Oncolytic Viral Therapy to Potentiate Immune Checkpoint Blockade in Immunologically Cold Brain Tumors

Principal Investigator: DIAZ, AARON
Program: PRCRP
Proposal Number: CA181015
Award Number: W81XWH-19-1-0348
Funding Mechanism: Translational Team Science Award
Partnering Awards: CA181015P1, CA181015P2
Award Amount: $834,570.00


Brain and spinal-cord cancers comprise the second most common type of cancer in children. Standard-of-care therapy includes surgery and radiation. Although these therapies slow disease progression considerably, they can also cause disabling side-effects, cognitive impairments, and learning disabilities. This gap in cancer treatment impacts the health and wellbeing of military members, Veterans, their beneficiaries, and the general public. There is a critical need for improved therapies for childhood brain tumors with fewer side effects.

Accordingly, the Department of Defense has designated brain cancer, pediatric brain tumors, and cancers in children as Topic Areas for the 2018 Translational Team Science Award. Our proposal addresses each of those areas. Moreover, our proposal develops immunotherapies, also a 2018 Topic Area, that harness a patient's own immune cells to hunt down and kill tumor cells.

Our proposal develops an exciting new approach known as oncolytic virus. It is a remarkable fact that some common viruses (e.g., measles, poliovirus) preferentially infect and kill tumor cells. This fact was discovered at the beginning of the 20th century. However, it was not until recently that we had the technology to modify virus, to enhance its killing efficiency and selectivity in killing only tumor cells, making oncolytic virus a viable approach.

Oncolytic viruses are also immunotherapies. This is due to the unique way in which the virus kills tumor cells. Oncolytic viruses kill tumor cells through a process known as immunologic cell death. This process not only kills the tumor cell but also releases proteins that stimulate an antitumor immune response. This is particularly advantageous in brain tumors, since brain tumors are notorious for being immunosuppressed and immunologically cold.

Another exciting development in immunotherapy is immune-checkpoint blockade, a strategy by which anti-tumor immunity is accelerated by de-repressing inhibitory checkpoints. However, while immune-checkpoint blockade has been successful in blood cancers, it has been less successful in solid tumors, which have less infiltrating immune cells to begin with. Brain tumors have been among the most resistant, since they are so immunologically cold. Our preliminary data; however, show that virus therapy can "wake up" the immune system and potentiate subsequent immune-checkpoint inhibition.

We propose studies to develop combining oncolytic virus with immune-checkpoint blockade in pediatric brain tumors. Our proposal applies single-cell sequencing to tumor biopsies from patients in our measles-virus pediatric brain-tumor clinical trial. We also perform studies in mice that test the effect of combining oncolytic virus with checkpoint-blockade strategies. Our proposal incorporates the talents of a diverse team of researchers. Dr. Kasahara is a leader in the development of in oncolytic viral therapies, including viral therapeutics with FDA "Breakthrough Therapy" designation. Dr. Mueller is a pediatric neuro-oncologist with significant experience conducting clinical trials in children with brain tumors. Dr. Diaz is a pioneer in the field of high-throughput single-cell sequencing of clinical samples.

We have a track record in obtaining funding for clinical trials (currently 10 active trials and 4 more under active development). We work with several non-profits, and we anticipate that we will be successful in raising additional funds for an expansion of our ongoing clinical trial of measles virus to include combination therapies with immune-checkpoint inhibitors, based on the success of the preclinical studies proposed here.