Cytokine-Coding Oncolytic Adenovirus TILT-123 Is Safe, Selective, and Effective as a Single Agent and in Combination with Immune Checkpoint Inhibitor Anti-PD-1
Riikka Havunen, Riikka Kalliokoski, Mikko Siurala, Suvi Sorsa, João M Santos, Victor Cervera-Carrascon, Marjukka Anttila, Akseli Hemminki, Riikka Havunen, Riikka Kalliokoski, Mikko Siurala, Suvi Sorsa, João M Santos, Victor Cervera-Carrascon, Marjukka Anttila, Akseli Hemminki
Abstract
Oncolytic viruses provide a biologically multi-faceted treatment option for patients who cannot be cured with currently available treatment options. We constructed an oncolytic adenovirus, TILT-123, to support T-cell therapies and immune checkpoint inhibitors in solid tumors. Adenoviruses are immunogenic by nature, are easy to produce in large quantities, and can carry relatively large transgenes. They are the most commonly used gene therapy vectors and are well tolerated in patients. TILT-123 expresses two potent cytokines, tumor necrosis factor alpha and interleukin-2, to stimulate especially the T-cell compartment in the tumor microenvironment. Before entering clinical studies, the safety and biodistribution of TILT-123 was studied in Syrian hamsters and in mice. The results show that TILT-123 is safe in animals as monotherapy and in combination with an immune checkpoint inhibitor anti-PD-1. The virus treatment induces acute changes in circulating immune cell compartments, but the levels return to normal by the middle of the treatment period. The virus is rapidly cleared from healthy tissues, and it does not cause damage to vital organs. The results support the initiation of a phase 1 dose-escalation trial, where melanoma patients receiving a tumor-infiltrating lymphocyte therapy are treated with TILT-123 (NCT04217473).
Keywords: adenovirus; biodistribution; immunotherapy; oncolytic virus; safety.
Conflict of interest statement
R.H., R.K., and S.S. are employees of TILT Biotherapeutics Ltd. A.H., J.S., and V.C-C are employees and shareholders of TILT Biotherapeutics Ltd. A.H is a shareholder of Targovax ASA.
Figures
References
- Garber K. China approves world’s first oncolytic virus therapy for cancer treatment. J. Natl. Cancer Inst. 2006;98:298–300. doi: 10.1093/jnci/djj111.
- Ranki T., Pesonen S., Hemminki A., Partanen K., Kairemo K., Alanko T., Lundin J., Linder N., Turkki R., Ristimaki A., et al. Phase I study with ONCOS-102 for the treatment of solid tumors-an evaluation of clinical response and exploratory analyses of immune markers. J. Immunother Cancer. 2016;4:1–18. doi: 10.1186/s40425-016-0121-5.
- Lang F.F., Conrad C., Gomez-Manzano C., Yung W.K.A., Sawaya R., Weinberg J.S., Prabhu S.S., Rao G., Fuller G.N., Aldape K.D., et al. Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma. J. Clin. Oncol. 2018 doi: 10.1200/JCO.2017.75.8219.
- Nemunaitis J., Tong A.W., Nemunaitis M., Senzer N., Phadke A.P., Bedell C., Adams N., Zhang Y.A., Maples P.B., Chen S., et al. A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol. Ther. 2010;18:429–434. doi: 10.1038/mt.2009.262.
- Eriksson E., Milenova I., Wenthe J., Stahle M., Leja-Jarblad J., Ullenhag G., Dimberg A., Moreno R., Alemany R., Loskog A. Shaping the Tumor Stroma and Sparking Immune Activation by CD40 and 4-1BB Signaling Induced by an Armed Oncolytic Virus. Clin. Cancer Res. 2017;23:5846–5857. doi: 10.1158/1078-0432.CCR-17-0285.
- Kuryk L., Moller A.W., Jaderberg M. Combination of immunogenic oncolytic adenovirus ONCOS-102 with anti-PD-1 pembrolizumab exhibits synergistic antitumor effect in humanized A2058 melanoma huNOG mouse model. Oncoimmunology. 2018;8:e1532763. doi: 10.1080/2162402X.2018.1532763.
