Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024 Sep 3;30(17):3715-3725.
doi: 10.1158/1078-0432.CCR-23-3874.

Safety, Efficacy, and Biological Data of T-Cell-Enabling Oncolytic Adenovirus TILT-123 in Advanced Solid Cancers from the TUNIMO Monotherapy Phase I Trial

Santeri A Pakola #  1 , Katriina J Peltola #  2 , James H A Clubb  1   3 , Elise Jirovec  1 , Lyna Haybout  1   3 , Tatiana V Kudling  1 , Tuomo Alanko  4 , Riitta Korpisaari  4 , Susanna Juteau  5 , Marjut Jaakkola  2 , Jorma Sormunen  4 , Jukka Kemppainen  4 , Annabrita Hemmes  6 , Teijo Pellinen  6 , Mirte van der Heijden  1 , Dafne C A Quixabeira  1   3 , Claudia Kistler  3 , Suvi Sorsa  1   3 , Riikka Havunen  1   3 , Joao M Santos  1   3 , Victor Cervera-Carrascon  1   3 , Akseli Hemminki  1   2   3
Affiliations
Clinical Trial

Safety, Efficacy, and Biological Data of T-Cell-Enabling Oncolytic Adenovirus TILT-123 in Advanced Solid Cancers from the TUNIMO Monotherapy Phase I Trial

Santeri A Pakola et al. Clin Cancer Res. .

Abstract

Purpose: TILT-123 (igrelimogene litadenorepvec) is an oncolytic adenovirus armed with TNFa and IL2, designed to induce T-cell infiltration and cytotoxicity in solid tumors.

Patients and methods: TUNIMO (NCT04695327) was a single-arm, multicenter phase I dose-escalation trial designed to assess the safety of TILT-123 in advanced solid cancers refractory to standard therapy. Patients received intravenous and intratumoral TILT-123. The primary endpoint was safety by adverse events (AE), laboratory values, vital signs, and electrocardiograms. Secondary endpoints included tumor response, pharmacokinetics, and predictive biomarkers.

Results: Twenty patients were enrolled, with a median age of 58 years. Most prevalent cancer types included sarcomas (35%), melanomas (15%) and ovarian cancers (15%). No dose-limiting toxicities were observed. The most frequent treatment-related AEs included fever (16.7%), chills (13.0%), and fatigue (9.3%). Ten patients were evaluable for response on day 78 with RECIST 1.1, iRECIST or PET-based evaluation. The disease control rate by PET was 6/10 (60% of evaluable patients) and 2/10 by RECIST 1.1 and iRECIST(20%of evaluable patients). Tumor size reductions occurred in both injected and non-injected lesions. TILT-123 was detected in injected and non-injected tumors, and virus was observed in blood after intravenous and intratumoral injections. Treatment resulted in reduction of lymphocytes in blood, with concurrent lymphocyte increases in tumors, findings compatible with trafficking.

Conclusions: TILT-123 was safe and able to produce antitumor effects in local and distant lesions in heavily pre-treated patients. Good tolerability of TILT-123 facilitates combination studies, several of which are ongoing (NCT04217473, NCT05271318, NCT05222932, and NCT06125197). See related commentary by Silva-Pilipich and Smerdou, p. 3649.

