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Sari Pesonen,
Iulia Diaconu,
Lotta Kangasniemi,
Tuuli Ranki,
Anna Kanerva,
Saila K Pesonen,
Ulrike Gerdemann,
Ann M Leen,
Kalevi Kairemo,
Minna Oksanen,
Elina Haavisto,
Sirkka-Liisa Holm, Aila Karioja-Kallio,
Satu Kauppinen,
Kaarina P L Partanen,
Leena Laasonen,
Tima Joensuu,
Tuomo Alanko,
Vincenzo Cerullo,
Akseli Hemminki
[show abstract]
[hide abstract]
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 Research 02/2012; 72(7):1621-31. · 7.86 Impact Factor
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Vincenzo Cerullo,
Iulia Diaconu,
Lotta Kangasniemi,
Maria Rajecki,
Sophie Escutenaire,
Anniina Koski,
Valentina Romano,
Noora Rouvinen,
Tamara Tuuminen,
Leena Laasonen, [......],
Satu Kauppinen,
Timo Joensuu,
Minna Oksanen,
Sirkka-Liisa Holm,
Elina Haavisto, Aila Karioja-Kallio,
Anna Kanerva,
Sari Pesonen,
Petteri T Arstila,
Akseli Hemminki
[show abstract]
[hide abstract]
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 (T(regs)) 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.
Molecular Therapy 06/2011; 19(9):1737-46. · 6.87 Impact Factor
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Sari Pesonen,
Iulia Diaconu,
Vincenzo Cerullo,
Sophie Escutenaire,
Mari Raki,
Lotta Kangasniemi,
Petri Nokisalmi,
Gianpietro Dotti,
Kilian Guse,
Leena Laasonen, [......],
Eerika Karli,
Elina Haavisto,
Minna Oksanen, Aila Karioja-Kallio,
Päivi Hannuksela,
Sirkka-Liisa Holm,
Satu Kauppinen,
Timo Joensuu,
Anna Kanerva,
Akseli Hemminki
[show abstract]
[hide abstract]
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.
International Journal of Cancer 05/2011; 130(8):1937-47. · 5.44 Impact Factor
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Sophie Escutenaire,
Vincenzo Cerullo,
Iulia Diaconu,
Laura Ahtiainen,
Päivi Hannuksela,
Minna Oksanen,
Elina Haavisto, Aila Karioja-Kallio,
Sirkka-Liisa Holm,
Lotta Kangasniemi,
Camilla Ribacka,
Satu Kauppinen,
Timo Joensuu,
T Petteri Arstila,
Sari Pesonen,
Anna Kanerva,
Akseli Hemminki
[show abstract]
[hide abstract]
ABSTRACT: Successful tumor targeting of systemically administered oncolytic adenoviruses may be hindered by interactions with blood components.
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.
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.
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.
Annals of medicine 03/2011; 43(2):151-63. · 3.52 Impact Factor
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Anniina Koski,
Lotta Kangasniemi,
Sophie Escutenaire,
Sari Pesonen,
Vincenzo Cerullo,
Iulia Diaconu,
Petri Nokisalmi,
Mari Raki,
Maria Rajecki,
Kilian Guse, [......],
Leena Laasonen,
Kaarina Partanen,
Matteo Ugolini,
Andreas Helminen,
Eerika Karli,
Päivi Hannuksela,
Saila Pesonen,
Timo Joensuu,
Anna Kanerva,
Akseli Hemminki
[show abstract]
[hide abstract]
ABSTRACT: Augmenting antitumor immunity is a promising way to enhance the potency of oncolytic adenoviral therapy. Granulocyte-macrophage colony-stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific CD8(+) cytotoxic T-lymphocytes. Serotype 5 adenoviruses (Ad5) are commonly used in cancer gene therapy. However, expression of the coxsackie-adenovirus receptor is variable in many advanced tumors and preclinical data have demonstrated an advantage for replacing the Ad5 knob with the Ad3 knob. Here, a 5/3 capsid chimeric and p16-Rb pathway selective oncolytic adenovirus coding for GMCSF was engineered and tested preclinically. A total of 21 patients with advanced solid tumors refractory to standard therapies were then treated intratumorally and intravenously with Ad5/3-D24-GMCSF, which was combined with low-dose metronomic cyclophosphamide to reduce regulatory T cells. No severe adverse events occurred. Analysis of pretreatment samples of malignant pleural effusion and ascites confirmed the efficacy of Ad5/3-D24-GMCSF in transduction and cell killing. Evidence of biological activity of the virus was seen in 13/21 patients and 8/12 showed objective clinical benefit as evaluated by radiology with Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Antiadenoviral and antitumoral immune responses were elicited after treatment. Thus, Ad5/3-D24-GMCSF seems safe in treating cancer patients and promising signs of efficacy were seen.
