Publications by authors named "Tuomo Alanko"

17 Publications

  • Page 1 of 1

Safety, pharmacokinetics, and efficacy of budigalimab with rovalpituzumab tesirine in patients with small cell lung cancer.

Cancer Treat Res Commun 2021 25;28:100405. Epub 2021 May 25.

Cancer Care Center, Blacktown Hospital, Sydney, NSW, Australia. Electronic address:

Background: Agents targeting programmed cell death protein 1 (PD-1) have been approved as monotherapy for patients with small cell lung cancer (SCLC). In preclinical models, the combined targeting of PD-1 and delta-like protein 3 resulted in enhanced antitumor activity. Herein, we report results from the expansion arm of study NCT03000257 evaluating the combination of the anti-PD-1 antibody budigalimab and the targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T) in patients with previously treated SCLC.

Materials And Methods: This expansion arm of a multicenter, open-label, multi-arm, first-in-human phase 1 clinical trial enrolled adult patients with progressive SCLC. The primary objective was to assess safety and tolerability. Patients received budigalimab 375 mg via intravenous infusion every 3 weeks, and Rova-T was administered as a dose of 0.3 mg/kg intravenously, on day 1 of the first and third 3-week cycle.

Results: As of October 2019, 31 patients with SCLC were enrolled and treated with budigalimab plus Rova-T. The combination was tolerated, with the most common treatment-emergent adverse events (in >30%) being pleural effusion, fatigue, and cough. The overall response rate was 24.1%, with one confirmed complete response and six confirmed partial responses. The overall response rate in patients with high delta-like protein 3 expression was similar (21.1%). The median progression-free survival was 3.48 months.

Conclusion: Combination therapy with budigalimab and Rova-T had promising efficacy and appeared to be tolerated in patients with SCLC. Although Rova-T development has been discontinued, development of budigalimab combined with other anticancer agents is ongoing.

Clinical Trial Registration Number: NCT03000257 Statement on originality of the work The manuscript represents original work and has not been submitted for publication elsewhere nor previously published. Statement of prior presentation Data from this study were previously presented at the European Society for Medical Oncology (ESMO) Congress 2019.
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http://dx.doi.org/10.1016/j.ctarc.2021.100405DOI Listing
May 2021

First-in-human phase 1 study of budigalimab, an anti-PD-1 inhibitor, in patients with non-small cell lung cancer and head and neck squamous cell carcinoma.

Cancer Immunol Immunother 2021 Jul 3. Epub 2021 Jul 3.

START Madrid-FJD, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain.

Background: Budigalimab is a humanized, recombinant immunoglobulin G1 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We present the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic data from patients enrolled in the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts of the phase 1 first-in-human study of budigalimab monotherapy (NCT03000257; registered 15 December 2016).

Patients And Methods: Patients with recurrent/metastatic HNSCC or locally advanced/metastatic NSCLC naive to PD-1/PD-1-ligand inhibitors were enrolled; patients were not selected on the basis of oncogene driver mutations or PD-L1 status. Budigalimab was administered at 250 mg intravenously Q2W or 500 mg intravenously Q4W until disease progression/unacceptable toxicity. The primary endpoints were safety and PK; the secondary endpoint was efficacy. Exploratory endpoints included biomarker assessments.

Results: In total, 81 patients were enrolled (HNSCC: N = 41 [PD-L1 positive: n = 19]; NSCLC: N = 40 [PD-L1 positive: n = 16]); median treatment duration was 72 days (range, 1-617) and 71 days (range, 1-490) for the HNSCC and NSCLC cohorts, respectively. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (HNSCC: n = 9, 22%; NSCLC: n = 5, 13%). Both dosing regimens had comparable drug exposure and increased interferon gamma-induced chemokines, monokine induced by gamma interferon, and interferon-gamma-inducible protein 10. Objective response rates were 13% (90% CI, 5.1-24.5) in the HNSCC cohort and 19% (90% CI, 9.2-32.6) in the NSCLC cohort. Median progression-free survival was 3.6 months (95% CI, 1.7-4.7) and 1.9 months (95% CI, 1.7-3.7) in the HNSCC and NSCLC cohorts.

Conclusions: The safety, efficacy and biomarker profiles of budigalimab are similar to other PD-1 inhibitors. Development of budigalimab in combination with novel anticancer agents is ongoing.
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http://dx.doi.org/10.1007/s00262-021-02973-wDOI Listing
July 2021

Follow-Up of Cancer Patients Receiving Anti-PD-(L)1 Therapy Using an Electronic Patient-Reported Outcomes Tool (KISS): Prospective Feasibility Cohort Study.

