Case–Control Estimation of the Impact of Oncolytic Adenovirus on the Survival of Patients With Refractory Solid Tumors

Abstract

Oncolytic immunotherapy with cytokine armed replication competent viruses is an emerging approach in cancer treatment. In a recent randomized trial, an increase in response rate was seen but the effect on overall survival is not known with any virus. To facilitate randomized trials, we performed a case-control study assessing the survival of 270 patients treated in an Advanced Therapy Access Program (ATAP), in comparison to matched concurrent controls from the same hospital. The overall survival of all virus treated patients was not increased over controls. However, when analysis was restricted to GMCSF-sensitive tumor types treated with GMSCF-coding viruses, a significant improvement in median survival was present (from 170 to 208 days, P = 0.0012, N = 148). An even larger difference was seen when analysis was restricted to good performance score patients (193 versus 292 days, P = 0.034, N = 90). The survival of ovarian cancer patients was especially promising as median survival nearly quadrupled (P = 0.0003, N = 37). These preliminary data lend support to initiation of randomized clinical trials with GMCSF-coding oncolytic adenoviruses.

A century of oncolysis evolves into oncolytic immunotherapy

“…Many of the more promising viruses were used to treat cancer patients in an individualized therapy scheme, the Advanced Therapy Access Program: (ATAP), PETCT D Positron emission tomography-computed tomography, between 2007 and 2012. [2][3][4][5] In general, the adverse events were tolerable and less severe than those related to common chemotherapy.…”

“…An explanation for this finding could be that anti-viral antibodies help in induction of danger signaling at the tumor, breaking immunosuppressive tolerance, thus contributing to antitumor immunity. [2][3][4][5] Moreover, viruses may be able to hide from antibodies by using cells as stealth vehicles, or the mere quantity of virions produced by large tumors may simply overwhelm the opsonizing capacity of humoral immunity. Over and above antibodies, there might be also other relevant differences between different adenoviral serotypes.…”

“…Induction of neutralizing antibodies was seen regularly after treatments, but this is of unknown clinical relevance as there were examples of patient benefit in all classes of patients: those who had antibodies at baseline or not, and those whose antibodies were induced or not. [2][3][4][5][6] Based on quantitation of viral genomes in blood, oncolytic replication seems to taper off after several days or weeks in some cases, and repeated doses result in smaller replication peaks. However, there were frequent examples of patients where replication seemed to persist for months, but this did not correlate with efficacy or lack thereof.…”

“…Nevertheless, it can be summarized that all of the 10 used viruses were able to cause oncolysis and immune response while case examples of efficacy were repeatedly seen in patients. [2][3][4][5][6] Viruses were given safely intravenously and intratumorally. Induction of neutralizing antibodies was seen regularly after treatments, but this is of unknown clinical relevance as there were examples of patient benefit in all classes of patients: those who had antibodies at baseline or not, and those whose antibodies were induced or not.…”

Trial Watch—Oncolytic viruses and cancer therapy

“…172 The safety and efficacy of Cavatak TM (a proprietary variant of Coxsackievirus A21) 173 administered intratumorally or intravenously as standalone immunotherapeutic agent have been evaluated in 57 subjects with unresectable Stage IIIC-IV melanoma (NCT01227551), 174,175 and in 30 individuals with other advanced solid malignancies (NCT02043665). 176 The clinical profile of ONCOS-102 (a GM-CSF-expressing human serotype 5 adenovirus optimized to replicate in malignant cells, also known as CGTG-102 or Ad5/3-D24-GMCSF) 177,178 has been investigated in nine subjects with melanoma, who received ONCOS-102 in combination with standard-of-care chemotherapy, 179 in two cohorts of 15 sarcoma patients and 90 subjects bearing GM-CSF-sensitive tumors, who were treated with ONCOS-102 as standalone immunotherapeutic intervention, 177,180 in 13 patients with solid tumors refractory to standard therapies, who received ONCOS-102 in combination with low-dose cyclophosphamide, 181 as well as in 12 patients with solid tumors, receiving ONCOS-102 i.t. and i.v.…”