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Published on: June 19, 2018
Transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans: mechanistic and
Santeri A Pakola1, James H A Clubb1,2, Tatiana V Kudling1
1Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.
Background:
Oncolytic viruses (OVs) are promising immunotherapeutics to treat immunologically cold tumors. However, research on the mechanism of action of OVs in humans and clinically relevant biomarkers is still sparse. To induce strong T-cell responses against solid tumors, TILT-123 (Ad5/3-E2F-d24-hTNFa-IRES-hIL2, igrelimogene litadenorepvec) was developed. TILT-123 encodes two transgenes: tumor necrosis alpha (TNFa) and interleukin-2 (IL-2). TUNIMO (NCT04695327) was a phase I clinical trial using TILT-123 in patients with advanced solid tumors aiming to assess the safety, efficacy, and immunological effects of TILT-123. Research presented in this study evaluated the immunological effects of TILT-123 in the TUNIMO trial by using biological samples collected from the patients during the study, with an objective to leverage the findings to develop possible biomarkers of response and gain insights into possible synergistic combination treatments.
Methods:
20 patients with advanced solid tumors were treated with TILT-123. Response to therapy was assessed with contrast-enhanced CT and fluorodeoxyglucose positron emission tomography, along with overall survival (OS) calculation. Biological samples from patients were collected in the form of blood and tumor biopsies. Collected samples were analyzed with immunohistochemistry, transcriptomics, proteomics, and flow cytometry.
Results:
TILT-123 induced cyclical decreases in blood lymphocyte count, and more substantial blood lymphocyte count correlated with better radiographical response and longer OS. Lymphocyte count findings were confirmed with external control dataset of 96 patients. More substantial lymphocyte count change was linked to stronger immune activation in plasma proteome after intravenous TILT-123 and the presence of TILT-123 mRNA in tumors. Regarding other assays. tumor biopsies profiled showed increased amounts of CD8+ T cells, CD4+ T cells and NK cells after intravenous TILT-123, but not after intratumoral TILT-123. Transcriptional differences were seen in tumors after intravenous therapy and intratumoral therapy, with patients benefitting therapy showing stronger downregulation of immune activation at all time points.
Conclusions:
TILT-123 therapy induced accumulation of effector lymphocytes in tumors. Peripheral lymphocyte count decrease is a promising biomarker for assessing oncolytic adenovirus therapy response.
Insights
Oncolytic virus TILT-123 therapy increased effector lymphocytes in tumors. Peripheral lymphocyte count decrease shows promise as a biomarker for oncolytic adenovirus therapy response in patients with advanced solid tumors.
Area of Science:
- Oncolytic virotherapy
- Immunotherapy
- Cancer research
Background:
- Oncolytic viruses (OVs) are emerging immunotherapeutics for cold tumors.
- Research on OV mechanisms and biomarkers in humans is limited.
- TILT-123 (igrelimogene litadenorepvec) encodes tumor necrosis alpha and interleukin-2 to enhance T-cell responses.
Purpose of the Study:
- Evaluate immunological effects of TILT-123 in the TUNIMO clinical trial.
- Identify potential biomarkers of response to TILT-123 therapy.
- Gain insights into synergistic combination treatments for advanced solid tumors.
Main Methods:
- Phase I TUNIMO trial treated 20 patients with advanced solid tumors using TILT-123.
- Therapy response assessed via CT, PET scans, and overall survival (OS).
- Biological samples (blood, tumor biopsies) analyzed using immunohistochemistry, transcriptomics, proteomics, and flow cytometry.
Main Results:
- TILT-123 induced cyclical decreases in blood lymphocyte counts, correlating with better response and OS.
- Increased CD8+, CD4+ T cells, and NK cells observed in tumors post-intravenous TILT-123.
- Peripheral lymphocyte decrease linked to immune activation and TILT-123 mRNA presence in tumors.
Conclusions:
- TILT-123 therapy promotes effector lymphocyte accumulation in tumors.
- Peripheral lymphocyte count decrease is a potential biomarker for oncolytic adenovirus therapy response.
