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1. Supplementary Data from Oncolytic Adenovirus ICOVIR-7 in Patients with Advanced and Refractory Solid Tumors

Author

Nokisalmi, Petri, primary, Pesonen, Sari, primary, Escutenaire, Sophie, primary, Särkioja, Merja, primary, Raki, Mari, primary, Cerullo, Vincenzo, primary, Laasonen, Leena, primary, Alemany, Ramon, primary, Rojas, Juan, primary, Cascallo, Manel, primary, Guse, Kilian, primary, Rajecki, Maria, primary, Kangasniemi, Lotta, primary, Haavisto, Elina, primary, Karioja-Kallio, Aila, primary, Hannuksela, Päivi, primary, Oksanen, Minna, primary, Kanerva, Anna, primary, Joensuu, Timo, primary, Ahtiainen, Laura, 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. Data from Oncolytic Adenovirus Coding for Granulocyte Macrophage Colony-Stimulating Factor Induces Antitumoral Immunity in Cancer Patients

Author

Cerullo, Vincenzo, primary, Pesonen, Sari, primary, Diaconu, Iulia, primary, Escutenaire, Sophie, primary, Arstila, Petteri T., primary, Ugolini, Matteo, primary, Nokisalmi, Petri, primary, Raki, Mari, primary, Laasonen, Leena, primary, Särkioja, Merja, primary, Rajecki, Maria, primary, Kangasniemi, Lotta, primary, Guse, Kilian, primary, Helminen, Andreas, primary, Ahtiainen, Laura, primary, Ristimäki, Ari, primary, Räisänen-Sokolowski, Anne, primary, Haavisto, Elina, primary, Oksanen, Minna, primary, Karli, Eerika, primary, Karioja-Kallio, Aila, primary, Holm, Sirkka-Liisa, primary, Kouri, Mauri, primary, Joensuu, Timo, primary, Kanerva, Anna, primary, and Hemminki, Akseli, primary

Published
2023
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7. 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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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 Figures 1-6, Tables 1-3 from Oncolytic Adenovirus Coding for Granulocyte Macrophage Colony-Stimulating Factor Induces Antitumoral Immunity in Cancer Patients

Author

Cerullo, Vincenzo, primary, Pesonen, Sari, primary, Diaconu, Iulia, primary, Escutenaire, Sophie, primary, Arstila, Petteri T., primary, Ugolini, Matteo, primary, Nokisalmi, Petri, primary, Raki, Mari, primary, Laasonen, Leena, primary, Särkioja, Merja, primary, Rajecki, Maria, primary, Kangasniemi, Lotta, primary, Guse, Kilian, primary, Helminen, Andreas, primary, Ahtiainen, Laura, primary, Ristimäki, Ari, primary, Räisänen-Sokolowski, Anne, primary, Haavisto, Elina, primary, Oksanen, Minna, primary, Karli, Eerika, primary, Karioja-Kallio, Aila, primary, Holm, Sirkka-Liisa, primary, Kouri, Mauri, primary, Joensuu, Timo, primary, Kanerva, Anna, primary, and Hemminki, Akseli, primary

Published
2023
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12. 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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13. 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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14. Immunological Effects of Low-dose Cyclophosphamide in Cancer Patients Treated With Oncolytic Adenovirus

Author

Cerullo, Vincenzo, Diaconu, Iulia, Kangasniemi, Lotta, Rajecki, Maria, Escutenaire, Sophie, Koski, Anniina, Romano, Valentina, Rouvinen, Noora, Tuuminen, Tamara, Laasonen, Leena, Partanen, Kaarina, Kauppinen, Satu, Joensuu, Timo, Oksanen, Minna, Holm, Sirkka-Liisa, Haavisto, Elina, Karioja-Kallio, Aila, Kanerva, Anna, Pesonen, Sari, Arstila, Petteri T, and Hemminki, Akseli

Published
2011
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15. Treatment of Cancer Patients With a Serotype 5/3 Chimeric Oncolytic Adenovirus Expressing GMCSF

