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12 BioPharm International ® Emerging Therapies 2022 eBook www.biopharminternational.com where stem cells come in. The role of stem cells is three-fold. Stem cells: • Protect the oncolytic viruses from elimination by the patient's immune system • Amplif y t he v ira l par ticles, ser v ing as m in i bioreactors for this therapy • P r o duce p ote nt i m mu ne mo du l ator s , a ble to modif y instantly the tumor microenviron- ment to support virus multiplication and tumor cell targeting. Calidi has been developing cells, derived from fat tis- sue, suited to deliver an oncolytic virus to solid tumors, as was shown in a Phase I trial of an oncolytic vaccinia virus delivered by autologous stromal vascular fraction cells for the treatment of solid tumors (3). Similarly, the labs of Matt Lesniak and Karen Aboody have been de- veloping an oncolytic adenovirus, which, when loaded into a neural stem cell line, displayed enhanced ther- apeutic efficacy in a mouse model of glioblastoma—a very aggressive brain tumor (4). Their ongoing work led to a Phase I clinical trial of a drug named NeuroNova (NNV), with results demonstrating NNV's strong po- tential to treat glioblastoma in humans (2). Oncolytic viruses vs. other methods BioPharm: How does the use of oncoly tic vir uses as a method of treatment compare to the methods that are on the market today? What are the dif fer- ences in how they f unction? Minev: Cancer treatments today are highly var- ied, but one thing they have in common is that they of ten come with severe side effects that diminish the quality of life. For example, while many chemo- therapies are toxic to cells proliferating rapidly and out of control, they do not specifically target cancer cells. Therefore, these drugs kill healthy cells in ad- dition to cancer, which causes severe side effects. Immunotherapies on the market today are designed to treat cancer in a more targeted way. These include monoclonal antibodies, checkpoint inhibitors, T cell therapy, and cancer vaccines. Harnessing the im- mune system to seek and destroy cancer cells the- oretically leaves healthy cells unharmed. In prac- tice, however, the different immunotherapies can be remarkably ef fective but come with a range of immune-related side effects. Oncolytic viral therapy is a type of immunother- apy t hat is exceptiona l ly power f ul because of its dual mode of action: initially, the oncoly tic vir us infects, multiplies, and spreads, directly killing can- cer cells. As the contents of the tumor cells dissipate into the tumor microenvironment alongside viral antigens, the patient's immune system activates to clear away any remaining cancer cells. Moreover, the safety profile of oncolytic virus therapies is bet- ter than other immunotherapy drugs. For example, chimeric antigen receptor T cell therapies can trig- ger life-threatening toxicity events in the patient. In contrast, oncolytic virus therapies cause only mild, f lu-like symptoms in patients. Developing treatments BioPharm: What has the development of treatments using oncolytic viruses been like? What challenges did you encounter along the way? Minev: In the last seven years, Calidi's scientific and manufacturing teams led by Antonio Santidrian have overcome numerous challenges. We were able to develop many optimized protocols for stem cell expansion and characterization, including the de- velopment of specific media and growth factor cock- tails as well as precise protocols for stem cell loading with oncolytic viruses. Importantly, we perfected the freezing and thawing protocols for our therapies to allow instant preparation of our products without the need for any additional processing steps at the clinical sites. This development is essential to allow effective commercial development of our products to be able to treat thousands of patients with cancer. FDA reviewed investigational new drug (IND) ap- plications for NNV swiftly and has reviewed a draft of an IND for SuperNova, providing invaluable advice and recommendations for the final IND submission. Additionally, the scientific community has shown a great deal of support and excitement for the promis- ing early preclinical and Phase I data. Manufacturing challenges BioPharm: Do you foresee any challenges in manu- facturing treatments using oncolytic viruses? Minev: As already mentioned, due to the exten- sive manufacturing development and optimization, we do not foresee any significant challenges during the scale-up of our therapeutic products. The core components of our t herapies are a l logeneic stem cells and viral particles, which are straightforward a nd cost-ef fec t ive to ex pa nd com mercia l ly. T he subsequent production step of the therapy is highly streamlined: the components are combined and the process of loading the oncolytic virus into stem cells has been optimized extensively at our company over the past seven years. References 1. Nat iona l Ca ncer Inst it ute, "Ta limogene La her- parepvec," www.cancer.gov, accessed July 2022. 2. J. Fares et a l., Lancet Oncol, DOI:10.1016/S1470- 2045(21)00245-X (June 29, 2021). 3. B. Minev et al., J Transl Med, DOI:10.1186/s12967- 019-2011-3 (Aug. 19, 2019). 4. A. Ahmed et al., Mol Ther, DOI:10.1038/mt.2011.100 (Sept. 1, 2011). ■