Cowpea mosaic virus stimulates antitumor immunity through recognition by multiple MYD88-dependent toll-like receptors

Mao, Chenkai; Beiss, Veronique; Fields, Jennifer; Steinmetz, Nicole F.; Fiering, Steven

doi:10.1016/j.biomaterials.2021.120914

Cited by 44 publications

(110 citation statements)

References 83 publications

Supporting

Mentioning

102

Contrasting

Order By: Relevance

“…We recently demonstrated that the CPMV signals through TLR-2, TLR-4, and TLR-7. 55 The temporal variability of antibody titers is likely influenced by the intrinsic properties of peptides ( Table 1 ; hydrophobicity, length, or relative positioning of certain residues) and could be evaluated in future studies. For example, it would be useful to establish the attributes of peptides that elicit high antibody titers after a single dose when displayed on the CPMV and whether the administration of single doses of CPMV-362 and CPMV-988 would achieve lasting high antibody titers similar to those obtained after the prime-boost schedule.…”

Section: Discussionmentioning

confidence: 99%

“… 63 CPMV genomic RNA has been identified as a TLR-7 agonist, and its absence during antigen processing can mitigate the self-adjuvant properties of CPMV vaccines. 55 The difference of the antibody titers of CPMV implants compared to prime-boost formulations requires further analysis and may reflect a combination of RNA loss or other structural changes that influence subsequent interactions with (and activation of) innate immune cells. Future work will explore the addition of cryoprotectants before or during the lyophilization step to maintain the RNA cargo or addition of other TLR agonists as adjuvants.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cowpea Mosaic Virus Nanoparticle Vaccine Candidates Displaying Peptide Epitopes Can Neutralize the Severe Acute Respiratory Syndrome Coronavirus

et al. 2021

Self Cite

View full text Add to dashboard Cite

The development of vaccines against coronaviruses has focused on the spike (S) protein, which is required for the recognition of host-cell receptors and thus elicits neutralizing antibodies. Targeting conserved epitopes on the S protein offers the potential for pan-beta-coronavirus vaccines that could prevent future pandemics. We displayed five B-cell epitopes, originally identified in the convalescent sera from recovered severe acute respiratory syndrome (SARS) patients, on the surface of the cowpea mosaic virus (CPMV) and evaluated these formulations as vaccines. Prime-boost immunization of mice with three of these candidate vaccines, CPMV-988, CPMV-1173, and CPMV-1209, elicited high antibody titers that neutralized the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro and showed an early Th1-biased profile (2–4 weeks) transitioning to a slightly Th2-biased profile just after the second boost (6 weeks). A pentavalent slow-release implant comprising all five peptides displayed on the CPMV elicited anti-S protein and epitope-specific antibody titers, albeit at a lower magnitude compared to the soluble formulations. While the CPMV remained intact when released from the PLGA implants, processing results in loss of RNA, which acts as an adjuvant. Loss of RNA may be a reason for the lower efficacy of the implants. Finally, although the three epitopes (988, 1173, and 1209) that were found to be neutralizing the SARS-CoV were 100% identical to the SARS-CoV-2, none of the vaccine candidates neutralized the SARS-CoV-2 in vitro suggesting differences in the natural epitope perhaps caused by conformational changes or the presence of N -linked glycans. While a cross-protective vaccine candidate was not developed, a multivalent SARS vaccine was developed. The technology discussed here is a versatile vaccination platform that can be pivoted toward other diseases and applications that are not limited to infectious diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cowpea Mosaic Virus Nanoparticle Vaccine Candidates Displaying Peptide Epitopes Can Neutralize the Severe Acute Respiratory Syndrome Coronavirus

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…[ 27 ] In this previous work, CPMV was administered directly into an identified tumor; while non‐infectious toward mammals, the plant virus nanoparticles (VNPs) act as an adjuvant that activate the immune system via recognition of multiple pattern recognition receptors, namely toll‐like receptor (TLR)‐2, 4, and 7. [ 28 ] The CPMV‐mediated local innate immune activation leads to remodeling of the TME and recruitment and activation of innate immune cells. This is followed by tumor cell killing (mediated by neutrophils and natural killer cells) [ 26 , 29 ] and tumor antigen processing, which ultimately activates the adaptive arm resulting in cell‐mediated systemic anti‐tumor immunity.…”

Section: Introductionmentioning

confidence: 99%

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

Chung

Park²,

Cai³

et al. 2021

Advanced Science

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Our data indicate that RNA-free, empty CPMV (eCPMV) particles are recognized by TLR2 and TLR4. RNA-containing CPMV particles signal additionally through TLR7 [7]. In particular, CPMV signals through interferon gamma (IFN-γ) [8,9] as well as type-I interferons [7].…”

Section: Introductionmentioning

confidence: 99%

“…RNA-containing CPMV particles signal additionally through TLR7 [7]. In particular, CPMV signals through interferon gamma (IFN-γ) [8,9] as well as type-I interferons [7]. The innate immunostimulation recruits innate immune cells into the TME, i.e., reprogramming of M2 to M1 macrophages, infiltration of N1 neutrophils, etc.…”

Section: Introductionmentioning

confidence: 99%

Plant Viral Nanoparticle Conjugated with Anti-PD-1 Peptide for Ovarian Cancer Immunotherapy

Gautam

Beiss

Wang

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Immunotherapy holds tremendous potential in cancer therapy, in particular, when treatment regimens are combined to achieve synergy between pathways along the cancer immunity cycle. In previous works, we demonstrated that in situ vaccination with the plant virus cowpea mosaic virus (CPMV) activates and recruits innate immune cells, therefore reprogramming the immunosuppressive tumor microenvironment toward an immune-activated state, leading to potent anti-tumor immunity in tumor mouse models and canine patients. CPMV therapy also increases the expression of checkpoint regulators on effector T cells in the tumor microenvironment, such as PD-1/PD-L1, and we demonstrated that combination with immune checkpoint therapy improves therapeutic outcomes further. In the present work, we tested the hypothesis that CPMV could be combined with anti-PD-1 peptides to replace expensive antibody therapies. Specifically, we set out to test whether a multivalent display of anti-PD-1 peptides (SNTSESF) would enhance efficacy over a combination of CPMV and soluble peptide. Efficacy of the approaches were tested using a syngeneic mouse model of intraperitoneal ovarian cancer. CPMV combination with anti-PD-1 peptides (SNTSESF) resulted in increased efficacy; however, increased potency against metastatic ovarian cancer was only observed when SNTSESF was conjugated to CPMV, and not added as a free peptide. This can be explained by the differences in the in vivo fates of the nanoparticle formulation vs. the free peptide; the larger nanoparticles are expected to exhibit prolonged tumor residence and favorable intratumoral distribution. Our study provides new design principles for plant virus-based in situ vaccination strategies.

show abstract

Cowpea mosaic virus stimulates antitumor immunity through recognition by multiple MYD88-dependent toll-like receptors

Cited by 44 publications

References 83 publications

Cowpea Mosaic Virus Nanoparticle Vaccine Candidates Displaying Peptide Epitopes Can Neutralize the Severe Acute Respiratory Syndrome Coronavirus

Cowpea Mosaic Virus Nanoparticle Vaccine Candidates Displaying Peptide Epitopes Can Neutralize the Severe Acute Respiratory Syndrome Coronavirus

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

Plant Viral Nanoparticle Conjugated with Anti-PD-1 Peptide for Ovarian Cancer Immunotherapy

Contact Info

Product

Resources

About