Recent preclinical research by Susanne G. Warner, M.D., surgical oncologist, and Yuman Fong, M.D., the Sangiacomo Family Chair in Surgical Oncology, and his team has shown that a treatment that can provide durable anti-tumor immunity against colorectal cancer, and potentially to other types of solid tumors, is quickly becoming more than a possibility.
Treatments that eradicate cancer while providing tumor regression and anti-tumor immunity would provide lifesaving opportunities for all cancer types, but for patients who have colon cancer, which is the third most common cancer in the U.S., excluding skin cancer, it could vastly improve the current treatment landscape.
The researchers’ study, of which Warner was the senior author, determined that derivatives of an oncolytic virus known as CF33 had enhanced anti-tumor efficacy against colon cancer when given in combination with an immune checkpoint inhibitor, was recently published in the American Association for Cancer Research journal Molecular Cancer Therapeutics.
Priming colon cancer for immune checkpoint inhibition
Cancers can be challenging to treat for a number of reasons, one of which is their ability to evade recognition, and subsequent eradication, by the immune system. But oncolytic viruses, which have the ability to selectively infect, replicate within and kill tumor cells, are also able to recruit immune cells to tumor microenvironments. In doing so they prime the environment for other immunotherapies, like immune checkpoint inhibitors or chimeric antigen receptor (CAR) T cell therapies, to activate a T cell response against the cancer. Additionally, oncolytic viruses can also lead to an antiviral immune response, once again priming the tumor environment for a T cell-based immunotherapy.
To capitalize on this, the researchers turned to CF33 — an oncolytic virus previously designed by Fong that is known to have a robust immune response and efficacy against colorectal cancer cells and xenografts. For this study, the team engineered derivatives of the recombinant orthopoxvirus to allow for the insertion of a future transgene or to be imageable by positron emission tomography in order to visualize viral replication.
In order to understand how tumor cells responded to an infection with CF33-derivatives, the investigators examined the regulation of programmed death ligand-1 (PD-L1) in human and mouse colon cancer cells. PD-L1, a cell-surface protein expressed by innate immune system cells like macrophages and dendritic cells, is part of the programmed cell death-1 (PD-1) and PD-L1 pathway. The pathway serves as an immune checkpoint to prevent destruction of self or downregulate the immune response; however, tumor cells can also express PD-L1, and in doing so they evade activation and the response of cytotoxic T cells. The team found that PD-L1 mRNA was upregulated after viral infection in addition to seeing an increase of tumor-infiltrating lymphocytes, including macrophages and CD8+ T cells.
The presence of these cells in combination with increased expression of PD-L1 indicated that the environment was primed for the benefits an immune checkpoint inhibitor could provide; it would allow for the influx of T cells to kill tumor cells as well as activate proliferation of a longer-term adaptive response.
Synergy of CF33 and anti-PD-L1 leads to a durable anti-tumor response
To test their hypothesis about whether the use of the checkpoint inhibitor anti-PD-L1 could stimulate anti-tumor immunity, the team tested mice in four separate treatment groups: control with no treatment, anti-PD-L1 alone, CF33-derivative alone and a combination of CF33-derivative and anti-PD-L1. The data showed that the combination resulted in tumor regression, and when the mice were rechallenged with tumor cells, regrowth didn’t occur with the exception of one mouse.
To elucidate the specificity of this anti-tumor response, mice that received the combination therapy were rechallenged in one flank with the same tumor cell type (MC38-Luc) they’d been “cured” of as well as a different tumor cell type (Pan02-GFP) in the opposite flank. None of the mice regrew MC38-Luc tumors, but all of the mice with the exception of one grew Pan02-GFP tumors, indicating that the immunity is tumor specific.
When T cells were isolated and analyzed by flow cytometry from the four treatment groups, the activation signatures were higher in mice cured by virus treatment versus mice cured by anti-PD-L1 treatment alone. In addition, higher levels of interferon gamma were present in the supernatants of T cells exposed to the virus, suggesting the importance of an antiviral immune response as a primer for a more systemic anti-tumor immune response.
“This study demonstrates that a designer virus we created to infect a wide variety of cancers can make tumor cells very recognizable to the immune system,” Fong said. It also points to the potential for oncolytic viruses to turn “cold tumors” that are resistant to treatment into “hot tumors” that can be recognized by the immune system. CF33 has been shown to induce anti-tumor immunity against other cancers, including triple-negative breast cancer cell lines, brain tumor cells, liver cancer models and pancreatic, prostate, ovarian, lung, head and neck cancer.
The easy ability to insert transgenes or reporters into an oncolytic virus that allow for visualization adds an edge to this type of treatment that’s not available with other treatments. “If we can perfect the technique, we can give someone a viral injection and watch it work — see where it goes and identify cancer cells that we didn’t even know existed,” Warner said. “Doctors would have real-time data and know if we should give a patient a higher dose or where to direct the treatment based on tumors that have not yet been killed.”
The ability to fully assess the extent of treatment needed while simultaneously delivering therapy is a new approach in the field referred to as theranostic precision medicine. City of Hope is at the forefront of developing more therapies that can diagnose and treat concurrently. A clinical trial to test the safety of this treatment in human patients is expected to open in 2021.
See how oncolytic viruses can be used to treat cancer and induce anti-tumor and antiviral immunity.