PubMed Disclaimer

Conflict of interest statement

S.A. Pakola reports grants from Helsinki University Hospital Research Funds, Cancer Foundation Finland, Jane and Aatos Erkko Foundation, Red Cross Blood Service, and Sigrid Juselius Finland, other support from TILT Biotherapeutics Oy, and grants from the European Commission during the conduct of the study. K.J. Peltola reports other support from TILT Therapeutics during the conduct of the study and from Faron Pharmaceuticals outside the submitted work, as well as personal fees from BMS, MSD, IPSEN, Roche, Bayer, and Novartis. J.H.A. Clubb reports being employed and a shareholder at TILT Biotherapeutics. L. Haybout reports other support from TILT Biotherapeutics during the conduct of the study. T. Alanko reports other support from TILT Biotherapeutics during the conduct of the study; personal fees and non-financial support from AstraZeneca and MSD; personal fees and other support from Bristol Myers Squibb, Roche, and Incyte; personal fees, non-financial support, and other support from Pfizer; personal fees from Servier and Nordic Drugs; other support from AbbVie, Bayer, Boehringer Ingelheim, Lilly, Debiopharm Group, GlaxoSmithKline, and TILT Biotherapeutics; and non-financial support from Merck outside the submitted work. A. Hemmes reports other support from TILT Biotherapeutics during the conduct of the study. T. Pellinen reports grants from Roche Glycart AG outside the submitted work. D.C. Quixabeira reports personal fees from TILT Biotherapeutics during the conduct of the study and outside the submitted work. C. Kistler reports other support from TILT Biotherapeutics and from TILT Biotherapeutics during the conduct of the study. S. Sorsa reports grants from the European Innovation Council—European Commission and personal fees from TILT Biotherapeutics during the conduct of the study. R. Havunen reports personal fees from TILT Biotherapeutics and other support from TILT Biotherapeutics during the conduct of the study. J.M. Santos reports personal fees, non-financial support, and other support from TILT Biotherapeutics; grants from the European Innovation Council and Business Finland during the conduct of the study; and personal fees, non-financial support, and other support from TILT Biotherapeutics outside the submitted work. V. Cervera-Carrascon reports personal fees from TILT Biotherapeutics during the conduct of the study and outside the submitted work. A. Hemminki reports grants from Helsinki University Hospital Research funds, Cancer Foundation Finland, Jane and Aatos Erkko Foundation, Red Cross Blood Service, and Sigrid Juselius Finland; other support from TILT Biotherapeutics Oy; grants from the European Commission during the conduct of the study; personal fees and other support from TILT Biotherapeutics Oy and Aeruginosa Oy; and other support from Circio Holdings ASA outside the submitted work; in addition, A. Hemminki reports patents for Enhanced adoptive cell therapy licensed to TILT Biotherapeutics Oy, Oncolytic adenoviruses coding for BI-specific antibodies and methods and uses related thereto licensed to TILT Biotherapeutics Oy, Oncolytic adenovirus and checkpoint inhibitor combination therapy pending to TILT Biotherapeutics Oy, Oncolytic virus vector coding for variant IL2 (vIL-2) polypeptide pending to TILT Biotherapeutics Oy, and Oncolytic adenovirus combination therapy pending to TILT Biotherapeutics Oy. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
A, Trial outline. B, Lymphocyte changes after TILT-123, all cohorts pooled. C, Leukocyte changes after TILT-123, all cohorts pooled. D, Neutrophil changes after TILT-123, all cohorts pooled. E, Virus detection in blood by qPCR, before treatment, 1 hour post-treatment and 16 hours post-treatment, all dose cohorts available pooled (N = 10 patients). F, Virus detection in blood by qPCR 1 hour after intravenous dose, stratified by intravenous dose given. G, Virus detection in blood by qPCR 1 hour after intratumoral dose, stratified by intratumoral dose given. For all graphs, mean ± SEM shown. For B–D, P value from two-sided t test shown for graphs. LLOQ, lower limit of quantification; ns, non-significant (P > 0.05); *, P < 0.05; ****, P < 0.001.
Figure 2.
Figure 2.
A, Response evaluation in all injected lesions, evaluated by CT. B, Response evaluation in all injected lesions, evaluated by PET. C, Response evaluation in allimaged non-injected lesions, evaluated by CT. D, Response evaluation in all imaged non-injected lesions, evaluated by PET. Best response shown for A–D if patient continued to extension. E, Intravenous dose given versus sum SUVmax change of measured lesions on day 78. F, Intratumoral dose given versus sum SUVmax change of measured lesions on day 78. G, Overall survival in the trial. H, Progressionfree survival in the trial. I, Time to progression in the trial. J, Swimmer plot of the patients enrolled in the trial. For E and F, linear fit shown with 95% confidence intervals shown with R2 for goodness of fit and P value for slope deviation from zero. For G–I, disease control defined with PET-based criteria and comparison of disease control and no disease control evaluated with Mantel–Cox Log-rank test. ***, P < 0.001; ****, P < 0.0001.
Figure 3.
Figure 3.
A, Volume and PET signal changes in patient 20103 with metastatic anaplastic thyroid carcinoma, showing disappearance of PET signal for injected abdominal lesion, and disappearance of mesenteric and pulmonal lesions by PET and CT. B, Changes in PET signal in patient 20202 with metastatic NSCLC, showing decrease in PET signal for injected (62% SUVmax decrease) and non-injected lesion (54% SUVmax decrease). C, Visual changes in tumor in patient 20108 with adenocystic adenocarcinoma of the head and neck, showing marked necrosis of the tumor post-treatment.
Figure 4.
Figure 4.
A, Virus staining (violet) in tumor biopsies from patient 20202 at different time points across the trial, showing productive virus replication in injected and noninjected lesions; scale bar, 50 mm. B, Tumor IHC from patient 20202 staining for DAPI, CD8, and CD56 showing increased numbers of effector lymphocytes in injected and non-injected lesions post-treatment; scale bar, 100 μm. C, Neutralizing antibodies (NAbs) against TILT-123 at baseline in all patients. D, Neutralizing antibody presence compared with disease control at day 78. Disease control defined as SMD or better at day 78. No disease control defined as PMD or NA at day 78. Groups compared with the Fisher’s exact test. E, Baseline neutralizing antibody presence compared with overall survival across trial. Groups compared with the MaxCombo log-rank test. F, Neutralizing antibody titer across trial in all dose cohorts. Baseline defined as day 1 pre-treatment value, for days 1 to 64 the highest titer shown for each day (pre-or post-treatment). G, Serum proteomic changes 16 hours after intravenous dosing of TILT-123, pooled patients from cohorts 1 to 5 (n = 15). H, Serum proteomic changes 16 hours after first dose of intratumoral dosing of TILT-123, pooled patients from cohorts 1 to 5 (n = 15). I, Serum proteomic changes 16 hours after second dose of intratumoral dosing of TILT-123, pooled patients from cohorts 1 to 5 (n = 15). For G–I, difference between pre‐and post-treatment protein calculated with the Mann–Whitney U test; ns, non-significant (P > 0.05).
See this image and copyright information in PMC

