S100A9‐Targeted Cowpea Mosaic Virus as a Prophylactic and Therapeutic Immunotherapy against Metastatic Breast Cancer and Melanoma

Abstract

Prognosis and treatment of metastatic cancer continues to be one of the most difficult and challenging areas of oncology. Treatment usually consists of chemotherapeutics, which may be ineffective due to drug resistance, adverse effects, and dose‐limiting toxicity. Therefore, novel approaches such as immunotherapy have been investigated to improve patient outcomes and minimize side effects. S100A9 is a calcium‐binding protein implicated in tumor metastasis, progression, and aggressiveness that modulates the tumor microenvironment into an immunosuppressive state. S100A9 is expressed in and secreted by immune cells in the pre‐metastatic niche, as well as, post‐tumor development, therefore making it a suitable targeted for prophylaxis and therapy. In previous work, it is demonstrated that cowpea mosaic virus (CPMV) acts as an adjuvant when administered intratumorally. Here, it is demonstrated that systemically administered, S100A9‐targeted CPMV homes to the lungs leading to recruitment of innate immune cells. This approach is efficacious both prophylactically and therapeutically against lung metastasis from melanoma and breast cancer. The current research will facilitate and accelerate the development of next‐generation targeted immunotherapies administered as prophylaxis, that is, after surgery of a primary breast tumor to prevent outgrowth of metastasis, as well as, therapy to treat established metastatic disease.

Metastatic Colon Cancer Treatment Using S100A9-Targeted Cowpea Mosaic Virus Nanoparticles

“…26 In a RAW-Blue assay, the H6 and G3 peptides were unable to elicit any immunogenic response. 26 While native CPMV can delay tumor growth, it is the targeting that imparts the added efficacy. Past ovarian cancer studies using native CPMV have demonstrated that CPMV induces the upregulation of immunostimulatory cytokines such as IFNγ and IL-6 while decreasing levels of immunosuppressive cytokines like IL-10 and TGFβ.…”

Virus Like Particles: A Self-Assembled Toolbox for Cancer Therapy

“…Therefore, VLPs offer a unique opportunity to combine benefits of the multiple surfaces and supramolecular self-assembly of liposomes with the polyvalency and robustness of polymers, while also coming in a variety of shapes and sizes that provide a unique versatility over most other materials [41]. They are so diverse that their innate substructures have therapeutic applications for a multitude of cancer treatment such as chemotherapy, phototherapy [42], immunotherapy [43] and combinations with imaging. All these unique abilities of VLP nanoparticles to self-assemble, and for multifaceted functionalization, biocompatibility, immunogenicity, and high stability, create an ideal material for designing many therapeutic agents [27,37,40].…”

“…al. showed [43] the use of GGGS linker to modify their peptide of choice with thiol and azide groups for conjugation via thiol-maleimide chemistry and azide-alkyne click chemistry respectively. Poly(ethylene)glycol (PEG) linkers are popular amongst several nanocarrier platforms for providing structural stability and improving circulation half-time [73].…”

Injectable Hydrogel Containing Cowpea Mosaic Virus Nanoparticles Prevents Colon Cancer Growth

“…13 In recent work, we also demonstrated that CPMV targeted to the lungs primes innate immune activation and therefore protects from the onset of lung metastasis. 14 Mechanistically, CPMV modulates the tumor microenvironment (TME) by activating the innate immune cells (switch of M2 to M1 macrophages), recruitment and activation of natural killer (NK) cells, dendritic cells (DCs), and N1 neutrophils, thereby initiating a cascade of tumor cell killing mechanisms, resulting in efficient presentation of both tumor-associated and neoantigens, and generation of a functionally active adaptive antitumor immunity via tumor antigen-specific CD4 ± and CD8 ± effector and memory T cells. 8,10 Based on this body of data, we hypothesized that intraperitoneal (IP) administration of CPMV could protect from the onset of metastatic colon tumor growth.…”

“…We have demonstrated that CPMV elicits potent systemic and durable antitumor immunity through priming the innate immune system; efficacy has been reported in mouse models of colon cancer , and other tumor models , and in canine patients . In recent work, we also demonstrated that CPMV targeted to the lungs primes innate immune activation and therefore protects from the onset of lung metastasis . Mechanistically, CPMV modulates the tumor microenvironment (TME) by activating the innate immune cells (switch of M2 to M1 macrophages), recruitment and activation of natural killer (NK) cells, dendritic cells (DCs), and N1 neutrophils, thereby initiating a cascade of tumor cell killing mechanisms, resulting in efficient presentation of both tumor-associated and neoantigens, and generation of a functionally active adaptive antitumor immunity via tumor antigen-specific CD4 ± and CD8 ± effector and memory T cells. , …”