Researchers at the Karolinska Institute report CAR T-cell therapy was found to be effective against ovarian cancer in mice. The researchers hope that the discovery will pave the way for a clinical trial to see how effective the treatment is for women with the disease.
Their work is published in the Journal for ImmunoTherapy of Cancer in a paper titled, “Tuned activation of MSLN-CAR T cells induces superior anti-tumor responses in ovarian cancer models.”
“Limited persistence of functional CAR T cells in the immunosuppressive solid tumor microenvironment remains a major hurdle in the successful translation of CAR T-cell therapy to treat solid tumors,” wrote the researchers. “Fine-tuning of CAR T-cell activation by mutating CD3ζ chain immunoreceptor tyrosine-based activation motifs (ITAMs) in CD19-CAR T cells (containing the CD28 costimulatory domain) has proven to extend functional CAR T cell persistence in preclinical models of B cell malignancies.”
“This therapy is currently available for patients with blood cancer, and we want to investigate if we can use the method to treat ovarian cancer,” said the study’s joint last author Isabelle Magalhaes, PhD, docent at the department of oncology-pathology at Karolinska Institute. “Despite many improvements to the available therapy, the prognosis for women with ovarian cancer is still poor.”
Until now, CAR T-cell therapy has proved largely ineffective against solid tumors.
“Tumors often arise in an environment that’s unfavorable for T cells, in part due to a low oxygen level,” said Jonas Mattsson, MD, PhD, visiting professor at Karolinska Institute, and the second joint last author. “This can cause attacking T cells to be neutralized, which impairs the therapeutic effect. So, we wanted to examine if it would still work.”
The researchers tested three types of CAR molecules programmed to attack mesothelin, a protein found in many ovarian tumors. The researchers repeatedly exposed ovarian cancer cells to the programmed CAR T cells in test tubes and conducted several experiments on mice.
They observed three CAR T cells significantly prolonged the lives of the mice with cancer compared to those in the control group, with the type called M1xx CAR T cells proving the most efficacious. The mice that were injected with T cells that express that particular molecule saw a reduction in tumor size and lived even longer than the others.
“In several mice, there were no tumor cells left that we could detect, and the effect lasted just over three months after the treatment started. This is evidence that immunotherapy involving CAR T cells that attack the mesothelin protein is a promising one for ovarian cancer,” explained Mattsson.
The researchers hope their findings pave the way for a clinical study. “Our goal is to predict the optimal conditions for producing CAR T cells able to infiltrate and attack the tumor and survive in the bodies of women with ovarian cancer,” concluded Mattsson.