April 2022: According to preliminary data from a phase I/II clinical trial that was presented during the AACR Annual Meeting 2022, which was held from April 8-13, a new chimeric antigen receptor (CAR) T-cell product had an acceptable safety profile and showed early signs of efficacy as a monotherapy and in combination with an mRNA vaccine in patients with solid tumours. This information was presented in April.
The application of CAR T-cell therapy to solid tumours has proven to be difficult, despite the fact that it has fundamentally altered the treatment options available for hematologic cancers.
According to the presenter, John Haanen, MD, PhD, a medical oncologist at the Netherlands Cancer Institute (NKI), Amsterdam, Netherlands said, “it is difficult to specifically direct the CAR T cells against tumour cells while sparing healthy ones because most of the proteins present on solid tumours that could be used as targets are also found at low levels on normal cells. “Other challenges include the limited persistence of CAR T cells observed in solid tumours,” as well as “their difficulty reaching the tumours and penetrating the centre of the mass,” according to the article.
Dr. John Hannen
Haanen and colleagues are conducting a first-in-human, open label, multicenter clinical trial to evaluate the safety and preliminary efficacy of a previously developed CAR T-cell product that targets CLDN6. CLDN6 is a tumor-specific antigen that is widely expressed in a variety of solid tumours but is silenced in healthy adult tissues. The purpose of this clinical trial is to determine whether or not the product is safe to use in humans and to determine whether or not it has preliminary therapeutic potential. This treatment was evaluated in preclinical models in conjunction with a CLDN6-encoding mRNA vaccine known as CARVac, which promotes the growth of CAR T cells. According to Haanen’s explanation, this combined treatment, which is known as BNT211, led to an increase in the transferred CAR T cells’ capacity to multiply and their persistence in the blood, which, in turn, led to an improvement in the ability to kill tumour cells.
Patients with relapsed or refractory advanced CLDN6-positive solid tumours were sought out by the researchers in order to test the effectiveness of the CLDN6 CAR T-cell therapy both on its own and in conjunction with CARVac.
Following lymphodepletion to reduce the total number of T cells present in the body and make room for the transferred CAR T cells, the clinical trial was divided into two parts. In the first part, increasing doses of CLDN6 CAR T cells were administered as monotherapy. In the second part, the same treatment was administered in combination with CARVac. In Part 2, CARVac was given to the patient every two to three weeks for the first one hundred days after the CAR T-cell transfer. Additionally, one patient received maintenance vaccinations every six weeks. When this report was written, a total of 16 patients had been treated up to that point.
A manageable cytokine release syndrome developed in approximately forty percent of patients, but there was no evidence of neurotoxicity in any of these patients. Cytopenia, also known as a low blood cell count, and abnormal immune responses were some of the other adverse events that occurred, but they all went away on their own. After receiving CARVac, some people experienced fleeting symptoms similar to the flu that lasted for up to 24 hours. According to Haanen, “CLDN6 CAR T treatment and CARVac seemed to be safe, with only a limited number of adverse events that were easily manageable.”
Four patients with testicular cancer and two patients with ovarian cancer experienced a partial response (PR) at six weeks after infusion, resulting in an overall response rate of nearly 43 percent. The patients who were evaluable for efficacy were divided into two groups: those who had testicular cancer and those who had ovarian cancer. Among the people who took part in the research and had a PR, there were two patients who were treated with the combination of CAR T cells and CARVac and four patients who received CAR T cells as a monotherapy. There was an 86% success rate in eradicating the disease. At 12 weeks after the infusion, it was found that initial partial responses had improved in all of the patients who could be evaluated. This led to a single complete response, which is still present six months after the infusion was given.
“It is astounding that the majority of patients with testicular cancer showed clinical benefit at dose level 2,” said Haanen. “The responses we have observed can be profound, including one ongoing complete remission.”
According to Haanen, “The infusion of CLDN6 CAR T, either alone or in combination with CARVac, is safe and holds promise for patients with CLDN6-positive cancers.” “CLDN6 was never targeted before with cellular therapy; however, in our study, this approach is already showing efficacy that may be better than the data from other CAR T trials in solid tumours,” said the researchers.
However, Haanen cautioned that these data are very early, and because only a small number of patients have been treated up to this point, it is premature to draw any major conclusions.
The investigation was funded by the subsidiary company of BioNTech SE known as BioNTech Cell & Gene Therapies GmbH. BioNTech provided financial support to NKI for its research. The company BioNTech has Haanen serving on its scientific advisory board. Financial compensation goes to NKI.
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