A Phase 1 Trial of Oncolytic Adenovirus ICOVIR-5 Administered Intravenously to Cutaneous and Uveal Melanoma Patients

Abstract

Oncolytic viruses represent a unique type of agents that combine self-amplification, lytic and immunostimulatory properties against tumors. A local and locoregional clinical benefit has been demonstrated upon intratumoral injections of an oncolytic herpes virus in melanoma patients, leading to its approval in USA and Europe for patients without visceral disease (up to stage IVM1a). However, in order to debulk and change the local immunosuppressive environment of tumors that cannot be injected directly, oncolyitc viruses need to be administered systemically. Among different viruses, adenovirus has been extensively used in clinical trials but with few evidences of activity upon systemic administration. Preclinical efficacy of a single intravenous administration of our oncolytic adenovirus ICOVIR5, an adenovirus type 5 responsive to the pRB pathway commonly deregulated in tumors, led us to use this virus in a dose-escalation phase I trial in metastatic melanoma patients. The results in 12 patients, treated with a single infusion of a dose up to 1E13 viral particles, show that ICOVIR5 can reach melanoma metastases upon a single intravenous administration but fails to induce tumor regressions. These results support the systemic administration of armed oncolytic viruses to treat disseminated cancer.

Innate immunity to adenovirus: lessons from mice

“…Second, the highly efficient binding of coagulation FX of human origin to HAdv-C5 was also shown for mouse coagulation FX [8]. Sixth and last, leukocytopenia and thrombocytopenia observed after intravenous administration of HAdv to mice [] are also observed in rabbits [150], nonhuman primates [59], and humans [148] but not in pigs [151]. Fourth, the cytosolic inactivation of HAdv-Ab complexes by TRIM21 appears to function in both mouse and human systems [141,142].…”

“…First, HAdv serotypes of species A, C, D, E, and F can utilize CAR of both human and mouse origin as a primary high-affinity attachment receptor to gain entry into human and mouse cells [39,40]. Fifth, high-dose intravenous delivery to mice [143] and nonhuman primates [59] of HAdv triggers an acute release of IL-6 and TNF-a, a response stereotypically observed in patients with severe natural HAdv infection [144][145][146] and during clinical gene therapy trials with systemic delivery of high doses of HAdv-based vectors [60,147,148]. Third, the natural IgM-and complement-mediated inactivation of FX-binding-ablated HAdv-C5-based vectors occurs in both mouse and human sera [26,27].…”

“…Fourth, the cytosolic inactivation of HAdv-Ab complexes by TRIM21 appears to function in both mouse and human systems [141,142]. Fifth, high-dose intravenous delivery to mice [143] and nonhuman primates [59] of HAdv triggers an acute release of IL-6 and TNF-a, a response stereotypically observed in patients with severe natural HAdv infection [144][145][146] and during clinical gene therapy trials with systemic delivery of high doses of HAdv-based vectors [60,147,148]. Sixth and last, leukocytopenia and thrombocytopenia observed after intravenous administration of HAdv to mice [] are also observed in rabbits [150], nonhuman primates [59], and humans [148] but not in pigs [151].…”

Delivery and Biosafety of Oncolytic Virotherapy

“…in clinical trials (44,77,(87)(88)(89). In addition, oncolytic adenovirus caused pleural effusion, dehydration, hypokalemia, severe liver dysfunction, and sepsis in clinical trials (90)(91)(92). Severe hematological abnormalities (leukopenia, lymphopenia, and neutropenia), hypokalemia and pancreatitis were observed in the trials of oncolytic pox virus (93)(94)(95)(96).…”

Effect of Transgene Location, Transcriptional Control Elements and Transgene Features in Armed Oncolytic Adenoviruses

“…Replication-selective oncolytic adenoviruses (OAds) with these modifications, such as CV706, CG7870, AdD24RGD, and ICOVIR5, entered clinical trials. However, despite occasional striking tumor responses, clinical efficacy remained low [7][8][9][10][11]. Thus, the potency of oncolytic adenoviruses should be further increased…”