Abstract 3569: Combining oncolytic adenovirus Delta-24-RGDOX with adoptive T cell therapy in localized treatment induces sustainable regression of disseminated solid tumors through antigen spreading
Authors: Jiang Hong , Shin Dong Ho , Yi Yanhua , Fan Xuejun , Gumin Joy , Alonso Marta M. , Lang Frederick F. , Gomez-Manzano Candelaria , Fueyo Juan 
Published: June 2022

CAR T therapy greatly improves the survival of patients with hematological malignancies. But its effect in solid tumors is suboptimal. Intratumoral injections of oncolytic viruses, including Delta-24-RGDOX (DNX-2440) from our group, directly lyse cancer cells and activate tumor microenvironment, leading to adaptive antitumor immunity. To take advantage of instant antitumor activity of T cells and virus-mediated in situ autovaccination against heterogeneous cancer cells, we hypothesize that intratumorally injections of tumor-targeting T cells followed by Delta-24-RGDOX overcome antigen escape of CAR T therapy, leading to more sustainable systemic anti-cancer immunity. Thus, we used subcutaneous (s.c.)/s.c. B16 melanoma mouse models to assess the effect of localized treatment in disseminated tumors. OVA (or gp100)-specific CD8+ T cells or CD19 CAR T cells were injected into the first tumor, followed by three injections of Delta-24-RGDOX into the same tumor. T cells and tumor cells from the mice were profiled for surface markers with flow cytometry and immune staining. Activity of splenocytes against tumor cells and specific tumor-associated-antigens (TAAs) was measured with ELISA. Tumor growth was monitored through measuring tumor size. The animal survival curves were plotted according to the Kaplan-Meier method. We found TAA-specific T cells injected into the first s.c. tumor showed tropism for disseminated s.c. and intracranial tumors, tumor draining lymph nodes, but not for spleen, peripheral blood and normal brain. Unlike untreated and Delta-24-RGDOX-treated tumor, T cell-treated tumor showed decreased expression of the target TAA which was depleted in the recurrent tumor. Moreover, Delta-24-RGDOX increased total T cell presence within the tumors, and the activity of the splenocytes against the tumor cells and other antigens than the one targeted by injected T cells. Consequentially, the combination of OVA-specific T cells and Delta-24-RGDOX was more potent to inhibit the injected and untreated disseminated tumor growth and caused improved survival rate than either of the agent alone (p &lt; 0.05). Importantly, we observed relapse of the regressed tumors in the group treated by T cells alone, but not in the combination group. The survivors from the combination therapy were protected from rechallenging with B16-OVA cells but not lung carcinoma cells, suggesting the development of immune memory. In summary, our study indicates the virus induces antigen spread, resulting in expansion of antitumor T cell repertoire to prevent cancer relapse in adoptive T cell therapy (ACT). Our data demonstrate that Delta-24-RGDOX collaborates with ACT to induce more potent systemic immunity against the tumors, leading to sustainable tumor regression.

Citation Format: Hong Jiang, Dong Ho Shin, Yanhua Yi, Xuejun Fan, Joy Gumin, Marta M. Alonso, Frederick F. Lang, Candelaria Gomez-Manzano, Juan Fueyo. Combining oncolytic adenovirus Delta-24-RGDOX with adoptive T cell therapy in localized treatment induces sustainable regression of disseminated solid tumors through antigen spreading [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3569.