- Thomas M.A., Spencer J.F., La Regina M.C., Dhar D., Tollefson A.E., Toth K., Wold W.S. Syrian hamster as a permissive immunocompetent animal model for the study of oncolytic adenovirus vectors. Cancer Res. 2006;66:1270–1276. doi: 10.1158/0008-5472.CAN-05-3497.
- Kanerva A., Zinn K.R., Chaudhuri T.R., Lam J.T., Suzuki K., Uil T.G., Hakkarainen T., Bauerschmitz G.J., Wang M., Liu B., et al. Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus. Mol. Ther. 2003;8:449–458. doi: 10.1016/S1525-0016(03)00200-4.
- Wang H., Li Z.Y., Liu Y., Persson J., Beyer I., Moller T., Koyuncu D., Drescher M.R., Strauss R., Zhang X.B., et al. Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11 and 14. Nat. Med. 2011;17:96–104. doi: 10.1038/nm.2270.
- Havunen R., Siurala M., Sorsa S., Gronberg-Vaha-Koskela S., Behr M., Tahtinen S., Santos J.M., Karell P., Rusanen J., Nettelbeck D.M., et al. Oncolytic Adenoviruses Armed with Tumor Necrosis Factor Alpha and Interleukin-2 Enable Successful Adoptive Cell Therapy. Mol. Ther. Oncolytics. 2016;4:77–86. doi: 10.1016/j.omto.2016.12.004.
- Watanabe K., Luo Y., Da T., Guedan S., Ruella M., Scholler J., Keith B., Young R.M., Engels B., Sorsa S., et al. Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses. JCI Insight. 2018;3 doi: 10.1172/jci.insight.99573.
- Cervera-Carrascon V., Siurala M., Santos J.M., Havunen R., Tahtinen S., Karell P., Sorsa S., Kanerva A., Hemminki A. TNFa and IL-2 armed adenoviruses enable complete responses by anti-PD-1 checkpoint blockade. Oncoimmunology. 2018;7:e1412902. doi: 10.1080/2162402X.2017.1412902.
- Cervera-Carrascon V., Quixabeira D.C.A., Havunen R., Santos J.M., Kutvonen E., Clubb J.H.A., Siurala M., Heinio C., Zafar S., Koivula T., et al. Comparison of Clinically Relevant Oncolytic Virus Platforms for Enhancing T Cell Therapy of Solid Tumors. Mol. Ther. Oncolytics. 2020;17:47–60. doi: 10.1016/j.omto.2020.03.003.
- Santos J.M., Havunen R., Siurala M., Cervera-Carrascon V., Tahtinen S., Sorsa S., Anttila M., Karell P., Kanerva A., Hemminki A. Adenoviral production of interleukin-2 at the tumor site removes the need for systemic postconditioning in adoptive cell therapy. Int. J. Cancer. 2017 doi: 10.1002/ijc.30839.
- Santos J.M., Cervera-Carrascon V., Havunen R., Zafar S., Siurala M., Sorsa S., Anttila M., Kanerva A., Hemminki A. Adenovirus Coding for Interleukin-2 and Tumor Necrosis Factor Alpha Replaces Lymphodepleting Chemotherapy in Adoptive T Cell Therapy. Mol. Ther. 2018;26:2243–2254. doi: 10.1016/j.ymthe.2018.06.001.
- Akinleye A., Rasool Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. J. Hematol. Oncol. 2019;12:1–13. doi: 10.1186/s13045-019-0779-5.
- Ribas A., Dummer R., Puzanov I., VanderWalde A., Andtbacka R.H.I., Michielin O., Olszanski A.J., Malvehy J., Cebon J., Fernandez E., et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2018;174:1031–1032. doi: 10.1016/j.cell.2018.07.035.
- Hsu J., Hodgins J.J., Marathe M., Nicolai C.J., Bourgeois-Daigneault M.C., Trevino T.N., Azimi C.S., Scheer A.K., Randolph H.E., Thompson T.W., et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Investig. 2018;128:4654–4668. doi: 10.1172/JCI99317.
- Pesce S., Greppi M., Tabellini G., Rampinelli F., Parolini S., Olive D., Moretta L., Moretta A., Marcenaro E. Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization. J. Allergy Clin. Immunol. 2017;139:335–346.e3. doi: 10.1016/j.jaci.2016.04.025.