JMIR Form Res 2020 Oct 28;4(10):e17898. Epub 2020 Oct 28.

Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland.

Background: Immune checkpoint inhibitors (ICIs) have become a standard of care for various tumor types. Their unique spectrum of side effects demands continuous and long-lasting assessment of symptoms. Electronic patient-reported outcome (ePRO) follow-up has been shown to improve survival and quality of life of cancer patients treated with chemotherapy.

Objective: This study aimed to investigate whether ePRO follow-up of cancer patients treated with ICIs is feasible. The study analyzed (1) the variety of patient reported symptoms, (2) etiology of alerts, (3) symptom correlations, and (4) patient compliance.

Methods: In this prospective, one-arm, multi-institutional study, we recruited adult cancer patients whose advanced cancer was treated with anti-programmed cell death protein 1 (PD)- ligand (L)1 agents in outpatient settings. The ePRO tool consisted of a weekly questionnaire evaluating the presence of typical side effects, with an algorithm assessing the severity of the symptom according to National Cancer Institute Common Terminology Criteria for Adverse Events and an urgency algorithm sending alerts to the care team. A patient experience survey was conducted monthly. The patients were followed up to 6 months or until disease progression.

Results: A total of 889 symptom questionnaires was completed by 37 patients (lung cancer, n=15; melanoma, n=9; genitourinary cancer, n=9; head and neck cancer, n=4). Patients showed good adherence to ePRO follow-up. The most common grade 1 symptoms were fatigue (28%) and itching (13%), grade 2 symptoms were loss of appetite (12%) and nausea (12%), and grade 3-4 symptoms were cough (6%) and loss of appetite (4%). The most common reasons for alerts were loss of appetite and shortness of breath. In the treatment benefit analysis, positive correlations were seen between clinical benefit and itching as well as progressive disease and chest pain.

Conclusions: According to the results, ePRO follow-up of cancer patients receiving ICIs is feasible. ePROs capture a wide range of symptoms. Some symptoms correlate to treatment benefit, suggesting that individual prediction models could be generated.

Trial Registration: Clinical Trials Register, NCT3928938; https://clinicaltrials.gov/ct2/show/NCT03928938.
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http://dx.doi.org/10.2196/17898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657724PMC
October 2020

Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study.

J Clin Oncol 2020 02 27;38(5):395-405. Epub 2019 Nov 27.

The Institute of Cancer Research and Royal Marsden Hospital, London, United Kingdom.

Purpose: Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population.

Methods: The phase II KEYNOTE-199 study included three cohorts of patients with mCRPC treated with docetaxel and one or more targeted endocrine therapies. Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1-positive and PD-L1-negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression. All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary end point was objective response rate per RECIST v1.1 assessed by central review in cohorts 1 and 2. Secondary end points included disease control rate, duration of response, overall survival (OS), and safety.

Results: Two hundred fifty-eight patients were enrolled: 133 in cohort 1, 66 in cohort 2, and 59 in cohort 3. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, < 1% to 11%) in cohort 2. Median duration of response was not reached (range, 1.9 to ≥ 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%.

Conclusion: Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging.
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http://dx.doi.org/10.1200/JCO.19.01638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186583PMC
February 2020

ePROs in the follow-up of cancer patients treated with immune checkpoint inhibitors: a retrospective study.

J Cancer Res Clin Oncol 2019 Mar 21;145(3):765-774. Epub 2019 Jan 21.

Department of Oncology and Radiotherapy, Oulu University Hospital (OYS), MRC Oulu, P.B. 22, 90029, Oulu, Finland.

Purpose: Patient-reported outcome (PRO) follow-up has been shown to improve quality of life (QoL) and survival of cancer patients receiving chemotherapy. Kaiku Health application is a web-based electronic PRO (ePRO) tool which is designed for follow-up of cancer patients receiving immune checkpoint inhibitors (ICI). Purpose of the current study is to investigate whether symptoms collected by Kaiku Health ePRO tool on cancer patients receiving immune checkpoint inhibitors (ICI) follows to symptoms reported in clinical trials and whether coupling of specific symptoms does occur.

Methods: We retrospectively collected data on symptom timing and severity, and QoL of patients followed with Kaiku Health IO module in two Finnish cancer centers between 2017 and 2018. Kaiku Health IO module consists of 18 adaptive questions, which assess the presence and severity of symptoms. Patients were requested (via e-mail) to fill online symptom questionnaires with 3-7 day interval and QoL questionnaires (QLQ-C30) with 1-2 month interval.