Molecular Therapy 10/2010; 18(10):1874-84. · 6.87 Impact Factor
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Petri Nokisalmi,
Sari Pesonen,
Sophie Escutenaire,
Merja Särkioja,
Mari Raki,
Vincenzo Cerullo,
Leena Laasonen,
Ramon Alemany,
Juan Rojas,
Manel Cascallo, [......],
Maria Rajecki,
Lotta Kangasniemi,
Elina Haavisto, Aila Karioja-Kallio,
Päivi Hannuksela,
Minna Oksanen,
Anna Kanerva,
Timo Joensuu,
Laura Ahtiainen,
Akseli Hemminki
[show abstract]
[hide abstract]
ABSTRACT: Twenty-one patients with cancer were treated with a single round of oncolytic adenovirus ICOVIR-7.
ICOVIR-7 features an RGD-4C modification of the fiber HI-loop of serotype 5 adenovirus for enhanced entry into tumor cells. Tumor selectivity is mediated by an insulator, a modified E2F promoter, and a Rb-binding site deletion of E1A, whereas replication is optimized with E2F binding hairpins and a Kozak sequence. ICOVIR-7 doses ranged from 2 x 10(10) to 1 x 10(12) viral particles. All patients had advanced and metastatic solid tumors refractory to standard therapies.
ICOVIR-7 treatment was well tolerated with mild to moderate fever, fatigue, elevated liver transaminases, chills, and hyponatremia. One patient had grade 3 anemia but no other serious side effects were seen. At baseline, 9 of 21 of patients had neutralizing antibody titers against the ICOVIR-7 capsid. Treatment resulted in neutralizing antibody titer induction within 4 weeks in 16 of 18 patients. No elevations of serum proinflammatory cytokine levels were detected. Viral genomes were detected in the circulation in 18 of 21 of patients after injection and 7 of 15 of the samples were positive 2 to 4 weeks later suggesting viral replication.
Overall, objective evidence of antitumor activity was seen in 9 of 17 evaluable patients. In radiological analyses, 5 of 12 evaluable patients had stabilization or reduction in tumor size. These consisted of one partial response, two minor responses and two cases of stable disease, all occurring in patients who had progressive disease before treatment. In summary, ICOVIR-7 treatment is apparently safe, resulting in anticancer activity, and is therefore promising for further clinical testing.
Clinical Cancer Research 06/2010; 16(11):3035-43. · 7.74 Impact Factor
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Vincenzo Cerullo,
Sari Pesonen,
Iulia Diaconu,
Sophie Escutenaire,
Petteri T Arstila,
Matteo Ugolini,
Petri Nokisalmi,
Mari Raki,
Leena Laasonen,
Merja Särkioja, [......],
Anne Räisänen-Sokolowski,
Elina Haavisto,
Minna Oksanen,
Eerika Karli, Aila Karioja-Kallio,
Sirkka-Liisa Holm,
Mauri Kouri,
Timo Joensuu,
Anna Kanerva,
Akseli Hemminki
[show abstract]
[hide abstract]
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 Research 06/2010; 70(11):4297-309. · 7.86 Impact Factor
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Sari Pesonen,
Iulia Diaconu,
Vincenzo Cerullo,
Sophie Escutenaire,
Mari Raki,
Lotta Kangasniemi,
Petri Nokisalmi,
Gianpietro Dotti,
Kilian Guse,
Leena Laasonen, [......],
Eerika Karli,
Elina Haavisto,
Minna Oksanen, Aila Karioja-Kallio,
Päivi Hannuksela,
Sirkka-Liisa Holm,
Satu Kauppinen,
Timo Joensuu,
Anna Kanerva,
Akseli Hemminki