Author

Koski, Anniina, Kangasniemi, Lotta, Escutenaire, Sophie, Pesonen, Sari, Cerullo, Vincenzo, Diaconu, Iulia, Nokisalmi, Petri, Raki, Mari, Rajecki, Maria, Guse, Kilian, Ranki, Tuuli, Oksanen, Minna, Holm, Sirkka-Liisa, Haavisto, Elina, Karioja-Kallio, Aila, Laasonen, Leena, Partanen, Kaarina, Ugolini, Matteo, Helminen, Andreas, Karli, Eerika, Hannuksela, Päivi, Pesonen, Saila, Joensuu, Timo, Kanerva, Anna, and Hemminki, Akseli

Published
2010
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16. Integrin targeted oncolytic adenoviruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors

Author

Pesonen, Sari, Diaconu, Iulia, Cerullo, Vincenzo, Escutenaire, Sophie, Raki, Mari, Kangasniemi, Lotta, Nokisalmi, Petri, Dotti, Gianpietro, Guse, Kilian, Laasonen, Leena, Partanen, Kaarina, Karli, Eerika, Haavisto, Elina, Oksanen, Minna, Karioja-Kallio, Aila, Hannuksela, Päivi, Holm, Sirkka-Liisa, Kauppinen, Satu, Joensuu, Timo, Kanerva, Anna, and Hemminki, Akseli

Published
2012
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17. T-cell Subsets in Peripheral Blood and Tumors of Patients Treated With Oncolytic Adenoviruses

Author

Taipale Kristian, Ristimaki Ari, Karioja-Kallio Aila, Juhila Juuso, Liikanen Ilkka, Kanerva Anna, Vähä-Koskela Markus, Hemminki Akseli, Lundin Johan, Linder Nina, Koski Anniina, Joensuu Timo, Turkki Riku, and Oksanen Minna

Subjects
Oncolytic adenovirus, Lymphocyte, medicine.medical_treatment, T cell, 03 medical and health sciences, 0302 clinical medicine, Immune system, Drug Discovery, Genetics, medicine, Molecular Biology, 030304 developmental biology, Pharmacology, 0303 health sciences, business.industry, Melanoma, Immunotherapy, medicine.disease, 3. Good health, Oncolytic virus, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Molecular Medicine, business, CD8
Abstract

The quality of the antitumor immune response is decisive when developing new immunotherapies for cancer. Oncolytic adenoviruses cause a potent immunogenic stimulus and arming them with costimulatory molecules reshapes the immune response further. We evaluated peripheral blood T-cell subsets of 50 patients with refractory solid tumors undergoing treatment with oncolytic adenovirus. These data were compared to changes in antiviral and antitumor T cells, treatment efficacy, overall survival, and T-cell subsets in pre- and post-treatment tumor biopsies. Treatment caused a significant ( P + cells, and decrease of CD4 + cells. Concomitant treatment with cyclophosphamide and temozolomide resulted in less CD4 + decrease ( P = 0.041) than cyclophosphamide only. Interestingly, we saw a correlation between T-cell changes in peripheral blood and the tumor site. This correlation was positive for CD8 + and inverse for CD4 + cells. These findings give insight to the interconnections between peripheral blood and tumor-infiltrating lymphocyte (TIL) populations regarding oncolytic virotherapy. In particular, our data suggest that induction of T-cell response is not sufficient for clinical response in the context of immunosuppressive tumors, and that peripheral blood T cells have a complicated and potentially misleading relationship with TILs.

Published
2015
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18. 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

Author

Kuryk, Lukasz, primary, Vassilev, Lotta, additional, Ranki, Tuuli, additional, Hemminki, Akseli, additional, Karioja-Kallio, Aila, additional, Levälampi, Onerva, additional, Vuolanto, Antti, additional, Cerullo, Vincenzo, additional, and Pesonen, Sari, additional

Published
2017
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20. 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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21. Integrin targeted oncolytic adenoviruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors

