Adenovirus Armed With TNFa and IL2 Added to aPD-1 Regimen Mediates Antitumor Efficacy in Tumors Refractory to aPD-1

Abstract

Immune checkpoint inhibitors such as anti-PD-1 have revolutionized the field of oncology over the past decade. Nevertheless, the majority of patients do not benefit from them. Virotherapy is a flexible tool that can be used to stimulate and/or recruit different immune populations. T-cell enabling virotherapy could enhance the efficacy of immune checkpoint inhibitors, even in tumors resistant to these inhibitors. The T-cell potentiating virotherapy used here consisted of adenoviruses engineered to express tumor necrosis factor alpha and interleukin-2 in the tumor microenvironment. To study virus efficacy in checkpoint-inhibitor resistant tumors, we developed an anti-PD-1 resistant melanoma model in vivo. In resistant tumors, adding virotherapy to an anti-PD-1 regimen resulted in increased survival (p=0.0009), when compared to anti-PD-1 monotherapy. Some of the animals receiving virotherapy displayed complete responses, which did not occur in the immune checkpoint-inhibitor monotherapy group. When adenoviruses were delivered into resistant tumors, there were signs of increased CD8 T-cell infiltration and activation, which - together with a reduced presence of M2 macrophages and myeloid-derived suppressor cells - could explain those results. T-cell enabling virotherapy appeared as a valuable tool to counter resistance to immune checkpoint inhibitors. The clinical translation of this approach could increase the number of cancer patients benefiting from immunotherapies.

Adenovirus Encoding Tumor Necrosis Factor Alpha and Interleukin 2 Induces a Tertiary Lymphoid Structure Signature in Immune Checkpoint Inhibitor Refractory Head and Neck Cancer

“…Indeed, previous reports have described increased TLS formation following ICI monotherapy. Likewise, although not representative of all ICI resistant phenotypes, we have previously reported a phenotypic change to the tumor microenvironment transcriptome following generation of anti-PD-1 resistance in a B16.OVA melanoma mouse model ( 21 , 34 , 35 ). These changes indicated suppression of T cell related genes.…”

Carvedilol targets β-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy

“…The resulting amplification of viral dose is advantageous in the treatment of disseminated malignancies like the clinically representative intraperitoneal models of HGSC we used here. T-cell immunity induced by oncolytic adenoviruses has been modelled in immunocompetent tumour-bearing mice but only following direct intratumoural injection of non-replicating adenoviruses into localised tumours 50 , 55 , 56 . Adenoviral species-specificity means that it has not yet been possible to evaluate the role of T cells in the antitumour response to replicating oncolytic adenoviruses, particularly following systemic delivery to mice with disseminated cancer.…”

Controlling Cell Trafficking: Addressing Failures in CAR T and NK Cell Therapy of Solid Tumours

“…Alongside the natural immunomodulation of OVs, their genetic modification allows for the tumour-localised expression of an extensive range of polypeptides or non-coding RNA to further enhance the inflammatory profile of the tumour, supporting immune cell migration and activation. A multitude of armed OVs have exhibited enhanced anti-tumour effects and are contenders for use alongside CAR T cell therapy [ 104 , 105 , 106 , 107 , 108 ]. OVs armed with an array of cytokines, chemokines, and bispecific T cell engagers (BiTEs) have been used to supplement the TME and have improved CAR T cell therapy efficacy in a range of preclinical studies [ 74 , 109 , 110 , 111 , 112 , 113 ].…”

“…The local expression of these cytokines promoted an anti-tumoural response by enhancing T cell proliferation, directly killing tumour cells, and by elevating the expression of other inflammatory factors [ 119 ]. The use of TILT-123 as a monotherapy and in combination with ACT has shown significant anti-tumoural activity, with modification of the tumour’s cytokine expression profile and increases in T cell infiltration, with compelling synergy with PD-L1 inhibition in a range of preclinical models [ 105 , 119 , 120 , 121 , 122 , 123 ]. TILT-123 is now being clinically investigated in two currently recruiting clinical trials, both as a monotherapy for solid tumours and in combination with tumour-infiltrating lymphocytes ACT for metastatic melanoma (NCT04695327, NCT04217473).…”