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1. Data from Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus

Author

Diaconu, Iulia, primary, Cerullo, Vincenzo, primary, Hirvinen, Mari L.M., primary, Escutenaire, Sophie, primary, Ugolini, Matteo, primary, Pesonen, Saila K., primary, Bramante, Simona, primary, Parviainen, Suvi, primary, Kanerva, Anna, primary, Loskog, Angelica S.I., primary, Eliopoulos, Aristides G., primary, Pesonen, Sari, primary, and Hemminki, Akseli, primary

Published
2023
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2. Supplementary Table 1 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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3. Supplementary Table 3 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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4. Supplementary Figure 2 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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5. Data from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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6. Supplementary Table 5 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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7. Supplementary Figure 6 from Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus

Author

Diaconu, Iulia, primary, Cerullo, Vincenzo, primary, Hirvinen, Mari L.M., primary, Escutenaire, Sophie, primary, Ugolini, Matteo, primary, Pesonen, Saila K., primary, Bramante, Simona, primary, Parviainen, Suvi, primary, Kanerva, Anna, primary, Loskog, Angelica S.I., primary, Eliopoulos, Aristides G., primary, Pesonen, Sari, primary, and Hemminki, Akseli, primary

Published
2023
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8. Supplementary Table 4 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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9. Supplementary Figure 3 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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10. Supplementary Table 2 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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11. Supplementary Figure 5 from Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus

Author

Diaconu, Iulia, primary, Cerullo, Vincenzo, primary, Hirvinen, Mari L.M., primary, Escutenaire, Sophie, primary, Ugolini, Matteo, primary, Pesonen, Saila K., primary, Bramante, Simona, primary, Parviainen, Suvi, primary, Kanerva, Anna, primary, Loskog, Angelica S.I., primary, Eliopoulos, Aristides G., primary, Pesonen, Sari, primary, and Hemminki, Akseli, primary

Published
2023
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12. Supplementary Figure 2 from Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus

Author

Diaconu, Iulia, primary, Cerullo, Vincenzo, primary, Hirvinen, Mari L.M., primary, Escutenaire, Sophie, primary, Ugolini, Matteo, primary, Pesonen, Saila K., primary, Bramante, Simona, primary, Parviainen, Suvi, primary, Kanerva, Anna, primary, Loskog, Angelica S.I., primary, Eliopoulos, Aristides G., primary, Pesonen, Sari, primary, and Hemminki, Akseli, primary

Published
2023
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13. Supplementary Figure 1 from Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus

Author

Diaconu, Iulia, primary, Cerullo, Vincenzo, primary, Hirvinen, Mari L.M., primary, Escutenaire, Sophie, primary, Ugolini, Matteo, primary, Pesonen, Saila K., primary, Bramante, Simona, primary, Parviainen, Suvi, primary, Kanerva, Anna, primary, Loskog, Angelica S.I., primary, Eliopoulos, Aristides G., primary, Pesonen, Sari, primary, and Hemminki, Akseli, primary

Published
2023
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14. Supplementary Figure 3 from Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus

Author

Diaconu, Iulia, primary, Cerullo, Vincenzo, primary, Hirvinen, Mari L.M., primary, Escutenaire, Sophie, primary, Ugolini, Matteo, primary, Pesonen, Saila K., primary, Bramante, Simona, primary, Parviainen, Suvi, primary, Kanerva, Anna, primary, Loskog, Angelica S.I., primary, Eliopoulos, Aristides G., primary, Pesonen, Sari, primary, and Hemminki, Akseli, primary

Published
2023
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15. Supplementary Figure 1 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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16. Supplementary Methods from Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus

Author

Diaconu, Iulia, primary, Cerullo, Vincenzo, primary, Hirvinen, Mari L.M., primary, Escutenaire, Sophie, primary, Ugolini, Matteo, primary, Pesonen, Saila K., primary, Bramante, Simona, primary, Parviainen, Suvi, primary, Kanerva, Anna, primary, Loskog, Angelica S.I., primary, Eliopoulos, Aristides G., primary, Pesonen, Sari, primary, and Hemminki, Akseli, primary