Author

Pesonen, Sari, primary, Diaconu, Iulia, additional, Cerullo, Vincenzo, additional, Escutenaire, Sophie, additional, Raki, Mari, additional, Kangasniemi, Lotta, additional, Nokisalmi, Petri, additional, Dotti, Gianpietro, additional, Guse, Kilian, additional, Laasonen, Leena, additional, Partanen, Kaarina, additional, Karli, Eerika, additional, Haavisto, Elina, additional, Oksanen, Minna, additional, Karioja-Kallio, Aila, additional, Hannuksela, Päivi, additional, Holm, Sirkka-Liisa, additional, Kauppinen, Satu, additional, Joensuu, Timo, additional, Kanerva, Anna, additional, and Hemminki, Akseli, additional

Published
2011
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22. In vivoandin vitrodistribution of type 5 and fiber-modified oncolytic adenoviruses in human blood compartments

Author

Escutenaire, Sophie, primary, Cerullo, Vincenzo, additional, Diaconu, Iulia, additional, Ahtiainen, Laura, additional, Hannuksela, Päivi, additional, Oksanen, Minna, additional, Haavisto, Elina, additional, Karioja-Kallio, Aila, additional, Holm, Sirkka-Liisa, additional, Kangasniemi, Lotta, additional, Ribacka, Camilla, additional, Kauppinen, Satu, additional, Joensuu, Timo, additional, Petteri Arstila, T., additional, Pesonen, Sari, additional, Kanerva, Anna, additional, and Hemminki, Akseli, additional

Published
2011
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23. Oncolytic Adenovirus Coding for Granulocyte Macrophage Colony-Stimulating Factor Induces Antitumoral Immunity in Cancer Patients

Author

Cerullo, Vincenzo, primary, Pesonen, Sari, additional, Diaconu, Iulia, additional, Escutenaire, Sophie, additional, Arstila, Petteri T., additional, Ugolini, Matteo, additional, Nokisalmi, Petri, additional, Raki, Mari, additional, Laasonen, Leena, additional, Särkioja, Merja, additional, Rajecki, Maria, additional, Kangasniemi, Lotta, additional, Guse, Kilian, additional, Helminen, Andreas, additional, Ahtiainen, Laura, additional, Ristimäki, Ari, additional, Räisänen-Sokolowski, Anne, additional, Haavisto, Elina, additional, Oksanen, Minna, additional, Karli, Eerika, additional, Karioja-Kallio, Aila, additional, Holm, Sirkka-Liisa, additional, Kouri, Mauri, additional, Joensuu, Timo, additional, Kanerva, Anna, additional, and Hemminki, Akseli, additional

Published
2010
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24. Oncolytic Adenovirus ICOVIR-7 in Patients with Advanced and Refractory Solid Tumors

Author

Nokisalmi, Petri, primary, Pesonen, Sari, additional, Escutenaire, Sophie, additional, Särkioja, Merja, additional, Raki, Mari, additional, Cerullo, Vincenzo, additional, Laasonen, Leena, additional, Alemany, Ramon, additional, Rojas, Juan, additional, Cascallo, Manel, additional, Guse, Kilian, additional, Rajecki, Maria, additional, Kangasniemi, Lotta, additional, Haavisto, Elina, additional, Karioja-Kallio, Aila, additional, Hannuksela, Päivi, additional, Oksanen, Minna, additional, Kanerva, Anna, additional, Joensuu, Timo, additional, Ahtiainen, Laura, additional, and Hemminki, Akseli, additional

Published
2010
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25. In vivo and in vitro distribution of type 5 and fiber-modified oncolytic adenoviruses in human blood compartments.

Author

Escutenaire, Sophie, Cerullo, Vincenzo, Diaconu, Iulia, Ahtiainen, Laura, Hannuksela, Päivi, Oksanen, Minna, Haavisto, Elina, Karioja-Kallio, Aila, Holm, Sirkka-Liisa, Kangasniemi, Lotta, Ribacka, Camilla, Kauppinen, Satu, Joensuu, Timo, Petteri Arstila, T., Pesonen, Sari, Kanerva, Anna, and Hemminki, Akseli

