Dafne C.A. Quixabeira

University of Helsinki

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Akseli Hemminki

University of Helsinki

Víctor Cervera-Carrascón

University of Helsinki

João M. Santos

Biocenter Finland

Riikka Havunen

Biocenter Finland

Santeri A. Pakola

University of Helsinki

James H.A. Clubb

Biocenter Finland

Tatiana V. Kudling

University of Helsinki

Suvi Sorsa

University of Helsinki

Elise Jirovec

University of Helsinki

Lyna Haybout

University of Helsinki

Cooperative Institutions

University of Helsinki

Helsinki University Hospital

Universidade Federal de Pernambuco

Biocenter Finland

Amsterdam University Medical Centers

Institute for Molecular Medicine Finland

Vrije Universiteit Amsterdam

Amsterdam UMC Location VUmc

Cancer Center Amsterdam

University of Turku

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Data from 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 Katriina Peltola James H.A. Clubb Elise Jirovec Lyna Haybout

<div>AbstractPurpose: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).<a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-24-1126" target="_blank">See related commentary by Silva-Pilipich and Smerdou, p. 3649</a></div>

10.1158/1078-0432.c.7429474

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50P Enhancing TIL and NK cells adoptive therapies with an engineered oncolytic adenovirus encoding a human vIL-2 cytokine for the treatment of human ovarian cancer

Immuno-Oncology Technology (2022)

Dafne C.A. Quixabeira Santeri A Pakola E. Jirovec S. Basnet J.M. Santos

Tumor-infiltrating lymphocytes (TILs) and natural killer (NK) adoptive cell therapies have shown promising results in advanced-stage melanoma and haematological malignancies, respectively. However, their limited persistence in vivo in absence of an exogenous source of IL-2, and migration to neoplastic sites have impaired their effectiveness in immunosuppressive tumor microenvironments, such as ovarian cancer. Here, we propose the use of an engineered oncolytic adenovirus encoding a vIL-2 cytokine, Ad5/3-E2F-d24-vIL2 (vIL-2 virus), to improve said cell therapies. Oncolytic adenoviruses are immunogenic agents that lyse infected cancer cells and recruit immune cells to the neoplastic site. Moreover, the vIL-2 virus continuously expresses a vIL-2 cytokine that preferentially stimulates effector lymphocyte proliferation over T regulatory cells. Fragments of resected human ovarian cancer tumors were received and processed into single-cell suspensions. Autologous TILs were expanded from said sample fragments, while PBMC cells from healthy donors were used as the source of allogeneic NK cells. To evaluate cancer cell killing, ovarian cancer ex vivo tumor cultures were co-cultured either with autologous TILs or with allogeneic NK cells in the presence or absence of the vIL-2 virus. Additionally, in vivo combination therapies efficacy was assessed with a patient-derived xenograft (PDX) ovarian cancer model. Immune cell profiling was performed following patient sample co-cultures and PDX tumor treatments. The addition of vIL-2 virus to the ovarian cancer ex vivo tumor cultures improved both TIL and NK cell therapies efficacy in vitro. Similarly, significantly better tumor control was achieved when the vIL-2 virus was given in conjunction with cell therapies compared to their respective controls. Mechanistically, vIL-2 virus treatment enhanced cell cytotoxicity of adoptively transferred TILs and NK cells in PDX tumors, and in ovarian cancer tumor cultures. Ad5/3-E2F-d24-vIL2 virus treatment seems to be a promising immunotherapeutic candidate to improve the response of adoptive cell therapies in human immunosuppressive solid tumors.

