<i>In situ</i>vaccine application of inactivated CPMV nanoparticles for cancer immunotherapy

Chariou, Paul L.; Beiss, Veronique; Ma, Yifeng; Steinmetz, Nicole F.

doi:10.1039/d0ma00752h

Cited by 22 publications

(43 citation statements)

References 39 publications

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“…This relative deficit in efficacy of eCPMV was attributed to the lack of RNA TLR7 signaling as eCPMV is devoid of RNA . Additionally, our previous data demonstrated that chemically inCPMV was less efficacious than CPMV but more so than eCPMV . Furthermore, our previous report indicated that UV inCPMVjust like chemically inCPMVmaintained immunostimulatory properties as measured by TLR activation in the RAW Blue TLR reporter cell line .…”

Section: Results and Discussionmentioning

confidence: 99%

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Inactivated Cowpea Mosaic Virus in Combination with OX40 Agonist Primes Potent Antitumor Immunity in a Bilateral Melanoma Mouse Model

et al. 2022

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Viral immunotherapies are being recognized in cancer treatment, with several currently approved or undergoing clinical testing. While contemporary approaches have focused on oncolytic viral therapies, our efforts center on the development of plant virus-based cancer immunotherapies. In a previous work, we demonstrated the potent efficacy of the cowpea mosaic virus (CPMV), a plant virus that does not replicate in animals, applied as an in situ vaccine. CPMV is an immunostimulatory drug candidate, and intratumoral administration remodels the tumor microenvironment leading to activation of local and systemic antitumor immunity. Efficacy has been demonstrated in multiple tumor mouse models and canine cancer patients. As wild-type CPMV is infectious toward various legumes and because shedding of infectious virus from patients may be an agricultural concern, we developed UV-inactivated CPMV (termed inCPMV) which is not infectious toward plants. We report that as a monotherapy, wild-type CPMV outperforms inCPMV in mouse models of dermal melanoma or disseminated colon cancer. Efficacy of inCPMV is less than that of CPMV and similar to that of RNA-free CPMV. Immunological investigation using knockout mice shows that inCPMV does not signal through TLR7 (toll-like receptor); structure−function studies indicate that the RNA is highly cross-linked and therefore unable to activate TLR7. Wild-type CPMV signals through TLR2, -4, and -7, whereas inCPMV more closely resembles RNA-free CPMV which signals through TLR2 and -4 only. The structural features of inCPMV explain the increased potency of wildtype CPMV through the triple pronged TLR activation. Strikingly, when inCPMV is used in combination with an anti-OX40 agonist antibody (administered systemically), exceptional efficacy was demonstrated in a bilateral B16F10 dermal melanoma model. Combination therapy, with in situ vaccination applied only into the primary tumor, controlled the progression of the secondary, untreated tumors, with 10 out of 14 animals surviving for at least 100 days post tumor challenge without development of recurrence or metastatic disease. This study highlights the potential of inCPMV as an in situ vaccine candidate and demonstrates the power of combined immunotherapy approaches. Strategic immunocombination therapies are the formula for success, and the combination of in situ vaccination strategies along with therapeutic antibodies targeting the cancer immunity cycle is a particularly powerful approach.

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Section: Results and Discussionmentioning

confidence: 99%

“…We reported that 750 mM βPL, 1 mM formalin, or 7.5 J cm –2 UV sufficiently inactivated CPMV (inCPMV) and prevented plant infection. When used as in situ vaccine treatment, chemically inCPMV outperformed RNA-free VLPs but was less efficacious than wild-type CPMV in a murine dermal melanoma model; UV inCPMV was not tested …”

Section: Introductionmentioning

confidence: 99%

Inactivated Cowpea Mosaic Virus in Combination with OX40 Agonist Primes Potent Antitumor Immunity in a Bilateral Melanoma Mouse Model

et al. 2022

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“…16,20 These studies reported using different sources of UV light with various intensities and power settings, which The plant virus cowpea mosaic virus (CPMV) has been shown to be inactivated at UV doses of 2.5−5 J cm −2 . 23,25 CPMV consists of a bipartite ssRNA virus forming a 31 nm icosahedron with pseudo T = 3 symmetry. The differences in the UV dose required to yield inactivated virus preparations can be explained by differences in virus structure and assembly: CPMV's ssRNA genome is encapsulated into the internal cavity of the capsid; in contrast, TMGMV's genome is incorporated into the nucleoprotein assembly.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Inactivated Plant Viruses as an Agrochemical Delivery Platform

Chariou

Hensley

et al. 2021

ACS Agric. Sci. Technol.

