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

Aayushma Gautam,Nicole F Steinmetz,Lu Wang,Chao Wang,Veronique Beiss

doi:10.3390/ijms22189733

Aayushma Gautam, Nicole F Steinmetz + Show 3 more

Open Access

https://doi.org/10.3390/ijms22189733

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Abstract

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.

Highlights

The immune system plays a critical role in tumor surveillance, and cancer immunotherapy is a recognized pillar of cancer therapy
We have demonstrated that cowpea mosaic virus (CPMV) in situ vaccination stimulates a potent antitumor immune response in mouse models of melanoma, ovarian cancer, breast cancer, colon cancer [8,9], and glioma [11]
The resulting CPMV-AUNP is purified by spin filtration using 100 kDa cut off centrifugal devices to remove excess peptides and is characterized using a combination of native and denaturing gel electrophoresis, transmission electron microscopy (TEM), size exclusion chromatography (SEC) to confirm structural integrity of the nanoparticles and to determine the number of peptides per CPMV-AUNP

Summary

Introduction

The immune system plays a critical role in tumor surveillance, and cancer immunotherapy is a recognized pillar of cancer therapy. Aggressive tumors present with an immunosuppressed tumor microenvironment (TME), which hinders intrinsic anti-tumor immunity [1]. Immunotherapies targeting the TME and the various checkpoints of the cancer immunity cycle hold promise in cancer immunotherapy because these approaches modulate the activity of the immune system to promote its anti-tumor functions [2]. Various immune checkpoints have been identified, with the PD-1/PD-L1 pathway being a prominent target for cancer immunotherapy and several approved monoclonal antibody therapies, such as Nivolumab by Bristol-Myers Squibb and Pembrolizumab by Merck. PD-1 and PD-L1 are co-inhibitory factors that function as a “brake” to keep immune responses under control

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