MAINZ, Germany—BioNTech SE recently announced a publication in Science regarding the company’s novel CAR-T therapeutic approach for solid tumors. The article, entitled “An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors,” provides preclinical proof-of-concept data for BioNTech’s first CAR-T product candidate: BNT211, an autologous CAR-T cell therapy targeting the oncofetal antigen Claudin 6. The study also outlines CARVac as a broadly applicable RNA vaccine approach to improve the therapeutic efficacy of CAR-T cell therapies.
According to Sean Marett, chief business and chief commercial officer for BioNTech, “BNT211 is CAR-T cell therapy targeting a new solid tumor antigen (Claudin 6, also CLDN6) that is combined with an accompanying mRNA-vaccine, called CARVac (CAR-T cell Amplifying RNA Vaccine). Our preclinical studies demonstrate that [therapeutic] challenges may be addressed by the additional application of the CARVac that encodes the CAR-T target, in this case CLDN6. By the additional body-wide presentation of the CAR-T target, the CAR-T cell population is re-stimulated leading to enhanced engraftment, proliferation and tumor infiltration rates.”
Although CAR-T cell therapy has shown significant clinical efficacy in blood cancers, it faces challenges in solid tumors, including a limited number of identified cancer-specific solid tumor targets, inefficient infiltration of CAR-T cells into solid tumors, and insufficient CAR-T cell persistence. BioNTech aims to overcome these hurdles.
“BNT211 was created as part of our CAR-T pipeline that uses tailored reprogramming of autologous T cells from cancer patients to recognize and address their tumors,” notes Marett. “A key hurdle for CAR-T therapy in solid tumors is the very limited number of validated CAR-antigens that are exclusively expressed on solid tumors. CLDN6 is a protein active in embryogenesis that is silenced in healthy cells during life, but specifically expressed in a variety of solid tumors.”
“Claudin 6 is a tight junction membrane protein which in normal tissue is solely expressed in embryonic cells, but is aberrantly expressed by a number of solid tumors such as uterine, testicular, ovarian and lung cancer. In preclinical tests of our CAR-T therapy directed against Claudin 6, we observed potent antitumoral efficacy, including eradication of advanced tumors in an ovarian carcinoma xenograft model,” he continues. “Furthermore, we did not observe any cross-reactivity with closely related CLDN-proteins or side effects in healthy tissues, underlining its specificity.”
“To further improve therapeutic impact, we are combining the CAR-T therapy with another of our proprietary platforms—our CARVac approach, which is based on our longstanding mRNA expertise. With our proprietary RNA-Lipoplex formulation, we can successfully deliver antigen-encoding mRNAs via IV application to lymphoid compartment resident antigen-presenting cells in the whole body promoting priming and strong expansion of antigen-specific (CAR)-T cells,” he adds.
In the published study, BNT211 was evaluated both in vitro in tumor cell lines and in vivo in mice with human ovarian cancer transplants. In mice, the CLDN6-CAR-T cell therapy demonstrated complete tumor regression of transplanted large human tumors within two weeks after initiation of treatment. The combination with CARVac achieved an improved engraftment, proliferation and expansion of CAR-T cells in vivo, resulting in tumor regression even at sub-therapeutic CAR-T doses.
CARVac was also successfully applied for CAR-T cells targeting the pan-cancer antigen CLDN18.2 and CD19, the target of approved CAR-T cell therapies. BioNTech believes that the combination of CAR-T cell therapy with CARVac underlines the value of cross-platform synergies in addressing development challenges in cancer treatment.
“There are two key challenges to using CAR-T therapies in solid tumors; solid tumor specificity and maintaining fit, active CAR-T cells that can attack and destroy tumor cells,” explains Marett. “Our first CAR-T candidate directed against CLDN6 in combination with our CARVac approach potentially may address both of these challenges, as evidenced by our preclinical data that we published recently in Science, leading us to prepare for clinical testing of our first CAR-T in combination with CARVac this year.”
He also says that “a great advantage of our mRNA-based CARVac technology is that it can easily be adapted to other CAR-T cell targets, and thus is potentially widely applicable—offering a broad potential to improve therapeutic efficacy of CAR-T cell therapies across a range of solid and liquid tumors, heralding a potentially new way of treating tumors with CAR-T cell therapies. In addition, our combination of CAR-T cell therapy with an mRNA therapeutic vaccine directed against the same target highlights the value of cross-platform synergies at BioNTech to address key development challenges in the treatment of cancer.”
“We plan to initiate a first-in-human Phase 1/2 clinical trial for validation of safety and efficacy of BNT211 in solid tumors, including ovarian, testicular, uterine and lung cancer, in the first half of 2020. It’s exciting to make progress in the challenging field of CAR-T therapy in solid tumors,” Marett tells DDNews.
Manufacturing to support clinical trials of BNT211 will be conducted at BioNTech’s state-of-the-art GMP-certified cell therapy manufacturing facility in Idar-Oberstein, Germany, which has been in operation since 1999. BioNTech initiated a multi-year capacity expansion at the facility in 2018, which the company expects to complete sometime in 2020.