References

    1. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 2017;168:707–23. - PMC - PubMed
    1. Havunen R, Siurala M, Sorsa S, Grönberg-Vähä-Koskela S, Behr M, Tähtinen S, et al. . Oncolytic adenoviruses armed with tumor necrosis factor alpha and interleukin-2 enable successful adoptive cell therapy. Mol Ther Oncolytics 2017;4:77–86. - PMC - PubMed
    1. Siurala M, Havunen R, Saha D, Lumen D, Airaksinen AJ, Tähtinen S, et al. . Adenoviral delivery of tumor necrosis factor-alpha and interleukin-2 enables successful adoptive cell therapy of immunosuppressive melanoma. Mol Ther 2016;24:1435–43. - PMC - PubMed
    1. Tähtinen S, Kaikkonen S, Merisalo-Soikkeli M, Grönberg-Vähä-Koskela S, Kanerva A, Parviainen S, et al. . Favorable alteration of tumor microenvironment by immunomodulatory cytokines for efficient T-cell therapy in solid tumors. PLoS ONE 2015;10:e0131242. - PMC - PubMed
    1. Wang H, Li Z-Y, Liu Y, Persson J, Beyer I, Möller T, et al. . Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11, and 14. Nat Med 2011;17:96–104. - PMC - PubMed

Publication types