American Association for Cancer Research
crc-23-0054-s05.pptx (273.13 kB)

Supplementary Figure 4 from Adjuvant therapy with oncolytic adenovirus Delta-24-RGDOX after intratumoral adoptive T-cell therapy promotes antigen spread to sustain systemic antitumor immunity

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posted on 2023-03-31, 13:25 authored by Hong Jiang, Dong Ho Shin, Yanhua Yi, Xuejun Fan, Joy Gumin, Jiasen He, Andrew G. Gillard, Frederick F. Lang, Candelaria Gomez-Manzano, Juan Fueyo

The effect of combining pmel-1 T cells and Delta-24-RGDOX. A, A cartoon depiction of the treatment scheme for schedule (left) and positions of tumor implantation, T-cell and virus injection (right). s.c.: subcutaneously; i.t.: intratumorally. B, Plots of the bioluminescence of the tumors from the indicated treatment groups. C, Survival plots of the treatment groups. n = 9 except n = 8 for combination group. RGDOX: Delta-24-RGDOX. ns: not significant (p > 0.05); **: p<0.01. log-rank test.



Cancer cell heterogeneity and immunosuppressive tumor microenvironment (TME) pose a challenge in treating solid tumors with adoptive cell therapies targeting limited tumor-associated antigens (TAAs), such as CAR T-cell therapy. We hypothesize that oncolytic adenovirus Delta-24-RGDOX activates the TME and promote antigen spread to potentiate the abscopal effect of adoptive TAA-targeting T-cells in localized intratumoral treatment. Herein, we used C57BL/6 mouse models with disseminated tumors derived from B16 melanoma cell lines to assess therapeutic effects and antitumor immunity. gp100-specific pmel-1 or OVA-specific OT-I T-cells were injected into the first subcutaneous (s.c.) tumor, followed by three injections of Delta-24-RGDOX. We found TAA-targeting T-cells injected into one s.c. tumor showed tumor tropism. Delta-24-RGDOX sustained the systemic tumor regression mediated by the T-cells, leading to improved survival rate. Further analysis revealed that, in mice with disseminated B16-OVA tumors, Delta-24-RGDOX increased CD8+ leukocyte density within treated and untreated tumors. Importantly, Delta-24-RGDOX significantly reduced the immunosuppression of endogenous OVA-specific cytotoxic T lymphocytes (CTLs) while increasing that of CD8+ leukocytes and, to a lesser extent, adoptive pmel-1 T-cells. Consequently, Delta-24-RGDOX drastically increased the density of the OVA-specific CTLs in both tumors, and the combination synergistically enhanced the effect. Consistently, the splenocytes from the combination group showed a significantly stronger response against other TAAs (OVA and TRP2) than gp100, resulted in higher activity against tumor cells. Therefore, our data demonstrate that, as an adjuvant therapy followed TAA-targeting T-cells in localized treatment, Delta-24-RGDOX activates TME and promotes antigen spread, leading to efficacious systemic antitumor immunity to overcome tumor relapse.