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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.

SUBMITTER: Kanerva A

PROVIDER: S-EPMC4445619 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Case-control estimation of the impact of oncolytic adenovirus on the survival of patients with refractory solid tumors.

Kanerva Anna A Koski Anniina A Liikanen Ilkka I Oksanen Minna M Joensuu Timo T Hemminki Otto O Palmgren Juni J Hemminki Kari K Hemminki Akseli A

Molecular therapy : the journal of the American Society of Gene Therapy 20141110 2

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 ...[more]

PMID: 25381801

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Project description:BACKGROUND:Enadenotucirev is a chimeric adenovirus with demonstrated preclinical tumor-selective cytotoxicity and a short half-life. Further clinical mechanism of action data showed that enadenotucirev can gain access to and replicate within different types of epithelial tumors. This phase 1 dose escalation study assessed intravenous (IV) dose escalation with enadenotucirev to establish the maximum tolerated dose (MTD) and subsequently identify a suitable schedule for repeated cycles. METHODS:Sixty-one patients with advanced epithelial tumors unresponsive to conventional therapy were enrolled and received enadenotucirev monotherapy as part of this study. During the phase 1a dose escalation (n = 22) and expansion (n = 9), delivery of enadenotucirev between 1 × 1010 and 1 × 1013 viral particles (vp) on days 1, 3, and 5 (single cycle) was used to determine an appropriate MTD. Subsequent treatment cohorts (phase 1a, n = 6 and phase 1b, n = 24) examined the feasibility of repeated dosing cycles in either 3-weekly or weekly dosing regimens. RESULTS:Enadenotucirev displayed a predictable and manageable safety profile at doses up to the MTD of 3 × 1012 vp, irrespective of infusion time or dosing schedule. The most commonly reported treatment-emergent adverse events (TEAEs) of grade 3 or higher were hypoxia, lymphopenia, and neutropenia. The frequency of all TEAEs (notably pyrexia and chills) was highest within 24 h of the first enadenotucirev infusion and decreased upon subsequent dosing. Additionally, delivery of three doses of enadenotucirev over 5 days optimized pharmacokinetic and chemokine profiles in the circulation over time. CONCLUSIONS:This study provides key clinical data in patients with solid epithelial tumors following treatment with IV enadenotucirev monotherapy and supports further investigation of enadenotucirev in combination with other therapeutic agents at doses up to the MTD of 3 × 1012 vp. TRIAL REGISTRATION:( ClinicalTrials.gov Identifier: NCT02028442 ). Trial registration date: 07 January 2014 - Retrospectively registered.

Project description:Cancer immunotherapies strive to overcome tumor-induced immune suppression and activate antitumor immune responses. Although cytotoxic T lymphocytes (CTLs) play a pivotal role in this process, natural killer (NK) cells have also demonstrated remarkable tumor-killing abilities, given their ability to discriminate tumor cells from normal cells and mediate specific antitumoral cytotoxicity. NK cells activation depends on a balance between activation and inhibition signals from several ligands/receptors. Among them, MICA/NKG2D axis is a master regulator of NK activation. MHC class I chain-related polypeptide A (MICA) expression is upregulated by many tumor cell lines and primary tumors and serves as a ligand for the activating NK group 2D (NKG2D) receptor on NK cells and subpopulations of T cells. However, cancer cells can cleave MICA, making it soluble and de-targeting tumor cells from NK cells, leading to tumor immune escape.In this study, we present ICOVIR15KK-MICAMut, an oncolytic adenovirus (OAdv) armed with a transgene encoding a non-cleavable MICA to promote NK-mediated cell-killing capacity and activate the immune response against cancer cells. We first demonstrated the correct MICA overexpression from infected cells. Moreover, our MICA-expressing OAdv promotes higher NK activation and killing capacity than the non-armed virus in vitro. In addition, the armed virus also demonstrated significant antitumor activity in immunodeficient mice in the presence of human PBMCs, indicating the activation of human NK cells. Finally, OAdv-MICA overexpression in immunocompetent tumor-bearing mice elicits tumor-specific immune response resulting in a greater tumor growth control.In summary, this study highlights the significance of NK cells in cancer immunotherapy and presents an innovative approach using a modified oncolytic virus to enhance NK cell activation and antitumor immune response. These findings suggest promising potential for future research and clinical applications.

Project description:BackgroundA limitation of approved oncolytic viruses is their requirement for intratumoral (i.t.) injection. TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a chimeric oncolytic adenovirus suitable for intravenous (i.v.) delivery due to its capsid modification and dual selectivity devices. It is armed with tumor necrosis alpha and interleukin-2 for promoting T-cell activation and lymphocyte trafficking to tumors, thereby enhancing the antitumor immune response. Here, we present the findings after a single i.v. administration of TILT-123 in three phase I dose escalation clinical trials.MethodsPatients with advanced solid tumors initially received a single i.v. dose of TILT-123 ranging from 3 × 109 to 4 × 1012 viral particles (VP). Blood was collected at baseline, 1, 16, and 192 h (7 days) post-treatment for bioavailability and serum analysis. Tumor biopsies were collected prior to treatment and 7 days post-treatment for analysis of viral presence and immunological effects. Patients did not receive any other cancer therapies during this period.ResultsAcross all three trials (TUNIMO, TUNINTIL, and PROTA), 52 total patients were treated with i.v. TILT-123. Overall, TILT-123 was found to be well-tolerated, with no dose-limiting toxicities observed. Post-treatment tumor biopsies showed expression of viral genes, presence of TILT-123 adenovirus proteins or DNA, and changes in immune cell infiltration from baseline. Increased virus dose did not lead to increased virus detection in tumors. Median overall survival was longer in patients with confirmed presence of TILT-123 in post-treatment biopsies (280 versus 190 days, p = 0.0405).ConclusionTILT-123 demonstrated safety and significant intratumoral immunomodulation following a single i.v. administration, warranting further investigation.Trial registrationsTUNIMO-NCT04695327. Registered 4 January 2021, https://clinicaltrials.gov/study/NCT04695327 . TUNINTIL-NCT04217473. Registered 19 December 2019, https://clinicaltrials.gov/study/NCT04217473 . PROTA-NCT05271318. Registered 4 February 2022, https://clinicaltrials.gov/study/NCT05271318 .

Dataset Information

Case-control estimation of the impact of oncolytic adenovirus on the survival of patients with refractory solid tumors.

Publications

Case-control estimation of the impact of oncolytic adenovirus on the survival of patients with refractory solid tumors.

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