Cowpea mosaic virus as a candidate for intratumoral immunotherapy: progress, challenges, and future directions

Immunotherapy has emerged as a new pillar of cancer therapeutics that utilizes the patients own immune system to target tumor cells, a particular advantage in the context of hard-to-treat cancers. Virus-based immunotherapies have shown great potential as cancer treatments, including oncolytic viruses, viral vectors and virus-like particles. Here, we discuss the development, applications, challenges, and future opportunities of cowpea mosaic virus (CPMV) as a plant virus-based candidate for intratumoral immunotherapy, focusing on the treatment of aggressive, metastatic and refractory solid tumors. Evidence of antitumor efficacy has been gathered from mouse tumor models and veterinary clinical trials involving canine cancer patients. CPMV is promising as a monotherapy and as part of combination therapies, including chemotherapy, radiation, checkpoint inhibitors, and cytokine therapies. The putative mechanism of action is described, highlighting key features such as the capsid proteins and RNA acting as Toll-like receptor (TLR) agonists for TLR-2, TLR-4 and TLR-7, as well as the presentation of unique epitopes that prime a Th-1 balanced immune response. The nanoparticle structure of CPMV enhances efficacy by exerting multivalency and avidity effects. The biodistribution, toxicity, and agronomical safety profile of CPMV is also described, especially in relation to tumor retention, hematologic toxicity, allergenicity and adverse events, and viral shedding. This body of work provides a thorough exploration of a cancer immunotherapy candidate in development for more than 10 years, positioning CPMV as a promising intratumoral platform for hard-to-treat cancers.