Published
2023
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17. Supplementary Figure 4 from Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, primary, Kangasniemi, Lotta, primary, Ranki, Tuuli, primary, Kanerva, Anna, primary, Pesonen, Saila K., primary, Gerdemann, Ulrike, primary, Leen, Ann M., primary, Kairemo, Kalevi, primary, Oksanen, Minna, primary, Haavisto, Elina, primary, Holm, Sirkka-Liisa, primary, Karioja-Kallio, Aila, primary, Kauppinen, Satu, primary, Partanen, Kaarina P. L., primary, Laasonen, Leena, primary, Joensuu, Tima, primary, Alanko, Tuomo, primary, Cerullo, Vincenzo, primary, and Hemminki, Akseli, primary

Published
2023
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18. Supplementary Figure 4 from Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus

Author

Diaconu, Iulia, primary, Cerullo, Vincenzo, primary, Hirvinen, Mari L.M., primary, Escutenaire, Sophie, primary, Ugolini, Matteo, primary, Pesonen, Saila K., primary, Bramante, Simona, primary, Parviainen, Suvi, primary, Kanerva, Anna, primary, Loskog, Angelica S.I., primary, Eliopoulos, Aristides G., primary, Pesonen, Sari, primary, and Hemminki, Akseli, primary

Published
2023
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22. Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus

Author

Diaconu, Iulia, Cerullo, Vincenzo, Hirvinen, Mari L M, Escutenaire, Sophie, Ugolini, Matteo, Pesonen, Saila K, Bramante, Simona, Parviainen, Suvi, Kanerva, Anna, Loskog, Angelica S I, Eliopoulos, Aristides G, Pesonen, Sari, Hemminki, Akseli, Diaconu, Iulia, Cerullo, Vincenzo, Hirvinen, Mari L M, Escutenaire, Sophie, Ugolini, Matteo, Pesonen, Saila K, Bramante, Simona, Parviainen, Suvi, Kanerva, Anna, Loskog, Angelica S I, Eliopoulos, Aristides G, Pesonen, Sari, and Hemminki, Akseli

Abstract

Oncolytic adenovirus is an attractive platform for immunotherapy because virus replication is highly immunogenic and not subject to tolerance. Although oncolysis releases tumor epitopes and provides costimulatory danger signals, arming the virus with immunostimulatory molecules can further improve efficacy. CD40 ligand (CD40L, CD154) induces apoptosis of tumor cells and triggers several immune mechanisms, including a T-helper type 1 (TH1) response, which leads to activation of cytotoxic T cells and reduction of immunosuppression. In this study, we constructed a novel oncolytic adenovirus, Ad5/3-hTERT-E1A-hCD40L, which features a chimeric Ad5/3 capsid for enhanced tumor transduction, a human telomerase reverse transcriptase (hTERT) promoter for tumor selectivity, and human CD40L for increased efficacy. Ad5/3-hTERT-E1A-hCD40L significantly inhibited tumor growth in vivo via oncolytic and apoptotic effects, and (Ad5/3-hTERT-E1A-hCD40L)–mediated oncolysis resulted in enhanced calreticulin exposure and HMGB1 and ATP release, which were suggestive of immunogenicity. In two syngeneic mouse models, murine CD40L induced recruitment and activation of antigen-presenting cells, leading to increased interleukin-12 production in splenocytes. This effect was associated with induction of the TH1 cytokines IFN-γ, RANTES, and TNF-α. Tumors treated with Ad5/3-CMV-mCD40L also displayed an enhanced presence of macrophages and cytotoxic CD8+ T cells but not B cells. Together, our findings show that adenoviruses coding for CD40L mediate multiple antitumor effects including oncolysis, apoptosis, induction of T-cell responses, and upregulation of TH1 cytokines.

Published
2012
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23. Abstract 3304: Oncolytic adenovirus with low-dose temozolomide induces autophagy and antitumor immune responses preclinically and in cancer patients.