- Zhang Y., Morgan R., Chen C., Cai Y., Clark E., Khan W.N., Shin S.U., Cho H.M., Al Bayati A., Pimentel A., et al. Mammary-tumor-educated B cells acquire LAP/TGF-beta and PD-L1 expression and suppress anti-tumor immune responses. Int. Immunol. 2016;28:423–433. doi: 10.1093/intimm/dxw007.
- Wang J.Z., Zhang Y.H., Guo X.H., Zhang H.Y., Zhang Y. The double-edge role of B cells in mediating antitumor T-cell immunity: Pharmacological strategies for cancer immunotherapy. Int. Immunopharmacol. 2016;36:73–85. doi: 10.1016/j.intimp.2016.04.018.
- Thibult M.L., Mamessier E., Gertner-Dardenne J., Pastor S., Just-Landi S., Xerri L., Chetaille B., Olive D. PD-1 is a novel regulator of human B-cell activation. Int. Immunol. 2013;25:129–137. doi: 10.1093/intimm/dxs098.
- Hemminki O., Hemminki A. A century of oncolysis evolves into oncolytic immunotherapy. Oncoimmunology. 2015;5:e1074377. doi: 10.1080/2162402X.2015.1074377.
- Kuryk L., Vassilev L., Ranki T., Hemminki A., Karioja-Kallio A., Levalampi O., Vuolanto A., Cerullo V., Pesonen S. Toxicological and bio-distribution profile of a GM-CSF-expressing, double-targeted, chimeric oncolytic adenovirus ONCOS-102-Support for clinical studies on advanced cancer treatment. PLoS ONE. 2017;12:e0182715. doi: 10.1371/journal.pone.0182715.
- Rodriguez-Garcia A., Gimenez-Alejandre M., Rojas J.J., Moreno R., Bazan-Peregrino M., Cascallo M., Alemany R. Safety and efficacy of VCN-01, an oncolytic adenovirus combining fiber HSG-binding domain replacement with RGD and hyaluronidase expression. Clin. Cancer Res. 2015;21:1406–1418. doi: 10.1158/1078-0432.CCR-14-2213.
- Wang F., Wang Z., Tian H., Qi M., Zhai Z., Li S., Li R., Zhang H., Wang W., Fu S., et al. Biodistribution and safety assessment of bladder cancer specific recombinant oncolytic adenovirus in subcutaneous xenografts tumor model in nude mice. Curr. Gene Ther. 2012;12:67–76. doi: 10.2174/156652312800099599.
- Ying B., Toth K., Spencer J.F., Meyer J., Tollefson A.E., Patra D., Dhar D., Shashkova E.V., Kuppuswamy M., Doronin K., et al. INGN 007, an oncolytic adenovirus vector, replicates in Syrian hamsters but not mice: Comparison of biodistribution studies. Cancer Gene Ther. 2009;16:625–637. doi: 10.1038/cgt.2009.6.
- Kanerva A., Wang M., Bauerschmitz G.J., Lam J.T., Desmond R.A., Bhoola S.M., Barnes M.N., Alvarez R.D., Siegal G.P., Curiel D.T., et al. Gene transfer to ovarian cancer versus normal tissues with fiber-modified adenoviruses. Mol. Ther. 2002;5:695–704. doi: 10.1006/mthe.2002.0599.
- Koski A., Bramante S., Kipar A., Oksanen M., Juhila J., Vassilev L., Joensuu T., Kanerva A., Hemminki A. Biodistribution Analysis of Oncolytic Adenoviruses in Patient Autopsy Samples Reveals Vascular Transduction of Noninjected Tumors and Tissues. Mol. Ther. 2015;23:1641–1652. doi: 10.1038/mt.2015.125.
- Cerullo V., Pesonen S., Diaconu I., Escutenaire S., Arstila P.T., Ugolini M., Nokisalmi P., Raki M., Laasonen L., Sarkioja M., et al. Oncolytic adenovirus coding for granulocyte macrophage colony-stimulating factor induces antitumoral immunity in cancer patients. Cancer Res. 2010;70:4297–4309. doi: 10.1158/0008-5472.CAN-09-3567.
- Krasnykh V.N., Mikheeva G.V., Douglas J.T., Curiel D.T. Generation of recombinant adenovirus vectors with modified fibers for altering viral tropism. J. Virol. 1996;70:6839–6846. doi: 10.1128/JVI.70.10.6839-6846.1996.
Source: PubMed