Ultralow-dose binary oncolytic/helper-dependent adenovirus promotes antitumor activity in preclinical and clinical studies

Abstract

We show that a binary oncolytic/helper-dependent adenovirus (CAdVEC) that both lyses tumor cells and locally expresses the proinflammatory cytokine IL-12 and PD-L1 blocking antibody has potent antitumor activity in humanized mouse models. On the basis of these preclinical studies, we treated four patients with a single intratumoral injection of an ultralow dose of CAdVEC (NCT03740256), representing a dose of oncolytic adenovirus more than 100-fold lower than used in previous trials. While CAdVEC caused no significant toxicities, it repolarized the tumor microenvironment with increased infiltration of CD8 T cells. A single administration of CAdVEC was associated with both locoregional and abscopal effects on metastases and, in combination with systemic administration of immune checkpoint antibodies, induced sustained antitumor responses, including one complete and two partial responses. Hence, in both preclinical and clinical studies, CAdVEC is safe and even at extremely low doses is sufficiently potent to induce significant tumor control through oncolysis and immune repolarization.

Intratumoral delivery of immunotherapy to treat breast cancer: current development in clinical and preclinical studies

“…The oncolytic adenovirus CAdVEC, which encodes for IL-12 and aPD-L1, was delivered in four metastatic BC patients as part of a phase 1 trial (NCT03740256) ( 60 , 61 ). A single i.t.…”

“…A single i.t. injection caused an influx of CD8+ T cells and TME repolarization without significant toxicity ( 60 ). Gene set enrichment analysis of tumors pre- and post- treatment indicated antigen processing and presentation enrichment ( 60 ).…”

“…injection caused an influx of CD8+ T cells and TME repolarization without significant toxicity ( 60 ). Gene set enrichment analysis of tumors pre- and post- treatment indicated antigen processing and presentation enrichment ( 60 ). AE’s were either grade 1/2, with fatigue, fever, and injection site pain being the most frequently reported ( 61 ).…”

“…AE’s were either grade 1/2, with fatigue, fever, and injection site pain being the most frequently reported ( 61 ). Clinically, when combined with systemic checkpoint inhibitors, CAdVEC caused local and abscopal antitumor responses, with three partial responses observed ( 60 , 61 ).…”

“…immunotherapy. Clinical anti-tumor responses were noted in the following clinical trials: NCT02423902, NCT01703754 ( 51 ), NCT01846091 ( 53 ), NCT03740256 ( 60 , 61 ), NCT02779855 ( 62 ), and NCT03567720 ( 67 ). Numerous preclinical studies across a range of immunotherapies have demonstrated elimination of treated tumors ( 69 , 76 – 79 , 86 – 88 , 111 , 117 , 121 , 123 , 129 – 132 , 144 ).…”