Author

Liikanen, Ilkka, primary, Ahtiainen, Laura, additional, Hirvinen, Mari L.M, additional, Barmante, Simona, additional, Cerullo, Vincenzo, additional, Nokisalmi, Petri, additional, Hemminki, Otto, additional, Diaconu, Iulia, additional, Pesonen, Sari, additional, Koski, Anniina, additional, Kangasniemi, Lotta, additional, Pesonen, Saila K., additional, Oksanen, Minna, additional, Zhao, Fang, additional, Laasonen, Leena, additional, Partanen, Kaarina, additional, Joensuu, Timo, additional, Kanerva, Anna, additional, and Hemminki, Akseli, additional

Published
2013
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24. Immune Response Is an Important Aspect of the Antitumor Effect Produced by a CD40L-Encoding Oncolytic Adenovirus

Author

Diaconu, Iulia, primary, Cerullo, Vincenzo, additional, Hirvinen, Mari L.M., additional, Escutenaire, Sophie, additional, Ugolini, Matteo, additional, Pesonen, Saila K., additional, Bramante, Simona, additional, Parviainen, Suvi, additional, Kanerva, Anna, additional, Loskog, Angelica S.I., additional, Eliopoulos, Aristides G., additional, Pesonen, Sari, additional, and Hemminki, Akseli, additional

Published
2012
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25. Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Pesonen, Sari, primary, Diaconu, Iulia, additional, Kangasniemi, Lotta, additional, Ranki, Tuuli, additional, Kanerva, Anna, additional, Pesonen, Saila K., additional, Gerdemann, Ulrike, additional, Leen, Ann M., additional, Kairemo, Kalevi, additional, Oksanen, Minna, additional, Haavisto, Elina, additional, Holm, Sirkka-Liisa, additional, Karioja-Kallio, Aila, additional, Kauppinen, Satu, additional, Partanen, Kaarina P. L., additional, Laasonen, Leena, additional, Joensuu, Tima, additional, Alanko, Tuomo, additional, Cerullo, Vincenzo, additional, and Hemminki, Akseli, additional

Published
2012
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26. Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Author

Iulia Diaconu, Vincenzo Cerullo, Tuuli Ranki, Ulrike Gerdemann, Kaarina Partanen, T. Joensuu, Akseli Hemminki, Leena Laasonen, Ann M. Leen, Kalevi Kairemo, Aila Karioja-Kallio, Lotta Kangasniemi, Minna Oksanen, Sari Pesonen, Elina Haavisto, Sirkka-Liisa Holm, Satu Kauppinen, Saila K. Pesonen, Anna Kanerva, Tuomo Alanko, Pesonen, Sari, Diaconu, Iulia, Kangasniemi, Lotta, Ranki, Tuuli, Kanerva, Anna, Pesonen, Saila K., Gerdemann, Ulrike, Leen, Ann M., Kairemo, Kalevi, Oksanen, Minna, Haavisto, Elina, Holm, Sirkka-Liisa, Karioja-Kallio, Aila, Kauppinen, Satu, Partanen, Kaarina P. L., Laasonen, Leena, Joensuu, Tima, Alanko, Tuomo, Cerullo, Vincenzo, and Hemminki, Akseli

Subjects
Adult, Male, Cancer Research, medicine.medical_treatment, Genetic enhancement, CD40 Ligand, Antibodies, Viral, medicine.disease_cause, Multimodal Imaging, Peripheral blood mononuclear cell, Virus, Adenoviridae, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Humans, Medicine, Virotherapy, Chemokine CCL5, Telomerase, 030304 developmental biology, Oncolytic Virotherapy, 0303 health sciences, business.industry, ELISPOT, Virion, Immunotherapy, Th1 Cells, Middle Aged, 3. Good health, Oncolytic virus, Th1 Cell, Oncology, Positron-Emission Tomography, 030220 oncology & carcinogenesis, Immunology, Neoplasm, Female, Tomography, X-Ray Computed, business, Human
Abstract

