Phase I study with ONCOS-102 for the treatment of solid tumors – an evaluation of clinical response and exploratory analyses of immune markers

Abstract

BackgroundWe conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined.MethodsThe study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT).ResultsNo dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients.ConclusionsONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors.Trial registrationNCT01598129. Registered 19/04/2012

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

“…Adenoviruses constitute an attractive option as oncolytic viruses, as their replication cycle is well known, present potent lytic activity, can be produced at high titres and are easily genetically modified. In the past 20 years, multiple preclinical and clinical trials have used these viruses as therapeutic agents in the treatment of different tumours [2][3][4][5][6][7] . Despite the encouraging results in terms of safety, the efficacy of adenoviral treatments still needs to be improved in order to increase the clinical usefulness of this strategy 8 .…”

Modeling the Efficacy of Oncolytic Adenoviruses In Vitro and In Vivo: Current and Future Perspectives

“…Kuryk and colleagues recently demonstrated that an Ad5/3 chimeric OAd armed with GMCSF (ONCOS-102) significantly reduced tumor volume when combined with pembrolizumab (anti-PD-L1) in huNOG mice (NOD/Shi-scid/IL-2Ry null ) humanized with CD34+ cord blood cells [95]. ONCOS-102 had previously shown a good safety profile and tumor control in 40% of patients in a Phase I clinical trial (NCT01598129) [96]. As the investigators found increased CD8+ T cell infiltration at patient tumor sites, as well as increased PD-L1 expression, they hoped to combine ONCOS-102 with checkpoint inhibitors and thus utilized the huNOG mouse model for preclinical testing to approximate the clinical setting.…”

Immunotherapy for malignant pleural mesothelioma: current status and future directions

“…Additionally, they showed an increase in pro-inflammatory cytokines, tumor infiltrating lymphocytes (TILs), and inhibitory ligands (e.g., PD-L1) in 11 out of 12 patients. These findings suggest that ONCOS-102 can be used as a priming agent that is implemented with other immunotherapies (33). As such, a phase Ib/II clinical trial is currently recruiting patients to assess the safety of ONCOS-102 combined with pemetrexed/ cisplatin; afterward, a randomized cohort will be assessed to determine if there is a correlation between clinical outcomes and immunologic data ( Table 1).…”