Abstract B29: Systemic antimelanoma immunity induced by oncolytic adenovirus Delta-24-RGDOX
Authors: Jiang Hong , Shin Dong Ho , Carrillo Caroline , Henry Verlene , Fan Xuejun , Nguyen Teresa T. , Rivera-Molina Yisel , Lang Frederick F. , Gomez-Manzano Candelaria , Fueyo Juan 
Published: June 2022

Abstract
OX40 ligand (OX40L)-expressing oncolytic adenovirus Delta-24-RGDOX induces efficacious antiglioma immunity in syngeneic intracranial glioma models of immunocompetent mice. It is unknown if the virus is effective to treat metastatic melanomas. To study the abscopal immunity against metastatic melanomas induced by intratumoral injection of the virus in primary melanomas, we established subcutaneous/subcutaneous (s.c./s.c.) and subcutaneous/intracranial (s.c./i.c.) melanoma models with B16-Red-FLuc cells in C57BL/6 mice. In the s.c./s.c. model, compared to treatment with PBS, through monitoring the tumor growth with bioluminescence imaging, we found three doses of intratumoral injection of the virus significantly inhibited the growth of both the injected and the untreated distant tumors, resulting in prolonged survival of the mice with 50% long-term survival (P = 0.001). The surviving mice are resistant to rechallenging with the same tumor cells but are susceptible to lung cancer cells, suggesting the development of immune memory specific to the virus-injected tumor type. In the s.c./i.c. model, viral injection into the s.c. tumor induced antimelanoma activity in the brain, resulting in growth inhibition of both the s.c. and i.c. tumors and an improved survival of the animals (p = 0.005). Through flow cytometry analysis of the tumor-infiltrating lymphocytes, we found the virus injection increased the presence of CD3+ T lymphocytes, CD3+CD4+ helper T cells, CD3+CD8+ cytotoxic T cells, and the frequency of PD-1+ and effector (CD44+ CD62L-) T cells and decreased the amount of exhausted (PD-1+ TIM3+) and regulatory T cells in the injected tumors. Consistently, analysis of T cells in the blood, spleen, and brain hemispheres with untreated tumor revealed the same virus-mediated changes. Interestingly, through monitoring the T cells specific for tumor-associated antigen (TAA) in the mice through bioluminescence imaging, we found injecting Delta-24-RGDOX into the first s.c. B16-OVA melanoma increased the proliferation of OT-I/Luc CD8+ T cells infused in the same tumor and their migration to the distant untreated tumor originated from B16-OVA cells but not to the tumor from B16F10 cells, providing direct evidence that intratumoral viral injection promotes the in situ expansion of TAA-specific T cells. In summary, localized intratumoral injection of Delta-24-RGDOX induced an in situ autovaccination of the treated melanoma, of which the effect changes the immune landscape of the treated mice, resulting in the immunity against the disseminated s.c. or i.c. tumors.
Citation Format: Hong Jiang, Dong Ho Shin, Caroline Carrillo, Verlene Henry, Xuejun Fan, Teresa T. Nguyen, Yisel Rivera-Molina, Frederick F. Lang, Candelaria Gomez-Manzano, Juan Fueyo. Systemic antimelanoma immunity induced by oncolytic adenovirus Delta-24-RGDOX [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B29.