The immunosuppressive environment of advanced tumors is a primary obstacle to the efficacy of immunostimulatory and vaccine approaches. Here, we report an approach to arm an oncolytic virus with CD40 ligand (CD40L) to stimulate beneficial immunologic responses in patients. A double-targeted chimeric adenovirus controlled by the hTERT promoter and expressing CD40L (CGTG-401) was constructed and nine patients with progressing advanced solid tumors refractory to standard therapies were treated intratumorally. No serious adverse events resulting in patient hospitalization occurred. Moderate or no increases in neutralizing antibodies were seen, suggesting effective Th1 immunologic effects. An assessment of the blood levels of virus indicated 17.5% of the samples (n = 40) were positive at a low level early after treatment, but not thereafter. In contrast, high levels of virus, CD40L, and RANTES were documented locally at the tumor. Peripheral blood mononuclear cells were analyzed by IFN-γ ELISPOT analysis and induction of both survivin-specific and adenovirus-specific T cells was seen. Antitumor T-cell responses were even more pronounced when assessed by intracellular cytokine staining after stimulation with tumor type–specific peptide pools. Of the evaluable patients, 83% displayed disease control at 3 months and in both cases in which treatment was continued the effect was sustained for at least 8 months. Injected and noninjected lesions responded identically. Together, these findings support further clinical evaluation of CGTG-401. Cancer Res; 72(7); 1621–31. ©2012 AACR.

Published
2012
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27. Serotype chimeric oncolytic adenovirus coding for GM-CSF for treatment of sarcoma in rodents and humans

Author

Bramante, S, Koski, A, Kipar, A, Diaconu, I, Liikanen, I, Hemminki, O, Vassilev, L, Parviainen, S, Cerullo, V, Pesonen, S K, Oksanen, M, Heiskanen, R, Rouvinen-Lagerström, N, Merisalo-Soikkeli, M, Hakonen, T, Joensuu, T, Kanerva, A, Pesonen, S, Hemminki, A, Bramante, Simona, Koski, Anniina, Kipar, Anja, Diaconu, Iulia, Liikanen, Ilkka, Hemminki, Otto, Vassilev, Lotta, Parviainen, Suvi, Cerullo, Vincenzo, Pesonen, Saila K, Oksanen, Minna, Heiskanen, Raita, Rouvinen-Lagerström, Noora, Merisalo-Soikkeli, Maiju, Hakonen, Tiina, Joensuu, Timo, Kanerva, Anna, Pesonen, Sari, Hemminki, Akseli, University of Zurich, and Hemminki, A

Subjects
Cancer Research, Xenograft Model Antitumor Assay, Prognosi, 10184 Institute of Veterinary Pathology, Mice, Nude, Injections, Intralesional, Virus Replication, Animal models of cancer, Adenoviridae, Mice, Tumor Cells, Cultured, 1306 Cancer Research, Oncolytic Virotherapy, Mesocricetu, Cancer gene therapy, Animal, Granulocyte-Macrophage Colony-Stimulating Factor, GM-CSF, Sarcoma, Genetic Therapy, Survival Rate, Oncolytic adenoviru, Oncology, 570 Life sciences, biology, 2730 Oncology, Female, Human
Abstract

Sarcomas are a relatively rare cancer, but often incurable at the late metastatic stage. Oncolytic immunotherapy has gained attention over the past years, and a wide range of oncolytic viruses have been delivered via intratumoral injection with positive safety and promising efficacy data. Here, we report preclinical and clinical results from treatment of sarcoma with oncolytic adenovirus Ad5/3-D24-GMCSF (CGTG-102). Ad5/3-D24-GMCSF is a serotype chimeric oncolytic adenovirus coding for human granulocyte-macrophage colony-stimulating factor (GM-CSF). The efficacy of Ad5/3-D24-GMCSF was evaluated on a panel of soft-tissue sarcoma (STS) cell lines and in two animal models. Sarcoma specific human data were also collected from the Advanced Therapy Access Program (ATAP), in preparation for further clinical development. Efficacy was seen in both in vitro and in vivo STS models. Fifteen patients with treatment-refractory STS (13/15) or primary bone sarcoma (2/15) were treated in ATAP, and treatments appeared safe and well-tolerated. A total of 12 radiological RECIST response evaluations were performed, and two cases of minor response, six cases of stable disease and four cases of progressive disease were detected in patients progressing prior to virus treatment. Overall, the median survival time post treatment was 170 days. One patient is still alive at 1,459 days post virus treatment. In summary, Ad5/3-D24-GMCSF appears promising for the treatment of advanced STS; a clinical trial for treatment of refractory injectable solid tumors including STS is ongoing.

