Adenoviral IL24 (Ad-IL24) Tumor Suppressor Immune Gene Therapy Reverses Checkpoint Inhibitor Resistance and Induces Abscopal Therapeutic Efficacy

Abstract

Immune checkpoint inhibitors represent an important advance in cancer therapeutics. However, the majority of cancer patients do not respond or become resistant to this form of immune therapy. Interleukin 24 (IL-24) is a tumor suppressor cytokine in the IL-10 family with multiple anti-cancer mechanisms including induction of apoptosis, inhibition of angiogenesis and activation of immune modulatory genes. We evaluated the ability of Ad-IL24 to reverse immune checkpoint inhibitor resistance and induce abscopal therapeutic effects in the highly immune therapy resistant murine B16F10 melanoma tumor model. To mimic clinical conditions of immune checkpoint inhibitor resistance, animals with established tumors were treated with anti-PD-1 before initiating Ad-IL24 intratumoral therapy. Consistent with previously published studies, anti-PD-1 had minimal to no therapeutic efficacy compared to control treatment. There was severe tumor size progression in animals treated with anti-PD-1 monotherapy and a modest decrease for primary tumors treated with Ad-IL24 alone. In contrast, there was a statistically significant reversal of anti-PD-1 resistance in tumors treated with combination Ad-IL24 + anti-PD-1 therapy. A statistical analysis of variance (ANOVA) comparison of tumor volumes for each treatment group revealed that the combined effect of Ad-IL24 and anti-PD-1 treatment was synergistic compared to either therapy alone (p-value = 0.002). Surprisingly, there was a statistically significant abscopal effect with decreased growth of contralateral tumors that were not injected with Ad-IL24 tumor suppressor therapy. A statistically significant decrease in abscopal tumor growth was observed in animals whose primary tumors were treated with Ad-IL24 + anti-PD-1 (P<0.0001) compared to the growth rate of tumors treated with anti-PD-1 alone. These findings imply that the combination Ad-IL24 + anti-PD-1 treatment induced systemic immunity mediating the abscopal effects. With respect to survival, combined Ad-IL24 and anti-PD-1 therapy demonstrated a statistically significant increase in survival compared to Ad-IL24 therapy alone (p = 0.0167) and anti-PD-1 therapy alone (p < 0.001) by the log rank test. Consistent with the synergistic effects on tumor growth, the increase in median survival for the combined Ad-IL24 and anti-PD-1 group was more than additive compared to the effects of Ad-IL24 and anti-PD-1 treatments. Overall, these results indicate that Ad-IL24 tumor suppressor immune gene therapy can reverse immune checkpoint inhibitor resistance and induce abscopal effects with statistically significant synergistic therapeutic efficacy. These findings support the planned clinical evaluation of combined Ad-IL24 and anti-PD-1 therapy in patients resistant to immune checkpoint inhibitor therapy.