瘤内过继性 T 细胞治疗后辅以溶瘤腺病毒 Delta-24-RGDOX 可促进抗原扩散以维持全身抗肿瘤免疫

UNLABELLED: Cancer cell heterogeneity and immunosuppressive tumor microenvironment (TME) pose a challenge in treating solid tumors with adoptive cell therapies targeting limited tumor-associated antigens (TAA), such as chimeric antigen receptor 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 ovalbumin (OVA)-specific OT-I T cells were injected into the first subcutaneous tumor, followed by three injections of Delta-24-RGDOX.

We found TAA-targeting T cells injected into one subcutaneous 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 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. SIGNIFICANCE: Adjuvant therapy with oncolytic viruses promotes antigen spread to potentiate localized intratumoral adoptive T-cell therapy with limited TAA targets, leading to sustainable systemic antitumor immunity to overcome tumor relapse.