1. Administration of necroptosis-targeting AAVs in conjunction within vivo promotes durable tumor clearance.
Administration of necroptosis-targeting AAVs in conjunction within vivo promotes durable tumor clearance. α-PD-1 (A) B16.F10-OVA tumor growth curves after intratumoral administration of 1 × 1011 IFUs of death-inducing AAVs or eGFP control AAV. n = 8 to 14 mice per group. (B) Intratumoral concentrations of inflammatory cytokines and chemokines 48 hours after intratumoral AAV injection. The gray dashed line represents the limit of detection. n = 3 to 4 mice per group. (C) Tumor growth of ipsilateral (I, treated) and contralateral (C, untreated) B16.F10-OVA tumors after AAV administration. n = 10 to 12 mice per group. (D) Survival curves of B16.F10-OVA tumor–bearing mice after coadministration of AAVs with isotype control antibody. n = 14 to 15 mice per group. (E) Survival curves of B16.F10-OVA tumor–bearing mice after coadministration of AAVs with α-PD-1. n = 13 to 16 mice per group. (F) B16.F10-OVA tumor growth upon coadministration of necroptosis-inducing coRIPK3 AAV with α-CD8+ depletion antibody. n = 8 to 10 mice per group. (G) B16.F10-OVA tumor growth in Batf3−/− or wild-type control mice after necroptosis-inducing AAV administration. n = 10 to 13 mice per group. (H) Left: Schematic of tumor rechallenge experiments in mice from (E) successfully clear B16.F10-OVA tumors. (H) Right: Survival of mice rechallenged with B16.F10-OVA cells on the same flank as initial tumor location. n = 8 to 10 mice per group. (I) Kaplan-Meier plot for overall survival of skin cutaneous melanoma patients in TCGA data set. Data are parsed on upper and lower quartiles (25%) of RIPK3 mRNA expression. n = 114 patients per group. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < Black arrows indicate intratumoral AAV injections. Error bars represent SEM. Data are pooled from two to four independent experiments (A to H).
Annelise G. Snyder et al. Sci. Immunol. 2019;4:eaaw2004
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