Abstract

Background. Successful tumor targeting of systemically administered oncolytic adenoviruses may be hindered by interactions with blood components. Materials and methods. Blood distribution of oncolytic adenoviruses featuring type 5 adenovirus fiber, 5/3 capsid chimerism, or RGD-4C in the fiber knob was investigated in vitro and in patients with refractory solid tumors. Results. Virus titers and prevalence in serum of patients increased over the first post-treatment week, suggesting replication. Detection of low virus loads was more sensitive in blood clots than in serum, although viral levels > 500 viral particles/mL did not differ significantly between both sample types. While adenovirus bound to erythrocytes, platelets, granulocytes, and peripheral blood mononuclear cells in vitro, the virus was mainly detectable in erythrocytes and granulocytes in cancer patients. Taken together with a temporary post-treatment decrease in thrombocyte counts, platelet activation by adenovirus and subsequent clearance seem likely to occur in humans. Fiber modifications had limited observed effect on virus distribution in blood cell compartments. Neutrophils, monocytes and cytotoxic T lymphocytes were the major leukocyte subpopulations interacting with adenoviruses. Conclusion. Serum and blood clots are relevant to estimate oncolytic adenovirus replication. Insight into viral interactions with blood cells may contribute to the development of new strategies for tumor delivery. [ABSTRACT FROM AUTHOR]

Published
2011
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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. Integrin targeted oncolytic adenoviruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors

Author

Petri Nokisalmi, Satu Kauppinen, Vincenzo Cerullo, Lotta Kangasniemi, Gianpietro Dotti, Anna Kanerva, Sophie Escutenaire, Iulia Diaconu, Akseli Hemminki, Eerika Karli, Kaarina Partanen, Sari Pesonen, Elina Haavisto, Aila Karioja-Kallio, Sirkka Liisa Holm, Leena Laasonen, Timo Joensuu, Minna Oksanen, Päivi Hannuksela, Mari Raki, Kilian Guse, Pesonen, Sari, Diaconu, Iulia, Cerullo, Vincenzo, Escutenaire, Sophie, Raki, Mari, Kangasniemi, Lotta, Nokisalmi, Petri, Dotti, Gianpietro, Guse, Kilian, Laasonen, Leena, Partanen, Kaarina, Karli, Eerika, Haavisto, Elina, Oksanen, Minna, Karioja-Kallio, Aila, Hannuksela, Päivi, Holm, Sirkka-Liisa, Kauppinen, Satu, Joensuu, Timo, Kanerva, Anna, and Hemminki, Akseli

Subjects
Male, Integrins, Cancer Research, viruses, medicine.medical_treatment, Integrin, Virus Replication, 0302 clinical medicine, Cancer immunotherapy, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Fatigue, Oncolytic Virotherapy, 0303 health sciences, ELISPOT, Middle Aged, Viral Load, 3. Good health, Oncolytic Viruses, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Oligopeptide, Female, Genetic Vector, Oligopeptides, Human, Oncolytic adenovirus, Adult, Fever, Genetic Vectors, Oncolytic Viruse, Real-Time Polymerase Chain Reaction, Adenoviridae, 03 medical and health sciences, Immune system, Cell Line, Tumor, medicine, Humans, 030304 developmental biology, Tumor marker, Aged, Chemotherapy, Antineoplastic Combined Chemotherapy Protocol, business.industry, Cancer, Granulocyte-Macrophage Colony-Stimulating Factor, medicine.disease, Oncolytic virus, Drug Resistance, Neoplasm, Immunology, DNA, Viral, Cancer research, Neoplasm, business
Abstract