Tumor-infiltrating lymphocytes

Oncolytic adenovirus

Ex vivo

Adoptive Cell Transfer

10.1016/j.iotech.2022.100155

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Presence and activity of HPV in primary lung cancer

Journal of Cancer Research and Clinical Oncology (2018)

Talita Helena Araújo de Oliveira Carolina Medeiros do Amaral Bianca de França São Marcos Kamylla Conceição Gomes Nascimento Ana Carine de Miranda Rios

Stain

10.1007/s00432-018-2748-8

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Systemic Delivery of Oncolytic Adenovirus to Tumors Using Tumor-Infiltrating Lymphocytes as Carriers

Cells (2021)

João M. Santos Camilla Heiniö Dafne C.A. Quixabeira Sadia Zafar James H.A. Clubb

Immunotherapy with tumor-infiltrating lymphocytes (TIL) or oncolytic adenoviruses, have shown promising results in cancer treatment, when used as separate therapies. When used in combination, the antitumor effect is synergistically potentiated due oncolytic adenovirus infection and its immune stimulating effects on T cells. Indeed, studies in hamsters have shown a 100% complete response rate when animals were treated with oncolytic adenovirus coding for TNFa and IL-2 (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) and TIL therapy. In humans, one caveat with oncolytic virus therapy is that intratumoral injection has been traditionally preferred over systemic administration, for achieving sufficient virus concentrations in tumors, especially when neutralizing antibodies emerge. We have previously shown that 5/3 chimeric oncolytic adenovirus can bind to human lymphocytes for avoidance of neutralization. In this study, we hypothesized that incubation of oncolytic adenovirus (TILT-123) with TILs prior to systemic injection would allow delivery of virus to tumors. This approach would deliver both components in one self-amplifying product. TILs would help deliver TILT-123, whose replication will recruit more TILs and increase their cytotoxicity. In vitro, TILT-123 was seen binding efficiently to lymphocytes, supporting the idea of dual administration. We show in vivo in different models that virus could be delivered to tumors with TILs as carriers.

Oncolytic adenovirus

Systemic administration

Adenovirus infection

10.3390/cells10050978

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Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors

Journal of Experimental & Clinical Cancer Research (2024)

Elise Jirovec Dafne C.A. Quixabeira James H.A. Clubb Santeri A. Pakola Tatiana V. Kudling

Abstract Background A 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. Methods Patients with advanced solid tumors initially received a single i.v. dose of TILT-123 ranging from 3 × 10 9 to 4 × 10 12 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. Results Across 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). Conclusion TILT-123 demonstrated safety and significant intratumoral immunomodulation following a single i.v. administration, warranting further investigation. Trial registrations TUNIMO—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 .

Oncolytic adenovirus

10.1186/s13046-024-03219-0

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Figure 3 from 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 Katriina Peltola James H.A. Clubb Elise Jirovec Lyna Haybout

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.

Oncolytic adenovirus

10.1158/1078-0432.26926519

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Figure 2 from 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 Katriina Peltola James H.A. Clubb Elise Jirovec Lyna Haybout

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.

Oncolytic adenovirus

10.1158/1078-0432.26926525

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Effective Combination Immunotherapy with Oncolytic Adenovirus and Anti-PD-1 for Treatment of Human and Murine Ovarian Cancers

Diseases (2022)

Camilla Heiniö James H.A. Clubb Tatiana V. Kudling Dafne C.A. Quixabeira Víctor Cervera-Carrascón

Ovarian cancer (OvCa) is one of the most common gynecological cancers and has the highest mortality in this category. Tumors are often detected late, and unfortunately over 70% of OvCa patients experience relapse after first-line treatments. OvCa has shown low response rates to immune checkpoint inhibitor (ICI) treatments, thus leaving room for improvement. We have shown that oncolytic adenoviral therapy with Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (aka. TILT-123) is promising for single-agent treatment of cancer, but also for sensitizing tumors for T-cell dependent immunotherapy approaches, such as ICI treatments. Therefore, this study set out to determine the effect of inhibition of the immune checkpoint inhibitors (ICI), in the context of TILT-123 therapy of OvCa. We show that simultaneous treatment of patient derived samples with TILT-123 and ICIs anti-PD-1 or anti-PD-L1 efficiently reduced overall viability. The combinations induced T cell activation, T cells expressed activation markers more often, and the treatment caused positive microenvironment changes, measured by flow cytometric assays. Furthermore, in an immunocompetent in vivo C57BL/6NHsda mouse model, tumor growth was hindered, when treated with TILT-123, ICI or both. Taken together, this study provides a rationale for using TILT-123 virotherapy in combination with TILT-123 and immune checkpoint inhibitors together in an ovarian cancer OvCa clinical trial.

