Transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans: mechanistic and biomarker findings from TUNIMO phase I trial
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-...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2025-01-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/1/e010493.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832583511986405376 |
|---|---|
| author | Tuomo Alanko Akseli Hemminki Víctor Cervera-Carrascón Riikka Havunen Kristian Taipale Dafne C A Quixabeira Jorma Sormunen Katriina Peltola Suvi Sorsa Santeri A Pakola Elise Jirovec Lyna Haybout Claudia Kistler Tatiana V Kudling Victor Arias James H A Clubb Mirte van der Heijden Teijo Pellinen Joao M Santos |
| author_facet | Tuomo Alanko Akseli Hemminki Víctor Cervera-Carrascón Riikka Havunen Kristian Taipale Dafne C A Quixabeira Jorma Sormunen Katriina Peltola Suvi Sorsa Santeri A Pakola Elise Jirovec Lyna Haybout Claudia Kistler Tatiana V Kudling Victor Arias James H A Clubb Mirte van der Heijden Teijo Pellinen Joao M Santos |
| author_sort | Tuomo Alanko |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ea814d2993f144ef95a0506dbe0caf6c |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-ea814d2993f144ef95a0506dbe0caf6c2025-01-28T12:15:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-01-0113110.1136/jitc-2024-010493Transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans: mechanistic and biomarker findings from TUNIMO phase I trialTuomo Alanko0Akseli Hemminki1Víctor Cervera-Carrascón2Riikka Havunen3Kristian Taipale4Dafne C A Quixabeira5Jorma Sormunen6Katriina Peltola7Suvi Sorsa8Santeri A Pakola9Elise Jirovec10Lyna Haybout11Claudia Kistler12Tatiana V Kudling13Victor Arias14James H A Clubb15Mirte van der Heijden16Teijo Pellinen17Joao M Santos18Docrates Cancer Center, Helsinki, FinlandCancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandCancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandCancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandHealth and Hospital Services, Wellbeing Services County of North Karelia – Siun sote, Joensuu, FinlandCancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandDocrates Cancer Center, Helsinki, FinlandComprehensive Cancer Center, HUS Helsinki University Hospital, Helsinki, FinlandCancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandCancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandCancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandCancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandTILT Biotherapeutics Ltd, Helsinki, FinlandCancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandCancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandCancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandCancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandDigital Microscopy and Molecular Pathology Unit, University of Helsinki Institute for Molecular Medicine, Helsinki, FinlandCancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandBackground 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.https://jitc.bmj.com/content/13/1/e010493.full |
| spellingShingle | Tuomo Alanko Akseli Hemminki Víctor Cervera-Carrascón Riikka Havunen Kristian Taipale Dafne C A Quixabeira Jorma Sormunen Katriina Peltola Suvi Sorsa Santeri A Pakola Elise Jirovec Lyna Haybout Claudia Kistler Tatiana V Kudling Victor Arias James H A Clubb Mirte van der Heijden Teijo Pellinen Joao M Santos Transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans: mechanistic and biomarker findings from TUNIMO phase I trial Journal for ImmunoTherapy of Cancer |
| title | Transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans: mechanistic and biomarker findings from TUNIMO phase I trial |
| title_full | Transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans: mechanistic and biomarker findings from TUNIMO phase I trial |
| title_fullStr | Transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans: mechanistic and biomarker findings from TUNIMO phase I trial |
| title_full_unstemmed | Transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans: mechanistic and biomarker findings from TUNIMO phase I trial |
| title_short | Transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans: mechanistic and biomarker findings from TUNIMO phase I trial |
| title_sort | transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans mechanistic and biomarker findings from tunimo phase i trial |
| url | https://jitc.bmj.com/content/13/1/e010493.full |
| work_keys_str_mv | AT tuomoalanko transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT akselihemminki transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT victorcerveracarrascon transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT riikkahavunen transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT kristiantaipale transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT dafnecaquixabeira transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT jormasormunen transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT katriinapeltola transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT suvisorsa transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT santeriapakola transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT elisejirovec transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT lynahaybout transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT claudiakistler transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT tatianavkudling transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT victorarias transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT jameshaclubb transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT mirtevanderheijden transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT teijopellinen transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial AT joaomsantos transientlymphocytecountdecreasecorrelateswithoncolyticadenovirusefficacyinhumansmechanisticandbiomarkerfindingsfromtunimophaseitrial |