The safety of oncolytic viruses for treatment of cancer has been shown in clinical trials while antitumor efficacy has often remained modest. As expression of the coxsackie-adenovirus receptor may be variable in advanced tumors, we developed Ad5-D24-RGD, a p16/Rb pathway selective oncolytic adenovirus featuring RGD-4C modification of the fiber. This allows viral entry through alpha-v-beta integrins frequently highly expressed in advanced tumors. Advanced tumors are often immunosuppressive which results in lack of tumor eradication despite abnormal epitopes being present. Granulocyte-macrophage colony stimulating factor (GMCSF) is a potent activator of immune system with established antitumor properties. To stimulate antitumor immunity and break tumor associated immunotolerance, we constructed Ad5-RGD-D24-GMCSF, featuring GMCSF controlled by the adenoviral E3 promoter. Preliminary safety of Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of human cancer was established. Treatments with Ad5-D24-RGD (N = 9) and Ad5-RGD-D24-GMCSF (N = 7) were well tolerated. Typical side effects were grade 1-2 fatigue, fever and injection site pain. 77% (10/13) of evaluable patients showed virus in circulation for at least 2 weeks. In 3 out of 6 evaluable patients, disease previously progressing stabilized after a single treatment with Ad5-RGD-D24-GMCSF. In addition, 2/3 patients had stabilization or reduction in tumor marker levels. All patients treated with Ad5-D24-RGD showed disease progression in radiological analysis, although 3/6 had temporary reduction or stabilization of marker levels. Induction of tumor and adenovirus specific immunity was demonstrated with ELISPOT in Ad5-RGD-D24-GMCSF treated patients. RGD modified oncolytic adenoviruses with or without GMCSF seem safe for further clinical development.

Published
2012

28. Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus

Author

Akseli Hemminki, Aila Karioja-Kallio, Leena Laasonen, Petteri Arstila, Noora Rouvinen, Iulia Diaconu, Anniina Koski, Sophie Escutenaire, Lotta Kangasniemi, Anna Kanerva, Kaarina Partanen, Vincenzo Cerullo, Satu Kauppinen, Valentina Romano, Timo Joensuu, Maria Rajecki, Minna Oksanen, Sari Pesonen, Elina Haavisto, Sirkka-Liisa Holm, Tamara Tuuminen, Cerullo, Vincenzo, Diaconu, Iulia, Kangasniemi, Lotta, Rajecki, Maria, Escutenaire, Sophie, Koski, Anniina, Romano, Valentina, Rouvinen, Noora, Tuuminen, Tamara, Laasonen, Leena, Partanen, Kaarina, Kauppinen, Satu, Joensuu, Timo, Oksanen, Minna, Holm, Sirkka-Liisa, Haavisto, Elina, Karioja-Kallio, Aila, Kanerva, Anna, Pesonen, Sari, Arstila, Petteri T., and Hemminki, Akseli

Subjects
Male, medicine.medical_treatment, Pharmacology, medicine.disease_cause, T-Lymphocytes, Regulatory, Antineoplastic Agent, 0302 clinical medicine, Cricetinae, Neoplasms, Drug Discovery, Medicine, Cytotoxic T cell, Child, Oncolytic Virotherapy, 0303 health sciences, Mesocricetu, Middle Aged, Combined Modality Therapy, 3. Good health, Treatment Outcome, 030220 oncology & carcinogenesis, Molecular Medicine, Female, Original Article, Genetic Vector, medicine.drug, Human, Oncolytic adenovirus, Adult, Cyclophosphamide, Adolescent, Genetic Vectors, Antineoplastic Agents, Virus, Drug Administration Schedule, Adenoviridae, 03 medical and health sciences, Young Adult, Genetic, Cell Line, Tumor, Genetics, Animals, Humans, Molecular Biology, 030304 developmental biology, Aged, Chemotherapy, Dose-Response Relationship, Drug, Mesocricetus, business.industry, Animal, Drug Discovery3003 Pharmaceutical Science, Immunotherapy, Oncolytic virus, Neoplasm, business
Abstract

Patients with advanced solid tumors refractory to and progressing after conventional therapies were treated with three different regimens of low-dose cyclophosphamide (CP) in combination with oncolytic adenovirus. CP was given with oral metronomic dosing (50 mg/day, N = 21), intravenously (single 1,000 mg dose, N = 7) or both (N = 7). Virus was injected intratumorally. Controls (N = 8) received virus without CP. Treatments were well tolerated and safe regardless of schedule. Antibody formation and virus replication were not affected by CP. Metronomic CP (oral and oral + intravenous schedules) decreased regulatory T cells (Tregs) without compromising induction of antitumor or antiviral T-cell responses. Oncolytic adenovirus given together with metronomic CP increased cytotoxic T cells and induced Th1 type immunity on a systemic level in most patients. All CP regimens resulted in higher rates of disease control than virus only (all P < 0.0001) and the best progression-free (PFS) and overall survival (OS) was seen in the oral + intravenous group. One year PFS and OS were 53 and 42% (P = 0.0016 and P < 0.02 versus virus only), respectively, both which are unusually high for chemotherapy refractory patients. We conclude that low-dose CP results in immunological effects appealing for oncolytic virotherapy. While these first-in-human data suggest good safety, intriguing efficacy and extended survival, the results should be confirmed in a randomized trial.