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Nanoparticle-based pesticide delivery systems have emerged to decrease the environmental and health impact of pesticides while increasing their efficacy. A majority of nanopesticides in the development pipeline are synthetic materials, some of which present their own environmental risks. We propose the development of naturally occurring nanomaterials, namely plant viruses such as tobacco mild green mosaic virus (TMGMV), for the delivery of pesticides. We and others have previously shown that plant virus-based nanoparticles have favorable soil mobility properties and thus could offer new avenues for the delivery of pesticides to target root-feeding pests. Toward the application of plant virus-based vectors as pesticide delivery agents, we optimized inactivation methods. We report the successful inactivation of TMGMV using 10 J cm −2 of ultraviolet light, 1.5 M βPL, or 1 M formalin; the lack of infectivity was confirmed using Nicotiana tabacum Tennessee 86, N. tabacum Samsun nn, and tropical soda apple (Solanum viarum).

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“…Purified virus nanoparticles were quantified using UV/vis spectroscopy and BCA assay and characterized by agarose gel electrophoresis using 1.2% (w/v) agarose gels in 1× TBE buffer, denaturing sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) using 4−12% Nu-PAGE gels (Invitrogen), transmission electron microscopy (TEM) using a Tecnai TEM at 80 kV and uracyl acetate-stained (2% (w/v)) samples, size exclusion chromatography (SEC) using a Superose 6 column and A ̈KTA explorer (GE Healthcare), as well as dynamic light scattering using a Zetasizer Nano ZSP/ Zen5600 instrument (Malvern Panalytical). Detailed methods are as described in ref 35 To investigate the antibody response against the three plant viruses, a direct ELISA was performed. In 96 well plates, 100 μg/well CPMV, CPSMV, or TRSV were coated for 1 h, at room temperature.…”

Section: ■ Methodsmentioning

confidence: 99%

Cowpea Mosaic Virus Outperforms Other Members of the Secoviridae as In Situ Vaccine for Cancer Immunotherapy

et al. 2022

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In situ vaccination for cancer immunotherapy uses intratumoral administration of small molecules, proteins, nanoparticles, or viruses that activate pathogen recognition receptors (PRRs) to reprogram the tumor microenvironment and prime systemic antitumor immunity. Cowpea mosaic virus (CPMV) is a plant virus thatwhile noninfectious toward mammals activates mammalian PRRs. Application of CPMV as in situ vaccine (ISV) results in a potent and durable efficacy in tumor mouse models and canine patients; data indicate that CPMV outperforms small molecule PRR agonists and other nonrelated plant viruses and virus-like particles (VLPs). In this work, we set out to compare the potency of CPMV versus other plant viruses from the Secoviridae. We developed protocols to produce and isolate cowpea severe mosaic virus (CPSMV) and tobacco ring spot virus (TRSV) from plants. CPSMV, like CPMV, is a comovirus with genome and protein homology, while TRSV lacks homology and is from the genus nepovirus. When applied as ISV in a mouse model of dermal melanoma (using B16F10 cells and C57Bl6J mice), CPMV outperformed CPSMV and TRSVagain highlighting the unique potency of CPMV. Mechanistically, the increased potency is related to increased signaling through toll-like receptors (TLRs)in particular, CPMV signals through TLR2, 4, and 7. Using knockout (KO) mouse models, we demonstrate here that all three plant viruses signal through the adaptor molecule MyD88with CPSMV and TRSV predominantly activating TLR2 and 4. CPMV induced significantly more interferon β (IFNβ) compared to TRSV and CPSMV; therefore, IFNβ released upon signaling through TLR7 may be a differentiator for the observed potency of CPMV-ISV. Additionally, CPMV induced a different temporal pattern of intratumoral cytokine generation characterized by significantly increased inflammatory cytokines 4 days after the second of 2 weekly treatments, as if CPMV induced a "memory response". This higher, longer-lasting induction of cytokines may be another key differentiator that explains the unique potency of CPMV-ISV.

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In situvaccine application of inactivated CPMV nanoparticles for cancer immunotherapy

Abstract: Cowpea mosaic virus (CPMV) is currently in the development pipeline for multiple biomedical applications, including cancer immunotherapy.

Cited by 22 publications

References 39 publications

Inactivated Cowpea Mosaic Virus in Combination with OX40 Agonist Primes Potent Antitumor Immunity in a Bilateral Melanoma Mouse Model

Inactivated Cowpea Mosaic Virus in Combination with OX40 Agonist Primes Potent Antitumor Immunity in a Bilateral Melanoma Mouse Model

Inactivated Plant Viruses as an Agrochemical Delivery Platform

Cowpea Mosaic Virus Outperforms Other Members of the Secoviridae as In Situ Vaccine for Cancer Immunotherapy

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