Claudin 6, a cell surface protein involved in cell junction formation, may be a promising target for CAR T-cell therapies against solid tumors, according to a proof-of-concept study in mice.
BNT211, a CAR T-cell therapy developed by BioNTech to target this protein, induced complete tumor regression in mice implanted with large human tumors. The tumor eradication occurred within two weeks of a single BNT211 infusion.
Interestingly, a vaccine that delivers Claudin 6 to specific immune cells was able to activate and expand the CAR T-cells inside the animals. This suggests a potential new approach for increasing the durability and efficacy of CAR T-cell therapies.
The study, “An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors,” was published in Science.
Autologous CAR T-cell therapy is a type of immunotherapy in which researchers collect a patient’s T-cells — immune cells with anti-cancer activity — and engineer them to recognize and eliminate cancer cells. The treated cells are then returned to the patient to fight the tumor.
While effective in treating blood cancers, CAR T-cell therapies have yielded more disappointing results in solid tumors. In addition to a lack of cancer-specific targets, CAR T-cells are largely unable to penetrate solid tumors. Even when they do, there are few proliferation signals to keep them alive for long periods.
Researchers at BioNTech, however, have been developing a CAR T-cell therapy with a new cancer target and an accompanying vaccine — called CAR-T cell Amplifying RNA Vaccine, or CARVac — that could increase the activation and proliferation of the therapeutic cells.
Claudin 6 was suggested as an ideal target for CAR-T cell therapy, since it is found solely in tumors and is expressed on the cell surface. Using this protein, the researchers tested their assumptions in animal models.
They transplanted human cancer cells — including ovarian, colon, stomach, and lung cancers — into mice and treated them with a single injection of CAR T-cells or control cells. While control mice had rapidly progressing tumors, those on the active treatment had complete tumor regression after two weeks. These mice had detectable CAR T-cells up to 25 days after treatment.
The models, however, were not suitable for testing the treatment’s safety, the researchers warned.
BioNTech then tested its CARVac platform as a means to increase CAR T-cell activation and persistence within the solid tumors. This approach consisted of delivering an RNA molecule — the intermediary between a gene and a protein — to specific B-cells to promote their production of the Claudin 6 protein.
These cells, known as antigen-presenting cells, work to “present” signals to effector T-cells, keeping them active and proliferating and telling them what their target is. By presenting Claudin 6 at their surface, these antigen-presenting cells are expected to stimulate CAR T-cell activation and expansion, keeping them alive and active for much longer periods than currently observed.
In mice, a single intravenous dose (into the vein) of the vaccine caused a significant increase in circulating CAR T-cells, even at the lowest vaccine dose tested. The response pattern of the CAR T-cells to the vaccine was similar to the physiological response of a T-cell responding to an antigen, indicative of the effectiveness of the approach.
The researchers then tested how CARVac affected the efficacy of BNT211 in mice with lung tumors. While tumor growth was delayed but ultimately not suppressed in mice without the vaccine, 60% of mice receiving the vaccine had a complete rejection of their tumors. These results also were replicated with colon carcinomas, underscoring the effectiveness of the CARVac method.
“The combination of CAR-T cell therapy with CARVac underlines the value of cross-platform synergies to address key development challenges in the treatment of cancer,” BioNTech said a press release.
The company is planning to initiate the first Phase 1/2 clinical trial in 2020, testing BNT211 in ovarian, testicular, uterine, and lung cancer patients.