Published
2011

29. Oncolytic adenovirus coding for granulocyte macrophage colony-stimulating factor induces antitumoral immunity in cancer patients

Author

Anne Räisänen-Sokolowski, Akseli Hemminki, Vincenzo Cerullo, Laura Ahtiainen, Iulia Diaconu, Lotta Kangasniemi, Eerika Karli, Kilian Guse, Ari Ristimäki, Matteo Ugolini, Sari Pesonen, Elina Haavisto, Sirkka-Liisa Holm, Andreas Helminen, Merja Särkioja, Mauri Kouri, Sophie Escutenaire, Timo Joensuu, Maria Rajecki, Petri Nokisalmi, Minna Oksanen, Anna Kanerva, Leena Laasonen, Aila Karioja-Kallio, Petteri Arstila, Mari Raki, Cerullo, Vincenzo, Pesonen, Sari, Diaconu, Iulia, Escutenaire, Sophie, Arstila, Petteri T., Ugolini, Matteo, Nokisalmi, Petri, Raki, Mari, Laasonen, Leena, Särkioja, Merja, Rajecki, Maria, Kangasniemi, Lotta, Guse, Kilian, Helminen, Andrea, Ahtiainen, Laura, Ristimäki, Ari, Räisänen-Sokolowski, Anne, Haavisto, Elina, Oksanen, Minna, Karli, Eerika, Karioja-Kallio, Aila, Holm, Sirkka-Liisa, Kouri, Mauri, Joensuu, Timo, Kanerva, Anna, and Hemminki, Akseli

Subjects
Oncolytic adenovirus, Cancer Research, Survivin, T-Lymphocytes, Epitopes, T-Lymphocyte, Biology, Transfection, Adenoviridae, Inhibitor of Apoptosis Proteins, 03 medical and health sciences, 0302 clinical medicine, Immunity, Cricetinae, Neoplasms, Inhibitor of Apoptosis Protein, Granulocyte Colony-Stimulating Factor, medicine, Macrophage, Cytotoxic T cell, Animals, Humans, 030304 developmental biology, Oncolytic Virotherapy, 0303 health sciences, Animal, ELISPOT, Microtubule-Associated Protein, Cancer, medicine.disease, 3. Good health, Oncolytic virus, Granulocyte macrophage colony-stimulating factor, T-Lymphocyte, Oncology, 030220 oncology & carcinogenesis, Immunology, Neoplasm, Immunotherapy, Microtubule-Associated Proteins, medicine.drug, Human
Abstract

Granulocyte macrophage colony-stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific cytotoxic T-cells through antigen-presenting cells. Oncolytic tumor cell–killing can produce a potent costimulatory danger signal and release of tumor epitopes for antigen-presenting cell sampling. Therefore, an oncolytic adenovirus coding for GMCSF was engineered and shown to induce tumor-specific immunity in an immunocompetent syngeneic hamster model. Subsequently, 20 patients with advanced solid tumors refractory to standard therapies were treated with Ad5-D24-GMCSF. Of the 16 radiologically evaluable patients, 2 had complete responses, 1 had a minor response, and 5 had disease stabilization. Responses were frequently seen in injected and noninjected tumors. Treatment was well tolerated and resulted in the induction of both tumor-specific and virus-specific immunity as measured by ELISPOT and pentamer analysis. This is the first time that oncolytic virus–mediated antitumor immunity has been shown in humans. Ad5-D24-GMCSF is promising for further clinical testing. Cancer Res; 70(11); 4297–309. ©2010 AACR.

Published
2010

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