Cervera-Carrascon et al. engineered oncolytic adenovirus to express TNF-α and IL-2, aiming to increase T cell infiltration and proliferation in the tumor microenvironment and increase the efficacy of checkpoint blockade. In patient-derived urological tumor histoculture, virotherapy alone and in combination with anti-PD-L1 decreased tumor cell viability and increased immunostimulatory cytokine production. Virotherapy and anti-PD-L1 synergized to reduce tumor growth and led to 100% survival and complete pathological responses in a melanoma mouse model. Virotherapy increased active CD8+ T cells and immunostimulatory cytokines in vivo.
Contributed by Shishir Pant
ABSTRACT: Checkpoint inhibitors have revolutionized cancer therapy and validated immunotherapy as an approach. Unfortunately, responses are seen in a minority of patients. Our objective is to use engineered adeno- viruses designed to increase lymphocyte trafficking and cytokine production at the tumor, to assess if they increase the response rate to checkpoint inhibition, as these features have been regarded as predictive for the responses. When Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (an oncolytic adenovirus coding for TNFa and IL-2, also known as TILT-123) and checkpoint inhibitors were used together in fresh urological tumor histo- cultures, a significant shift toward immune activity (not only tumor necrosis alpha and interleukin-2 but also interferon gamma and granzyme B) and increased T-cell trafficking signals (CXCL10) was observed. In vivo, our viruses enabled an anti-PD-L1 (a checkpoint inhibitor) delivering complete responses in all the treated animals (hazard ratios versus anti-PD-L1 alone 0.057 [0.007; 0.451] or virotherapy alone 0.067 [0.011; 0.415]). To conclude, when an engineered oncolytic adenovirus was utilized to modify the tumor microenvironment towards what meta-analyses have pointed as predictive markers for checkpoint inhibitory therapy, the response to them increased synergistically. Of note, key findings were confirmed in fresh patient-derived tumor explants.