Dividing Cancer Cell Oncology Research Concept 3d illustration proteins with lymphocytes gene editing  , t cells or cancer cells, meiosis, mitosis
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City of Hope scientists have developed a cancer-killing virus that they suggest could one day be used to improve the immune system’s ability to eradicate tumors in colon cancer patients. The team’s preclinical studies, reported in Molecular Cancer Therapeutics, represents a first step in demonstrating that the oncolytic virus, designated CF33, can target hard-to-treat tumors that “handcuff” the immune system and keep T cells from activating the immune system to kill cancer cells. Through their reported studies, the researchers demonstrated in mouse models that CF33 appears to increase expression of PD-L1 in tumor cells, and causes them to die in a way that stimulates an influx of activated immune cells. The team hopes to start clinical trials in 2021.

“CF33 is a safe, innovative virus City of Hope developed that can become a gamechanger because of how potent it is and because of its ability to recruit and activate immune cells,” said Susanne Warner, MD, a surgical oncologist at City of Hope and senior author of the study. “Our oncolytic virus trains the immune system to target a specific cancer cell. Preclinical models show that a combination treatment of oncolytic virus CF33 with anti-PD-L1 checkpoint inhibition leads to lasting antitumor immunity, meaning if a similar cancer cell ever tries to regrow, the immune system will be ready and waiting to shut it down.”

Warner and colleagues report their studies in a paper titled, “Recombinant Orthopoxvirus Primes Colon Cancer for Checkpoint Inhibitor and Cross-Primes T Cells for Antitumor and Antiviral Immunity.”

Colorectal cancer is the third leading cause of cancer-related deaths in the U.S., with 145,000 new cases diagnosed each year, and more than 50,000 deaths in 2019, the authors wrote. “Although surgery with or without chemotherapy can be curative at early stages, almost 50% of patients will ultimately develop liver metastases.” And while systemic chemotherapies can effectively lengthen lifespan for patients with unresectable metastatic disease, they will ultimately succumb to cancer, the team continued. “Thus, there is an urgent need for novel treatment paradigms to eradicate metastatic colorectal cancer and induce durable antitumor immunity for improved patient outcomes.”

Oncolytic viruses (OV) selectively infect, replicate in, and kill cancer cells, and the City of Hope team, along with other researchers, have demonstrated that OVs can activate T cells against tumor cells. To date, FDA has approved one oncolytic virus, T-VEC, which is a local immunotherapy treatment that kills melanoma cells, City of Hope said.

Yuman Fong, MD, the Sangiacomo Family Chair in Surgical Oncology at City of Hope, explained that CF33 has been designed to address a key problem in cancer, which is that most solid tumors do not respond to checkpoint inhibitors because the “uncloaked tumor cell” still isn’t recognized by the immune system. “CF33 selectively infects, replicates in and kills cancer cells. 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,” he said.

Fong and his team created the oncolytic recombinant orthopoxvirus, CF33, which they then tested against colon cancer, either alone, or in combination with immune checkpoint inhibitor therapy, against mouse models of colon cancer. “In this study, we tested if the antitumor efficacy of CF33-derivatives against colon cancer could be enhanced by immune-checkpoint inhibition (anti–PD-L1),” they explained. The results indicated that a combined treatment of the oncolytic virus and anti-PD-L1 was most effective against the cancer. Treatment also increased CD8+ T cells, which remember previous diseases and are ready to attack if reintroduced at a later time.

The treated animal models effectively developed anti-tumor immunity. “ … a combination of CF33 derivatives with anti–PD-L1 resulted in durable tumor regression and long-term survival, resistant to tumor rechallenge,” the investigators wrote. “We show that viral infection activates T cells against tumor cells and, in combination with checkpoint inhibition, confers durable antitumor response … Durable cure, defined as complete tumor regression and resistance to regrow tumors upon rechallenge with the same cells, was most often seen when virus treatment was combined with anti–PD-L1 administration.”

Fong and colleagues have in addition demonstrated antitumor immune efficacy of CF33 against triple-negative breast cancer cell lines, in brain tumor cells, in liver cancer models, and in pancreatic, prostate, ovarian, lung and head and neck cancer. Moreover, a recent City of Hope-led study found that CF33 could be combined with chimeric antigen receptor (CAR) T cell therapy to target and eliminate solid tumors that are otherwise difficult to treat with CAR T therapy alone.

Notably, the CF33 virus may be tracked by non-invasive PET scanning, which would enable a theranostic approach to treatment, whereby clinicians can concurrently treat and diagnose patients to enable more precise therapy. “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 next step for continued CF33 development will be to the virus platform in different solid tumor models. City of Hope has licensed CF33 to Imugene.

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