• The overall response rate was 33% (7 of 21 patients), with one complete response.
• In patients with germ cell tumors, the response rate was 57% as determined in the study.
• The overall disease control rate was 67% as reported in the study.

Meaning and Implications of the Study

CLDN6-targeted CAR T-cell therapy alone or in combination with CARVac appears safe and shows promise for patients with CLDN6-positive cancer.

CLDN6 had not previously been targeted with cellular therapy, but this approach shows efficacy that may be better than the data from other CAR T trials in solid tumors.

The BNT211-01 trial was modified to use an automated manufacturing process, and the repeat dose escalation is still ongoing.

However, we must be cautious because these are still early-stage study data and few patients have been treated; therefore, no substantial final conclusion can be reached at present.