TNFa and IL-2 armed adenoviruses enable complete responses by anti-PD-1 checkpoint blockade

Abstract

Releasing the patient's immune system against their own malignancy by the use of checkpoint inhibitors is delivering promising results. However, only a subset of patients currently benefit from them. One major limitation of these therapies relates to the inability of T cells to detect or penetrate into the tumor resulting in unresponsiveness to checkpoint inhibition. Virotherapy is an attractive tool for enabling checkpoint inhibitors as viruses are naturally recognized by innate defense elements which draws the attention of the immune system. Besides their intrinsic immune stimulating properties, the adenoviruses used here are armed to express tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2). These cytokines result in immunological danger signaling and multiple appealing T-cell effects, including trafficking, activation and propagation. When these viruses were injected into B16.OVA melanoma tumors in animals concomitantly receiving programmed cell-death protein 1 (PD-1) blocking antibodies both tumor growth control (p < 0.0001) and overall survival (p < 0.01) were improved. In this set-up, the addition of adoptive cell therapy with OT-I lymphocytes did not increase efficacy further. When virus injections were initiated before antibody treatment in a prime-boost approach, 100% of tumors regressed completely and all mice survived. Viral expression of IL2 and TNFa altered the cytokine balance in the tumor microenvironment towards Th1 and increased the intratumoral proportion of CD8+ and conventional CD4+ T cells. These preclinical studies provide the rationale and schedule for a clinical trial where oncolytic adenovirus coding for TNFa and IL-2 (TILT-123) is used in melanoma patients receiving an anti-PD-1 antibody.

Interleukin-7 loaded oncolytic adenovirus improves CAR-T cell therapy for glioblastoma

“…We also observed that when used with oAD-IL7, the tumor in ltrating T cells presented elevated PD1 and LAG-3 expression. This result has also been observed in previous study, such as using IL12 loaded oncolytic vaccinia, IL2 loaded oncolytic adenovirus, or bispeci c antibody loaded oncolytic adenovirus [27][28][29]. Other than T cells exhaustion, this result has been widely reported and was regarded as a sign of increased activation of tumorin ltrating T cells.…”

Combination of immunogenic oncolytic adenovirus ONCOS-102 with anti-PD-1 pembrolizumab exhibits synergistic antitumor effect in humanized A2058 melanoma huNOG mouse model

“…17,30 In contrast, other studies suggest that viral therapy can be enhanced by blockage of the PD-1:PD-L1 interaction and the combined therapy can increase antitumor efficacy. 42 In summary, synergistic antitumor effects were observed in the humanized mice treated with the combination of ONCOS-102 and pembrolizumab as demonstrated by reduced tumor volumes. Our results lead us to hypothesize that ONCOS-102 induced cell death of the tumor cells by recruiting immune cells to the tumor environment.…”

Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses

“…Arming oncolytic adenoviruses (OAds) with therapeutic transgenes is an attractive approach to increase their efficacy. OAds are a highly versatile therapeutic platform that allow oncoselective expression of a wide range of therapeutic molecules such as cytokines 9 , extracellular matrix modulators 7,10 , immune checkpoint blockades (IBCs) 11 , bi-specific T-cell engagers (BiTEs) 12 or prodrug converting enzymes 13 , allowing a multimodal tumour attack, from direct cell lysis to tumour microenvironment modulation.…”