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In Vivo Fate of Cowpea Mosaic Virus In Situ Vaccine: Biodistribution and Clearance
Cowpea mosaic virus (CPMV) is a nucleoprotein nanoparticle that functions as a highly potent immunomodulator when administered intratumorally and is used as an in situ vaccine. CPMV in situ vaccination remodels the tumor microenvironment and primes a highly potent, systemic, and durable antitumor immune response against the treated and untreated, distant metastatic sites (abscopal effect). Potent efficacy was demonstrated in multiple tumor mouse models and, most importantly, in canine cancer patients with spontaneous tumors. Data indicate that presence of anti-CPMV antibodies are not neutralizing and that in fact opsonization leads to enhanced efficacy. Plant viruses are part of the food chain, but to date, there is no information on human exposure to CPMV. Therefore, patient sera were tested for the presence of immunoglobulins against CPMV, and indeed, >50% of deidentified patient samples tested positive for CPMV antibodies. To get a broader sense of plant virus exposure and immunogenicity in humans, we also tested sera for antibodies against tobacco mosaic virus (>90% patients tested positive), potato virus X (<20% patients tested positive), and cowpea chlorotic mottle virus (no antibodies were detected). Further, patient sera were analyzed for the presence of antibodies against the coliphage Qβ, a platform technology currently undergoing clinical trials for in situ vaccination; we found that 60% of patients present with anti-Qβ antibodies. Thus, data indicate human exposure to CPMV and other plant viruses and phages. Next, we thought to address agronomical safety; i.e., we examined the fate of CPMV after intratumoral treatment and oral gavage (to mimic consumption by food). Because live CPMV is used, an important question is whether there is any evidence of shedding of infectious particles from mice or patients. CPMV is noninfectious toward mammals; however, it is infectious toward plants including black-eyed peas and other legumes. Biodistribution data in tumor-bearing and healthy mice indicate little leaching from tumors and clearance via the reticuloendothelial system followed by biliary excretion. While there was evidence of shedding of RNA in stool, there was no evidence of infectious particles when plants were challenged with stool extracts, thus indicating agronomical safety. Together these data aid the translational development of CPMV as a drug candidate for cancer immunotherapy
Pharmacology of a Plant Virus Immunotherapy Candidate for Peritoneal Metastatic Ovarian Cancer
Due to the increasing incidence of cancer, there is a
need to develop
new platforms that can combat this disease. Cancer immunotherapy is
a platform that takes advantage of the immune system to recognize
and eradicate tumors and metastases. Our lab has identified a plant
virus nanoparticle, cowpea mosaic virus (CPMV) as a promising approach
for cancer immunotherapy. When administered intratumorally, CPMV relieves
the immune system of tumor-induced immunosuppression and reprograms
the tumor microenvironment into an activated state to launch systemic
antitumor immunity. The efficacy of CPMV has been tested in many tumor
models and in canine cancer patients with promising results: tumor
shrinkage, systemic efficacy (abscopal effect), and immune memory
to prevent recurrence. To translate this drug candidate from the bench
to the clinic, studies that investigate the safety, pharmacology,
and toxicity are needed. In this work, we describe the efficacy of
CPMV against a metastatic ovarian tumor model and investigate the
biodistribution of CPMV after single or repeated intraperitoneal administration
in tumor-bearing and healthy mice. CPMV shows good retention in the
tumor nodules and broad bioavailability with no apparent organ toxicity
based on histopathology. Data indicate persistence of the viral RNA,
which remains detectable 2 weeks post final administration, a phenomenon
also observed with some mammalian viral infections. Lastly, while
protein was not detected in stool or urine, RNA was shed through excretion
from mice; however, there was no evidence that RNA was infectious
to plants. Taken together, the data indicate that systemic administration
results in broad bioavailability with no apparent toxicity. While
RNA is shed from the subjects, data suggest agronomical safety. This
data is consistent with prior reports and provides support for translational
efforts