Immuno-oncology is all the rage now in biotech publications, with due cause. It is producing some pretty impressive results in patients who failed other therapies. Most of what gets written about involves strengthening or unlocking the action of one immune cell, the T cell. But our immune systems are armed with many types of ammunition; we have multiple kinds of cells that can initiate or follow through in getting rid of unwanted invaders or cancers. CIRM funds three clinical trials that test these lesser-traveled routes to juicing up our immune response to cancer.While this field is hot now, it is not new. It has been elusive; researchers have tried for decades to harness our multi-talented immune system in the war on cancer. One of those researchers, Robert Dillman, who has been working on it for 25 years, now leads a CIRM-funded clinical trial in Phase 3, which is the last leg in a long journey to having a therapy approved for any patient with metastatic melanoma.
Another CIRM-funded team is also in a Phase 3 trial, in this case a therapy for the brain cancer glioblastoma developed by ImmunoCellular Therapeutics. The third CIRM-funded team at Stanford is in the middle of an early phase trial testing for safety and early signs of effectiveness with a therapy that could become an off-the-shelf therapy for many different cancers.
25-year effort getting results
Dillman now works for Caladrius Biosciences, the company conducting the Phase 3 trial in many medical centers around the U.S. He heads the clinical trial team funded by CIRM to conduct the California portion of the trial. But he has been working on the concept behind the therapy since the 1990s, most of the time at Hoag Hospital in Orange County. His mom was diagnosed with cancer when he was 14, and she died of the disease when he was an undergraduate at Stanford. His entire career has been focused on immuno-oncology.
The current effort uses a part of the immune system called dendritic cells that are derived from the patient’s blood. A patient’s tumor cells from a cell line and their dendritic cells are exposed to each other in a lab culture flask. What dendritic cells are really good at is gobbling up the cancer cells, then presenting pieces of the destroyed cancer cells to the immune cells responsible for getting rid of tumors. So, when given back to the patient the dendritic cells present the cancer bits, or antigens, like road maps to the immune cells that can then seek out and kill the cancer stem cells. The company produced a great video explaining the process.
Unlike most of the other immunotherapies that generally only present or target one CSC antigen, the Caladrius strategy presents a multitude of CSC antigens through the dendritic cells. The therapy has been associated with minimal side effects and theoretically should be more effective than other therapeutic cancer vaccine approaches. With so many specific targets, the cells are less likely to cause immune attack on healthy cells and more likely to find all the renegade tumor cells. This therapy is also a bit slower acting, which is actually a good thing. Many of the other immune therapies trigger such a strong immune response, they cause flu like symptoms that sometimes require the therapy to be halted. The dendritic cell therapy has few side effects reported so far.
Caladrius plans to conduct the trial at 32 locations, with 20 of them recruiting patients currently. The first patient was dosed in June, and a total of 250
patients will be randomly selected to get the therapy or not, with two thirds getting the therapy. The researchers plan to review the interim results as early as the end of 2017.
One patient from the earlier phase trials of the therapy, Norm Beegun, believes he definitely benefited from the treatment and told his story to our board in May.
Other approaches to ousting cancer
The CIRM-funded team at Stanford began an early phase trial in August 2014 using an antibody that blocks a receptor on the surface of CSCs called CD47. One of the researchers on the team, Irving Weissman, has dubbed that gene the “don’t eat me gene(video)” because it tells the immune system cells responsible for getting rid of tumors to not do their job. When CD47 is blocked, the immune system cells called macrophages are able to destroy—in essence eat—the CSCs.
The initial study primarily seeks to determine safety and the best dose for moving forward. It is enrolling patients with advanced-stage solid tumors. So far 12 patients have been treated with five different doses, and the team continues to screen patients for higher doses to be treated in the coming months. The trial is open only at Stanford Cancer Center under the leadership of Branimir Sikic.
The team at ImmunoCellular plans to enroll 400 brain cancer patients at 120 clinical trial sites around the U.S., Canada and Europe. They are also developing a way to turn a patient’s dendritic cells into a vaccine that helps the immune system target cancer stem cells.