August 1, 2016 (Vol. 36, No. 14)
By Combining Gene Therapy and Immunotherapy, Tocagen Induces Cancer to Embrace Its Own Demise
If cancer cells were capable of understanding the phrase, “You’re your own worst enemy,” they wouldn’t think it applied to them. Yet cancer cells can be made to subvert themselves, as Tocagen, a cancer-selective gene therapy company, has demonstrated. Tocagen has developed a way to instigate cooperation between cancer and the immune system, an entity cancer ordinarily shirks or shuns.
Tocagen utilizes retroviral replicating vectors (RRVs) that are designed to selectively deliver therapeutic genes to cancer cells. The RRVs ensure that the genes integrate into the DNA of dividing cancer cells, which then serve as a factory for producing additional RRVs, which spread to neighboring cancer cells.
So far, so straightforward. But the inserted genes have a twist. They cause the cancer cells to produce an enzyme that converts a prodrug that kills not only additional cancer cells, but also immunosuppressive cells in the tumor microenvironment. A brake is taken off the immune system, which is further activated by tumor-associated antigens and viral proteins released from dying cancer cells.
Tocagen calls its conditionally lytic viral approach to cancer therapy Toca 511 & Toca FC. It is being investigated initially for the treatment of recurrent high-grade glioma, an aggressive form of brain cancer. In a Phase I trial against high-grade glioma, Toca 511 & Toca FC has increased the probability of two-year survival to 40% and doubled survival from about 7 months to about 14 months, compared to an external control.
“Our approach uses replicating, nonpathogenic, retroviral vectors to deliver the gene cytosine deaminase (CD) to actively dividing cancer cells,” says Harry Gruber, M.D., Tocagen’s president and CEO. “Even with tumor antigen drift, the therapy is designed to continue to work.”
Gene delivery, the first step of the therapy, is accomplished by Toca 511, an injectable RRV that encodes CD, a prodrug activator enzyme. The replicating virus can be delivered intravenously (even for patients with high-grade glioma) or directly to tumor cells. It then spreads through the tumor by budding and cell-to-cell contact, programming other cells to make CD and providing a long-term presence of the therapeutic gene.
During the second step of the therapy, patients take a proprietary tablet called Toca FC for one week. The CD converts this extended-release form of the prodrug 5-fluorocytosine (5-FC) into an approved drug called 5-fluorouracil (5-FU) that kills cancer cells and, importantly, immunosuppressive myeloid cells—such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs)—that would otherwise survive to help tumor cells evade the immune system.
“Unlike classical oncolytic viruses, our virus can first stealthily spread through a tumor before inducing killing via the prodrug,” explains Dr. Gruber. “This illustrates the importance of the virus being conditionally lytic.”
This approach of creating 5-FU directly in the tumor microenvironment eliminates the side effects to healthy tissue that have limited its conventional systemic use. And as cancer cells die, they release tumor-associated antigens (including neoantigens) and denatured viral proteins that further activate immune cells to target cancer.
“The half-life of 5-FU, the active drug, is very short. It’s measured in minutes,” Dr. Gruber notes. The treatment cycle with Toca FC is repeated at approximately six-week intervals. “Each cycle,” he adds, “may reactivate the immune system against the body’s own cancer.”
A subset of 27 high-grade glioma patients received higher dosages. For this subset, there was a 40% probability of survival at 24 months, and median survival was 14.4 months—more than double that of an external matched control group of patients receiving the current standard of care (the chemotherapy drug lomustine). “We’re seeing patients with complete tumor regression that has lasted over two years, and others with marked tumor shrinkage,” reports Dr. Gruber.
Tocagen is recruiting patients with recurrent glioblastoma or anaplastic astrocytoma for a Phase II/III trial, called Toca 5, in the United States and Canada. Enrollment is expected to close around the end of 2016. The company plans to soon launch additional sites in Germany, Israel, and South Korea.
For patient monitoring, Siemens, in partnership with Tocagen, has developed diagnostic tests. “The tests show that after Toca 511 is administered, it remains undetected in the bloodstream for about one month,” asserts Dr. Gruber. “Then, after Toca 511 is detected, it is cleared from the bloodstream, even though in re-resected tumor the virus can be detected.”
It is also feasible that predictive assays could guide therapeutic choices. For example, before administering treatment, clinicians could have patients’ tissue samples assessed for a distinctive mRNA expression signature, one that was first observed in assessments of samples collected from untreated patients who ultimately responded well to Toca 511, surviving more than 12 months after treatment.
Future Trials and Applications
Opportunities also may exist by combining Toca 511 & Toca FC with checkpoint inhibitors. While checkpoint inhibitors alone have the potential for long-term benefits, they also create the substantial detriment of autoimmunity.
“Toca 511, in contrast, activates the immune system selectively within the tumor,” insists Dr. Gruber. “Therefore, it is designed to not activate the immune system against healthy tissue. Depending on the setting, this may help enable or enhance the clinical activity of checkpoint inhibitors.”
Preclinical work confirms that Tocagen’s approach has potential in combination therapies that include checkpoint inhibitors, particularly anti-PD-1 and anti-CTLA-4 antibodies. This work indicates that the combination therapy can reduce tumor growth, increase tumor-infiltrating lymphocytes, and decrease tumor-associated suppressor cells, macrophages, and monocytes, thus lengthening survival.
Tocagen is focusing on brain cancers, but the company plans to demonstrate the versatility of its platform. Studies of the platform’s effectiveness against other cancers are forthcoming.
“There are two very important milestones in the near future,” Dr. Gruber declares. “The first is completing enrollment of the Phase II/III trial at new sites.” The second milestone is the beginning of an intravenous study for patients with metastatic cancers.
“Based on the ability of the intravenously administered virus to reach tumors in the brain, and evidence showing anticancer immune activation in metastatic models, we believe the therapy also will be effective here,” states Dr. Gruber. Tumor shrinkage, measured by MRI, will be a key indicator of success. “We expect to start read-outs around the end of this year,” Dr. Gruber adds.
Cancer is becoming a manageable disease. “We’re starting to see a reasonable number of cancer types with survival rates that weren’t previously possible,” Dr. Gruber observes. Tocagen’s platform, using gene, viral, and immunologic approaches, “is the birth of a new way to create a new therapy. No one should have to die from cancer.”
Location: 3030 Bunker Hill Street, Suite 230, San Diego, CA 92109
Phone: (858) 412-8400
Principal: Harry E. Gruber, M.D., President and CEO
Number of Employees: 57
Focus: Tocagen is a clinical-stage company that uses gene therapy to selectively activate the immune system to combat cancer.