Evaluation of tumor immunity after administration of conditionally replicative adenoviral vector in canine osteosarcoma patients

Payal Agarwal,Elizabeth A Gammon,Maninder Sandey,Stephanie S Lindley,Jey W Koehler,Brad M Matz,Annette N Smith,Elena A Kashentseva,Igor P Dmitriev,David T Curiel,Bruce F Smith

doi:10.1016/j.heliyon.2021.e06210

Payal Agarwal, Elizabeth A Gammon + Show 9 more

Open Access

https://doi.org/10.1016/j.heliyon.2021.e06210

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Journal: Heliyon	Publication Date: Feb 1, 2021
Citations: 3	License type: cc-by

Affiliation: Auburn University, Washington University in St. Louis

Abstract

Osteosarcoma is one among the most common neoplasms in dogs. Current treatments show limited efficacy and fail to prevent metastasis. Conditionally replicative adenoviruses (CRAd) replicate exclusively in targeted tumor cells and release new virus particles to infect additional cells. We proposed that OC-CAVE1 (CAV2 with the E1A promoter replaced with the osteocalcin promotor) may also enhance existing immunity against tumors by overcoming immune tolerance via exposure of new epitopes and cytokine signaling. Eleven client-owned dogs with spontaneously occurring osteosarcomas were enrolled in a pilot study. All dogs were injected with OC-CAVE1 following amputation of the affected limb or limb-sparing surgery. Dogs were monitored for viremia and viral shedding. There was minimal virus shedding in urine and feces by the 6th day and no virus was present in blood after 4 weeks. CAV-2 antibody-titers increased in all of the patients, post-CRAd injection. Immunological assays were performed to monitor 1) humoral response against tumors, 2) levels of circulatory CD11c + cells, 3) levels of regulatory T cells, and 4) cytotoxic activity of tumor specific T cells against autologous tumor cells between pre-CRAd administration and 4 weeks post-CRAd administration samples. Administration of the CRAd OC-CAVE1 resulted in alteration of some immune response parameters but did not appear to result in increased survival duration. However, 2 dogs in the study achieved survival times in excess of 1 year. Weak replication of OC-CAVE1 in metastatic cells and delay of chemotherapy following CRAd treatment may contribute to the lack of immune response and improvement in survival time of the clinical patients.

Highlights

Appendicular osteosarcoma (OSA) is a common neoplasm in dogs, with at least 8,000–10,000 cases diagnosed per year, accounting for 5–6% of all canine malignancies and approximately 80% of all canine bone neoplasms [1, 2]
Amputation alone results in a median survival time of approximately 6 months, which increases to approximately one year if chemotherapy is added, but most dogs still succumb to metastatic disease [2, 4, 5]
Conditionally replicative adenoviruses (CRAd) have been proposed as a potent therapy for eradication of cancer stem cells (CSC) [7, 8]

Summary

Introduction

Appendicular osteosarcoma (OSA) is a common neoplasm in dogs, with at least 8,000–10,000 cases diagnosed per year, accounting for 5–6% of all canine malignancies and approximately 80% of all canine bone neoplasms [1, 2]. Amputation alone results in a median survival time of approximately 6 months, which increases to approximately one year if chemotherapy is added, but most dogs still succumb to metastatic disease [2, 4, 5]. A different strategy is needed to improve survival times by eradicating the remaining neoplastic cells and, in particular, focusing on eradication of micrometastatic disease. Oncolytic viruses are a promising tool for cancer gene therapy. Replication of the CRAd in turn releases thousands of new virus particles which may go on to infect new tumor cells [6]. CRAds have been proposed as a potent therapy for eradication of cancer stem cells (CSC) [7, 8]. CSCs are quiescent cells with a high tumorigenic potential and are resistant to many cancer therapies. It has been proposed that CSCs are responsible for causing tumor micro-metastases and relapse [9]

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