Date Published: February 21, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Anna E. Czapar, Brylee David B. Tiu, Frank A. Veliz, Jonathan K. Pokorski, Nicole F. Steinmetz.
The plant viral nanoparticle cowpea mosaic virus (CPMV) is shown to be an effective immunotherapy for ovarian cancer when administered as in situ vaccine weekly, directly into the intraperitoneal (IP) space in mice with disseminated tumors. While the antitumor efficacy is promising, the required frequency of administration may pose challenges for clinical implementation. To overcome this, a slow release formulation is developed. CPMV and polyamidoamine generation 4 dendrimer form aggregates (CPMV‐G4) based on electrostatic interactions and as a function of salt concentration, allowing for tailoring of aggregate size and release of CPMV. The antitumor efficacy of a single administration of CPMV‐G4 is compared to weekly administration of soluble CPMV in a mouse model of peritoneal ovarian cancer and found to be as effective at reducing disease burden as more frequent administrations of soluble CPMV; a single injection of soluble CPMV, does not significantly slow cancer development. The ability of CPMV‐G4 to control tumor growth following a single injection is likely due to the continued presence of CPMV in the IP space leading to prolonged immune stimulation. This enhanced retention of CPMV and its antitumor efficacy demonstrates the potential for viral–dendrimer hybrids to be used for delayed release applications.
Ovarian cancer is the leading cause of death among gynecologic malignancies in the United States. While platinum chemotherapies are usually initially effective in treating ovarian cancer, the development of platinum resistance often leads to disease recurrence, making clear that novel and more effective treatment strategies are needed.1 Immunotherapies hold great promise and a variety are currently under investigation for treatment of ovarian cancer and other malignancies.2, 3, 4, 5 We recently demonstrated the efficacy of an in situ vaccination strategy using the nanoparticles formed by the plant virus cowpea mosaic virus (CPMV); efficacy was demonstrated in several tumor types, including ovarian cancer.6 An in situ vaccine works through direct administration of an immune‐stimulatory agent, here CPMV, into the local tumor environment to reverse tumor‐mediated immunosuppression and resensitize the immune system to tumor specific antigens. A particular advantage of this approach is that in situ vaccines are not limited by the presence of known antigens in tumor tissue.7 The in situ vaccine triggers innate and adaptive antitumor responses, where the tumor itself serves as the antigen source eliminating the need to determine specific antigens for a given malignancy.7, 8
Virus–dendrimer hybrid materials are a novel class of materials with a number of potential applications targeting materials and human health. Here we present the application of the CPMV‐G4 hybrid assembly as an immunotherapy; specifically the assembly functions as a depot with slow release of the immunostimulatory nanoparticle CPMV in the IP cavity, therefore prolonging its therapeutic antitumor effect in a mouse model of IP disseminated ovarian cancer. A single administration of the CPMV‐G4 hybrid resulted in matched efficacy compared to weekly treatment using the soluble CPMV formulation. This is an important finding and may enable the in situ vaccine application of CPMV assemblies for difficult to inject tumors, such as ovarian cancer or gliomas; in these disease settings reducing the number of necessary administrations while maintaining a potent immunotherapy effect is an important goal to enable successful translation of in situ applied (immune)therapeutics.
Preparation of CPMV Nanoparticles and Generation 4 PAMAM Dendrimer: CPMV was propagated in black‐eyed pea plants (V. unguiculata) and isolated using previously reported protocols.42
The authors declare no conflict of interest.