CAR T-cell therapy has revolutionized the treatment of blood cancers, but until now, it has not been effective in treating solid tumors, such as breast or lung cancer.
"One of the main limitations is that most of the proteins present on solid tumors that could be used as targets are also found at low levels on normal cells, making it difficult to specifically direct the CAR T cells against tumor cells and spare healthy ones," said presenter Dr. John Haanen, PhD, a medical oncologist at the Netherlands Cancer Institute in Amsterdam. "Other challenges include the limited persistence of CAR T cells observed in solid tumors and their difficulty reaching the tumors and penetrating the center of the mass."
A new treatment, however, may show promise in treating some solid tumors. CLDN6 is an antigen expressed specifically in tumor cells that is not expressed in healthy adult tissue. The CAR T-cell therapy is designed to exploit this difference between cancerous and noncancerous cells to create a targeted cancer monotherapy. The CAR T-cell can also function as a combination therapy when paired with CARVac, a CLDN6-encoding mRNA vaccine. This combined therapy is known as BNT211.
Over the course of this first-in-human, open-label, multicenter trial, 16 patients were treated with increasing doses of CLDN6 CAR T-cells as a monotherapy or CAR T-cell therapy followed by BNT211 combination treatment. Therapies were administered after lymphodepletion in each patient to assess the therapeutic effects of the treatments more accurately. The main outcomes of the preliminary data demonstrated that both therapies effectively shrunk targeted tumors in six of 14 evaluable patients by 39% to 49%, specifically showing responses in patients with testicular and ovarian cancers.
Of the patients that showed this partial response, four were treated with the CAR T-cell monotherapy, while two received the BNT211 combination therapy. The BNT211 therapy showed successful expansion of CLDN6-specific CAR T cells and higher persistence of these CAR T cells in the blood, resulting in improved destruction of tumor cells, the researchers reported.
Furthermore, at 12 weeks postinfusion with either therapy, five patients with an initial response to the therapy showed further amplification of the response, with additional tumor shrinkage of 50% to 73%. Remarkably, treatment resulted in a complete response in one patient that has continued for six months after the initial infusion, the authors noted.
While the data for this trial is preliminary, the results demonstrate a novel target and effective therapy for solid tumors, which are notoriously difficult to penetrate. Nearly half of the patients in this trial responded to therapy, with one complete response showing possible long-term efficacy. The specificity of these therapies helps isolate cancerous cells, minimizing negative effects on healthy human cells.
CLDN6 and CARVac are also well tolerated regarding side effects, making them a potentially strong and safe treatment option for patients with CLDN6-positive cancers, the researchers said.
"The infusion of CLDN6 CAR T, alone or in combination with CARVac, is safe and holds promise for patients with CLDN6-positive cancers," Haanen said. "CLDN6 was never targeted before with cellular therapy, but in our study, this approach is already showing efficacy that may be better than the data from other CAR T trials in solid tumors."