First-in-Class CAR T Therapy GCAR1 Shows Early Promise Against Treatment-Resistant Solid Tumors
核心洞察
University of Calgary researchers developed GCAR1, a first-in-class CAR T-cell therapy targeting a novel marker on solid tumors, published in Nature and Nature Cancer.
Two patients with alveolar soft-cell sarcoma (搜索) received the therapy; the second patient showed tumor shrinkage and disappearance of lung metastases after combination immunotherapy.
A lung lesion measuring over 2.5 cm shrank to less than 1 cm, and a smaller lesion became barely visible on follow-up CT scans.
A team of researchers at the University of Calgary's Charbonneau Cancer Institute, in collaboration with McMaster University, has developed a first-in-class chimeric antigen receptor (CAR) T-cell therapy that is demonstrating strong preclinical and early clinical promise against treatment-resistant solid tumors. The experimental therapy, called GCAR1, targets a unique marker identified on a specific group of solid cancerous tumors and trains a patient's own immune system to recognize and destroy malignant cells. The findings were reported in companion papers published in Nature and Nature Cancer.
"We've developed a first-in-class CAR T cell therapy, called GCAR1, that is showing strong preclinical and early clinical promise in sarcoma and other cancers," said Dr. Douglas Mahoney, PhD, director of the Riddell Centre for Cancer Immunotherapy at the Cumming School of Medicine and principal investigator on the Nature Cancer study. "Our colleagues at McMaster University have further demonstrated its potential in mouse models of a deadly brain cancer."
A novel target for solid tumors
The GCAR1 therapy represents a departure from traditional CAR T-cell approaches, which have achieved remarkable success in hematologic malignancies but have struggled against solid tumors. By identifying a distinct target present on specific solid tumors, the Mahoney lab has provided a blueprint for extending CAR T therapy's reach. The target is also expressed on kidney cancers and glioblastomas, broadening the potential therapeutic scope.
The speed of translation from bench to bedside has been notable. "We have had laser focus on this new target since 2021. Within six-months of building the medicine we had data back from mouse studies. The results were so striking we were able to get approval and move the therapy to a patient in 2023," said Dr. Franz Zemp, PhD, first author of the study and adjunct assistant professor in the Department of Biochemistry and Molecular Biology. "That speed of translation from the lab to the clinic is remarkable."
Early clinical experience in sarcoma patients
In Calgary, the therapy has been administered to two Canadian patients diagnosed with alveolar soft-cell sarcoma (搜索), a rare type of malignant tumor. The first patient, Stéphanie Alain, lived significantly longer than expected; her doctors estimate the therapy extended her life expectancy by 18 months. Her willingness to participate throughout her treatments enabled scientists to study lung biopsies taken before and after treatment, along with data from dozens of blood samples, each comprising thousands of cells.
"We anticipated learning something from Stéphanie's tissue and studied lung biopsies taken before and after treatment. We also generated data from dozens of blood samples, each comprising many thousands of cells," said Dr. Sorana Morrissy, PhD, associate director of Discovery and Innovation at the Riddell Centre and co-principal investigator who led the data science team.
Insights gleaned from that data informed the treatment of a second patient, a 55-year-old Calgary man, who received GCAR1 in combination with a well-tolerated companion immunotherapy. The results have been overwhelmingly positive, and his progress continues to be monitored.
"This clinical trial gave me hope. I was told there wasn't anything more that could be done to treat my cancer," said Kent B., husband and father of two daughters. "I saw several CT scans of my cancer. It had metastasized to my lungs. After the second therapy the scans showed that many of the tumours shrank, and some had disappeared."
Measurable tumor regression
Kent's treatment at the Arthur J.E. Child Comprehensive Cancer Centre was overseen by Dr. Mona Shafey, MD, a hematologist and cell therapy specialist. She described the radiographic improvements in detail.
"One of the lesions in Kent's lungs was over 2.5 centimeters in size, and now it's less than one centimeter. There was another smaller lesion that we could see on the first scan and then barely see it on the second," said Shafey. "With research we can bring new experimental treatments to patients who have exhausted all standard treatments. Cancer Care Alberta's leadership in conducting early-phase clinical trials and caring for patients receiving novel therapies is helping accelerate promising research into treatments that can extend and improve lives."
Expanding the therapeutic horizon
The distinct marker targeted by GCAR1 is not limited to sarcoma. The Nature paper led by Dr. Sheila Singh, MD, PhD, at McMaster University reports on preclinical success of GCAR1 against glioblastomas, a deadly form of brain cancer with few effective treatment options. The researchers are currently studying Kent's tumor samples before and after GCAR1 therapy and are already working toward more advanced versions of the therapy.
The GCAR1 research is part of the Living Medicine Initiative at the Cumming School of Medicine, which develops therapies that use the body's own building blocks—including cells, genes, and microbes—to detect, respond to, and repair disease at its source.
Collaborative infrastructure and support
Boreal Biomanufacturing (搜索), part of The Ottawa Hospital, manufactured the virus used to engineer the CAR T cells, while BC Cancer (搜索) provided critical reagents required for biomanufacturing. The study was supported by philanthropic contributions and grants from the Canadian Cancer Society, Canadian Institutes of Health Research (CIHR), BioCanRx, Alberta Children's Hospital Foundation, and Alberta Cancer Foundation.
Mahoney and Zemp are the inventors of the GCAR therapy and have a patent pending.