Oncolytic adenovirus

Combination therapy

Immune checkpoint

Virotherapy

10.3390/diseases10030052

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Development of a Syrian hamster anti-PD-L1 monoclonal antibody enables oncolytic adenoviral immunotherapy modelling in an immunocompetent virus replication permissive setting

Frontiers in Immunology (2023)

James H.A. Clubb Tatiana V. Kudling Mykhailo Girych Lyna Haybout Santeri A. Pakola

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, but preclinical testing of hypotheses such as combination therapies has been complicated, in part due to species incompatibility issues. For example, one of few known permissive animal models for oncolytic adenoviruses is the Syrian hamster, for which an ICI, mainly an anti-PD-L1 monoclonal antibody (mAb) was not previously available. In this study, we developed an anti-Syrian hamster PD-L1 mAb to enable the evaluation of safety and efficacy, when combining anti-PD-L1 with an oncolytic adenovirus encoding tumour necrosis factor alpha (TNFα) and interleukin-2 (IL-2) (Ad5/3-E2F-D24-hTNFα-IRES-hIL-2 or TILT-123).Recombinant Syrian hamster PD-L1 was expressed and mice immunized for mAb formation using hybridoma technology. Clonal selection through binding and functional studies in vitro, in silico and in vivo identified anti-PD-L1 clone 11B12-1 as the primary mAb candidate for immunotherapy modelling. The oncolytic virus (OV) and ICI combination approach was then evaluated using 11B12-1 and TILT-123 in a Syrian hamster model of pancreatic ductal adenocarcinoma (PDAC).Supernatants from hybridoma parent subclone 11B12B4 provided the highest positive PD-L1 signal, on Syrian hamster PBMCs and three cancer cell lines (HT100, HapT1 and HCPC1). In vitro co-cultures revealed superior immune modulated profiles of cell line matched HT100 tumour infiltrating lymphocytes when using subclones of 7G2, 11B12 and 12F1. Epitope binning and epitope prediction using AlphaFold2 and ColabFold revealed two distinct functional epitopes for clone 11B12-1 and 12F1-1. Treatment of Syrian hamsters bearing HapT1 tumours, with 11B12-1 induced significantly better (p<0.05) tumour growth control than isotype control by day 12. 12F1-1 did not induce significant tumour growth control. The combination of 11B12-1 with oncolytic adenovirus TILT-123 improved tumour growth control further, when compared to monotherapy (p<0.05) by day 26.Novel Syrian hamster anti-PD-L1 clone 11B12-1 induces tumour growth control in a hamster model of PDAC. Combining 11B12-1 with oncolytic adenovirus TILT-123 improves tumour growth control further and demonstrates good safety and toxicity profiles.

Oncolytic adenovirus

Mesocricetus

10.3389/fimmu.2023.1060540

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Ad5/3 is able to avoid neutralization by binding to erythrocytes and lymphocytes

Cancer Gene Therapy (2020)

Sadia Zafar Dafne C.A. Quixabeira Tatiana V. Kudling Víctor Cervera-Carrascón João M. Santos

Oncolytic adenoviruses are promising cancer therapeutic agents. Clinical data have shown adenoviruses' ability to transduce tumors after systemic delivery in human cancer patients, despite antibodies. In the present work, we have focused on the interaction of a chimeric adenovirus Ad5/3 with human lymphocytes and human erythrocytes. Ad5/3 binding with human lymphocytes and erythrocytes was observed to occur in a reversible manner, which allowed viral transduction of tumors, and oncolytic potency of Ad5/3 in vitro and in vivo, with or without neutralizing antibodies. Immunodeficient mice bearing xenograft tumors showed enhanced tumor transduction following systemic administration, when Ad5/3 virus was bound to lymphocytes or erythrocytes (P < 0.05). In conclusion, our findings reveal that chimeric Ad5/3 adenovirus reaches non-injected tumors in the presence of neutralizing antibodies: it occurs through reversible binding to lymphocytes and erythrocytes.

Oncolytic adenovirus

Transduction (biophysics)

Systemic administration

10.1038/s41417-020-00226-z

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Citations (16)