Boosting CAR-T cells with mRNA Vaccines: New Immunotherapy Strategy

Cellular immunotherapies, such as those relying on modified T cells that target cancer antigens, have proved effective in treating patients with liquid cancers (e.g., B cell malignancies). Nevertheless, the efficacy of Chimeric Antigen Receptor T cells or CAR T cells against solid tumors (e.g., testicular, ovarian, and breast cancer) is limited and has gained increased attention in current cancer research. Therefore, investigators are keen to understand why CAR T cells fail against solid tumors so that they may develop approaches to bypass their limitations and develop more effective cell immunotherapies.

AACR 2022 Clinical Trials Plenary Session, Prof. John Haanen, M.D., Ph.D., Medical Oncology Department, Netherlands Cancer Institute, presented an update on “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”.

One new strategy aiming to empower CAR T cells against solid tumors is the immunotherapy BNT211, which leverages a BioNTech’s mRNA lipoplex vaccine formulation to promote CAR T cell persistence following cell infusion. As part of the Clinical Trials Plenary Session at the American Association for Cancer Research (AACR) 2022 annual meeting, Prof. John Haanen, M.D., Ph.D., Medical Oncology Department, Netherlands Cancer Institute, provided an update on the progress of a Phase 1/2 clinical trial (NCT04503278) evaluating the safety and efficacy of BNT211 mediated in vivo expansion in patients with Claudin 6 (CLDN6) positive advanced solid tumors.

BNT211 has two critical components, autologous CAR T cells targeting the tumor-specific antigen CLDN6 and an mRNA vaccine encoding CLDN6 (CAR-T Cell Amplifying RNA Vaccine or CARVac). CARVac targets antigen-presenting cells (APCs) in lymphoid tissue for CLDN6 expression and display. The ongoing Phase 1/2 study is the first time that such boosting strategy has been tested, involving an autologous CAR T cell infusion followed by a CAR T cell-amplifying mRNA vaccine to improve expansion, persistence, and overall CAR T cell function. It is also a first for targeting Claudin 6 with cell therapy.

Preclinical studies in mice demonstrated the efficacy of the CARVac strategy in improving the tumor-killing activity of CAR T cells. In mice engrafted with CLND6 CAR T cells, vaccination with CLND6-CARVac supported the production and presentation of CLDN6 by dendritic cells and consequently the expansion of adoptively transferred CAR T cells. Additionally, CLND6-CARVac improved the efficacy of a sub-optimal dose of CLND6 CAR T cells in tumor-bearing mice, inducing complete tumor regression instead of delayed tumor growth without CARVac (Reinhard et al. 2020).

Why is Claudin 6 relevant in cancer?

CLDN6, a tetraspanin membrane protein, is a member of the claudin family of integral tight junction proteins and plays a role in cell adhesion, polarity, and permeability (Du et al. 2021). CLDN6 is developmentally regulated, such that its expression, while high in most human fetal tissues, becomes significantly downregulated at postnatal stages, as confirmed at both transcript and protein levels. Nevertheless, the expression of CLDN6 becomes broadly upregulated in cancer tissues. For example, CLDN6 transcript and membrane protein expression have been confirmed in human solid tumors, including testicular, ovarian, uterine, and lung adenocarcinoma, making it an ideal target for cell therapy (Reinhard et al. 2020).

Clinical update on BNT211

Encouragingly, initial findings from 16 patients dosed with CLDN6 CAR T cells alone or in combination with CARVac have shown this novel treatment to be well tolerated and safe, albeit some instances of manageable cytokine release syndrome (CRS) have occurred. Partial anti-tumor responses were observed in ~40 % of patients as early as 6 weeks, and responses progressed for some over the 12 and 18 weeks post-treatment. Although preliminary, due to the small number of patients, responses correlated with the CAR T infusion dose and improved with combined CLDN6 CAR T and CARVac. Additionally, among individuals treated thus far, Dr. Haanen shared that, following CLDN6 CAR T cell infusion, complete remission of pulmonary metastasis was documented for a testicular cancer patient with multiple relapses and extensive pretreatment.

Overall, as shared by the Clinical Trials Plenary Session’s discussant Dr. Vincent Lam, M.D., Assistant Professor of Oncology and Director of the Esophageal Cancer Research Program at Johns Hopkins, the initial findings with BNT211 help validate CLDN6 as a relevant target in the treatment of patients with solid tumors, particularly, with testicular and ovarian cancer. Moreover, while boosting with CLDN6 CARVac shows it to be a safe strategy, studies still need to pinpoint the dosing and timing for optimal outcomes.


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