Published
2014

28. Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus

Author

Akseli Hemminki, Angelica Loskog, Saila K. Pesonen, Simona Bramante, Suvi Parviainen, Iulia Diaconu, A. Kanerva, Aristides G. Eliopoulos, Matteo Ugolini, Sophie Escutenaire, Sari Pesonen, Mari Hirvinen, Vincenzo Cerullo, Diaconu, Iulia, Cerullo, Vincenzo, Hirvinen, Mari L. M., Escutenaire, Sophie, Ugolini, Matteo, Pesonen, Saila K., Bramante, Simona, Parviainen, Suvi, Kanerva, Anna, Loskog, Angelica S. I., Eliopoulos, Aristides G., Pesonen, Sari, and Hemminki, Akseli

Subjects
Oncolytic adenovirus, Cancer Research, Xenograft Model Antitumor Assay, Genetic enhancement, CD40 Ligand, Melanoma, Experimental, Mice, Nude, chemical and pharmacologic phenomena, Apoptosis, Oncolytic Viruse, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Neoplasms, Cell Line, Tumor, Cytotoxic T cell, Medicine, Animals, Humans, CD154, Cytokine, 030304 developmental biology, Oncolytic Virotherapy, 0303 health sciences, CD40, biology, business.industry, Animal, Apoptosi, T-Lymphocytes, Helper-Inducer, Virology, Tumor site, Xenograft Model Antitumor Assays, 3. Good health, Mice, Inbred C57BL, Oncolytic Viruses, Urinary Bladder Neoplasms, Oncology, 030220 oncology & carcinogenesis, Urinary Bladder Neoplasm, biology.protein, Ovarian cancer cells, Cytokines, Neoplasm, business, Human, T-Lymphocytes, Cytotoxic
Abstract

Oncolytic adenovirus is an attractive platform for immunotherapy because virus replication is highly immunogenic and not subject to tolerance. Although oncolysis releases tumor epitopes and provides costimulatory danger signals, arming the virus with immunostimulatory molecules can further improve efficacy. CD40 ligand (CD40L, CD154) induces apoptosis of tumor cells and triggers several immune mechanisms, including a T-helper type 1 (TH1) response, which leads to activation of cytotoxic T cells and reduction of immunosuppression. In this study, we constructed a novel oncolytic adenovirus, Ad5/3-hTERT-E1A-hCD40L, which features a chimeric Ad5/3 capsid for enhanced tumor transduction, a human telomerase reverse transcriptase (hTERT) promoter for tumor selectivity, and human CD40L for increased efficacy. Ad5/3-hTERT-E1A-hCD40L significantly inhibited tumor growth in vivo via oncolytic and apoptotic effects, and (Ad5/3-hTERT-E1A-hCD40L)–mediated oncolysis resulted in enhanced calreticulin exposure and HMGB1 and ATP release, which were suggestive of immunogenicity. In two syngeneic mouse models, murine CD40L induced recruitment and activation of antigen-presenting cells, leading to increased interleukin-12 production in splenocytes. This effect was associated with induction of the TH1 cytokines IFN-γ, RANTES, and TNF-α. Tumors treated with Ad5/3-CMV-mCD40L also displayed an enhanced presence of macrophages and cytotoxic CD8+ T cells but not B cells. Together, our findings show that adenoviruses coding for CD40L mediate multiple antitumor effects including oncolysis, apoptosis, induction of T-cell responses, and upregulation of TH1 cytokines. Cancer Res; 72(9); 2327–38. ©2012 AACR.

Published
2012

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