Cell and gene therapies against pediatric cancers.
John Maris, MD
Children’s Hospital of Philadelphia
In years past, clinical trials testing a specific surgery, chemotherapy or radiation therapy were often for one type of cancer. The emergence of targeted immunotherapies, including cell and gene therapy, has moved the cancer research field away from the one-cancer-at-a-time approach.
Scientists are developing novel therapies capable of treating multiple types of cancer because cell and gene therapies are usually designed around helping the immune system identify a specific target, such as a protein, on or inside cancer cells. That target can be relevant to several types of cancer.
This multi-cancer approach to developing cell and gene therapies is the vision of ACGT Research Fellow John Maris, MD (Children’s Hospital of Philadelphia, CHOP).
“It’s going to be about the targets and not the type of cancer,” Dr. Maris says.
ACGT-funded collaboration for peptide-centric CAR T cells.
Dr. Maris is a pediatric oncologist, a co-head of the Pediatric Cancer Dream Team, and the Giulio D’Angio Chair in Neuroblastoma Research at Children’s Hospital of Philadelphia. He is part of a collaboration with Stephan Grupp, MD, and a biotech company, Hula Therapeutics, to develop cell and gene therapy for children with neuroblastoma.
Neuroblastoma is a nerve cell cancer diagnosed in approximately 800 children in the U.S. each year. Dr. Maris and Dr. Grupp received funding through the ACGT-Barbara Netter Fund Collaboration Challenge Award to develop a “peptide-centric” CAR T-cell therapy for this pediatric cancer.
CAR T-cell therapy is a type of cell and gene therapy in which genetic engineering helps the patient’s immune system attack cancer more effectively. Scientists modify the patient’s own immune system to look for a specific protein expressed by the cancer cells. There are CAR T-cell therapies approved by the U.S. Food and Drug Administration (FDA) for cancer, specifically blood cancers like leukemia and lymphoma.
Dr. Maris says the premise of CAR T-cell therapy must be adjusted for solid tumors such as neuroblastoma. Instead of targeting proteins, which are often hidden within the cells for solid tumors, he designs the CAR T cells to target fragments of essential intracellular proteins that rise to the cancer cells’ surface. These fragments are called peptides.
“We have been working on how to target essential proteins that are critical for cancer cells to survive,” Dr. Maris says. “Many protein targets can be downregulated by the cancer cell to avoid being attacked. If the cells cannot lose the target, then they won’t be able to downregulate the proteins and escape.”
Looking at other pediatric cancers.
The impact of this research is not restricted to neuroblastoma. By targeting peptides through the patient’s HLA system, Dr. Maris’ cell and gene therapy is designed in a way to cover a large portion of the childhood cancer patient population.
Dr. Maris’ long-term goal is to develop a peptide-centric CAR T-cell therapy for many types of cancer.
“We have a vision of future peptide-centric CARs where the eligibility to receive the therapy is just the HLA type and not the specific cancer type,” Dr. Maris says. “It expands the patient population.”
Partnering with a childhood cancer biotech company.
Part of the collaboration is teaming CHOP with a new biotechnology company called Hula Therapeutics. Dr. Maris says Hula will help with investment and navigating the FDA’s clinical trial and approval process.
“I’m a physician-scientist who is tired of seeing children get sick and tired from standard therapies such as chemotherapy,” Dr. Maris says. “I’m tired of new therapies not being developed for childhood cancers due to the pharmaceutical industry not prioritizing them due to fewer cases and therefore lower returns on investment.
“So, the idea was to create a spinout biotech company that is specifically for childhood cancers. It is designed for children with cancer to be first – before adults.”
Dr. Maris is thankful for funding from ACGT to help promote childhood cancer research and initiate these important collaborations.
“What is so special about Alliance for Cancer Gene Therapy is it’s creating a community,” Dr. Maris says. “I think creating that community around cell and gene therapy was the original vision, and we are delighted that childhood cancer research is a very firm part of this community.”
“We have a vision of future peptide-centric CARs where the eligibility to receive the therapy is just the HLA type and not the specific cancer type. It expands the patient population.”
