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www.biopharminternational.com Emerging Therapies 2022 eBook BioPharm International ® 11 far from the tumor site. Thus, all cancer cells at the tumor site, circulating in the blood, and at distant metastases—and any tumor cells that arise in the fu- ture—are subject to thorough eradication by the im- mune system, which reduces the risk of recurrence. More importantly, the oncolytic virus therapies have a high therapeutic index due to the following fea- tures: minimal systemic toxicity, non-overlapping with the toxicity of standard of care drugs; non-over- lapping mechanisms of action with the standard of ca re d r ugs, a l low i ng ef fect ive t reat ment combi- nations; low probabilit y of generating treatment resistance (not seen so far); and virus dose in targeted tumors increases over time, as opposed to classical drug pharmacokinetics where drug concentration decreases over time. BioPharm: Has other research been done on onco- lytic viruses, or are there any oncolytic virus-based drugs currently on the market? Minev: Decades of research on oncolytic viruses have been conducted before our work. But because the human immune system inactivated these viruses, they were largely ineffective in human trials. The only oncolytic virus therapy in the US market today, called talimogene laherparepvec (T-VEC), leverages the oncolytic herpes virus to treat advanced, inop- erable melanoma (1). T-VEC consists of unprotected vir us par ticles modif ied to activate some cells of the patient's immune system. Thus, the virus can- not persist long enough to have a significant thera- peutic effect because it is eliminated by the patient's immune system. Our strategy of loading oncolytic virus particles into stem cells takes a different approach. Because we allow the oncolytic virus to amplif y inside the stem cells and to produce important virally encoded factors prior to reaching the tumor, our therapies de- liver a tidal wave of oncolytic virus particles primed and ready to infect and k i l l t umor cel ls toget her with important virus-derived and stem cell-derived factors that are able to instantly modif y the tumor microenvironment to enhance the treatment effects. Therefore, our therapy is more complex and effective than just viruses packed inside cells. Deciding what to pursue BioPharm: What made you choose to research these viruses for potential research? What potential did it show at the onset? Minev: I was deeply impressed af ter seeing the results of the Phase I trial in glioblastoma, which lengthened patients' overall sur vival in this ver y dif f icult-to-treat tumor f rom 14.6 months to 18.4 months (2). Impor tantly, in the subset of patients with glioma with an unmethylated O6-methylgua- nine-DNA methyltransferase (MGMT) promoter, the median progression-free survival, and overall surviv- als were 8.8 vs. five months and 18.0 vs. 10 months, respectively (2). This was a remarkable achievement, as this tumor type is largely non-responsive to the ex- isting chemotherapy treatments. In this setting, the safety and tolerability of this drug were significantly impactful: it extended patients' lives and caused only mild side effects (i.e., symptoms of cold or f lu). I saw the potential for future trials testing more intensive treatments with NeuroNova (NNV) with the poten- tial for affecting more dramatic improvements in sur v iva l w it hout d i m i n ish i ng qua l it y of l i fe. In parallel, Calidi sought to utilize a similar approach to treat patients with advanced metastatic solid tu- mors. In a clinical trial, patients with a wide variety of solid tumors, including head and neck cancers, melanoma, and breast cancer, were treated using our approach (3). Again, side effects were minimal, and we were astounded to see some of these patients' tu- mors shrink significantly because of our treatment. Utilizing stem cells BioPharm: Why are oncolytic viruses housed within stem cells? What led to the discovery of using stem cells rather than other vectors? Minev: Oncolytic virus therapies over the years could not achieve their therapeutic potential because, when delivered to a patient unprotected, the viral particles were destroyed by the patient's immune sys- tem before they could affect the cancer cells. That's Oncolytic viruses have great potential to be harnessed to treat cancers because they replicate within tumor cells in a targeted fashion, leaving healthy cells unharmed. — Boris Minev, president, Calidi Biotherapeutics Development