Closing the gap between research and the clinic

In the 1980s, the world was still nearly 30 years away from the first cell and gene therapies to be approved for blood cancer. 

Even then, though, there was an opportunity. 

Hideho Okada, MD, PhD, was studying to earn his Medical Degree at the Nagoya University School of Medicine in Japan in the late 1980s. He remembers how optimistic researchers and professors were about the potential of using a greater understanding of molecular biology, such as the function of cells and proteins, to treat cancer. 

“At the same time, when I’d go to clinical rotation, the reality was that doctors were still giving chemotherapy and surgeons were trying to take out as much cancer tissue as possible,” he said. “Patients were experiencing toxicities. So there was a huge gap between the molecular biology research and the realities of the clinic.” 

Dr. Okada’s first mentor during his training in the Nagoya University School of Medicine Neurosurgery Department was Dr. Jun Yoshida, who was developing a gene therapy for the brain cancer glioblastoma. 

“I was so fascinated,” Dr. Okada said. “This was a way to bridge the gap I was feeling – by implementing molecular biology in the clinic.” 

Dr. Okada worked at the University of Pittsburgh from 1998-2014 before joining the University of California San Francisco, where he has worked since 2014. At UCSF, in addition to being a Professor of Neurological Surgery, Dr. Okada is a Principal Investigator at the institution’s Brain Tumor Center and the Director of the Brain Tumor Immunotherapy Center. 

His latest research has focused on developing a cancer cell and gene therapy for children with diffuse midline glioma (DMG). Cell and gene therapies harness the power of a patient’s immune system to eliminate cancer cells while minimizing damage to healthy tissue. 

The brain tumor DMG is the second most common type of primary, high-grade brain tumor diagnosed in children. Approximately 300 children each year in the United States are diagnosed. 

“This disease happens in pediatric patients and there are no effective treatments,” Dr. Okada said. 

Testing the therapy in a clinical trial

Dr. Okada identified a mutated protein within DMG cells (H3.3K27M) and created an engineered T-cell receptor (TCR) therapy to target this protein.  

Solid tumors, such as diffuse midline glioma, express most of their unique proteins within the cancer cells. This is why Dr. Okada developed an engineered TCR therapy. 

“If you want to target cancer-specific antigens, then you have to target cancer-specific mutations or alterations that uniquely happen in cancer cells,” Dr. Okada said. “If you look at cancer-specific mutations, more than 90% happen in intracellular proteins. So the mutations happen in proteins inside the cell, not on the surface.” 

The T-cell receptor therapy is now ready for a phase 1 clinical trial, which Alliance for Cancer Gene Therapy is helping fund with a multi-year grant. 

“There are three major budgetary components (to running a clinical trial),” Dr. Okada said. “One is to make cells, or cellular manufacturing. The second is to run the trial, such as costs for the hospital and patient management. The third is the analysis portion and analyzing samples from patients … and understanding the biology. 

“In my application to ACGT, we specifically requested funds for cellular manufacturing. ACGT funding is critical because if you don’t make the cells, then you can’t even start anything else.”  

The clinical trial is a full-circle moment for Dr. Okada, who saw the potential of cell and gene therapy for treating brain tumors more than 30 years ago but recognized a gap between promising research and what was happening in the clinic. Dr. Okada, along with ACGT, is helping close that gap. 

“By doing this first set of clinical trials, we will have some basis to move forward,” Dr. Okada said. “We can’t do everything at once with patients. We have to go step by step.”