Results: The IO module was used to follow 37 patients who had filled in total 559 symptom questionnaires. There was good adherence to ePRO follow-up with a median of 11 questionnaires filled per patient. The reported symptoms and their severity follow closely what has been seen in clinical trials investigating ICIs. Correlation analysis of the symptoms showed the strongest positive correlations between itching and rash; nausea and vomiting, decreased appetite, or stomach pain; cough and shortness of breath.

Conclusions: The results of the current study suggest that real-world symptom data collected through the ePRO application on cancer patients receiving ICI therapy aligns with the data from clinical trials. Correlations between different symptoms occur, which might reflect therapeutic efficiency, side effects, or tumor progression. These correlations should be further investigated with data coupled to clinical outcomes.
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http://dx.doi.org/10.1007/s00432-018-02835-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394667PMC
March 2019

Multimodal Primary Treatment of Metastatic Prostate Cancer with Androgen Deprivation and Radiation.

Anticancer Res 2016 12;36(12):6439-6447

Docrates Cancer Center, Helsinki, Finland.

Aim: We combined anti-androgen therapy with radiotherapy in a first-line setting for metastatic prostate cancer aiming to cause maximal cancer-cell death to delay the emergence of castration-resistant disease.

Materials And Methods: In this non-randomized retrospective series of 46 patients, the initial median prostate-specific antigen (PSA) was 98.5 μg/l (range=6.7-15,500), median Gleason score 9 and most men had at least TNM disease. All patients received luteinizing hormone releasing hormone analog or degarelix with bicalutamide. If PSA remained above 1 μg/l, docetaxel was initiated. At PSA nadir, all patients received radical radiotherapy of the prostate.

Results: The median follow-up time was 4.38 years (range=0.36-11.24). Most radiotherapy-related adverse events were grade 1 and transient. There were no grade 4 events. Overall survival (OS) at 5 years was 81.3%.

Conclusion: The feasibility and safety of aggressive multimodality treatment were good resulting in an excellent median OS of 8.35 years.
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http://dx.doi.org/10.21873/anticanres.11242DOI Listing
December 2016

Phase I study with ONCOS-102 for the treatment of solid tumors - an evaluation of clinical response and exploratory analyses of immune markers.

J Immunother Cancer 2016 15;4:17. Epub 2016 Mar 15.

Docrates Cancer Center, Helsinki, Finland.

Background: We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined.

Methods: The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT).

Results: No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients.

Conclusions: ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors.

Trial Registration: NCT01598129. Registered 19/04/2012.
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http://dx.doi.org/10.1186/s40425-016-0121-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791966PMC
March 2016

Local treatment of a pleural mesothelioma tumor with ONCOS-102 induces a systemic antitumor CD8 T-cell response, prominent infiltration of CD8 lymphocytes and Th1 type polarization.

Oncoimmunology 2014 Nov 15;3(10):e958937. Epub 2014 Dec 15.

Oncos Therapeutics ; Helsinki, Finland.

Late stage cancer is often associated with reduced immune recognition and a highly immunosuppressive tumor microenvironment. The presence of tumor infiltrating lymphocytes (TILs) and specific gene-signatures prior to treatment are linked to good prognosis, while the opposite is true for extensive immunosuppression. The use of adenoviruses as cancer vaccines is a form of active immunotherapy to initialise a tumor-specific immune response that targets the patient's unique tumor antigen repertoire. We report a case of a 68-year-old male with asbestos-related malignant pleural mesothelioma who was treated in a Phase I study with a granulocyte-macrophage colony‑stimulating factor (GM-CSF)-expressing oncolytic adenovirus, Ad5/3-D24-GMCSF (ONCOS-102). The treatment resulted in prominent infiltration of CD8 lymphocytes to tumor, marked induction of systemic antitumor CD8 T-cells and induction of Th1-type polarization in the tumor. These results indicate that ONCOS-102 treatment sensitizes tumors to other immunotherapies by inducing a T-cell positive phenotype to an initially T-cell negative tumor.
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http://dx.doi.org/10.4161/21624011.2014.958937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292415PMC
November 2014

VMAT technique enables concomitant radiotherapy of prostate cancer and pelvic bone metastases.

Acta Oncol 2015 Jun 13;54(6):847-53. Epub 2014 Oct 13.

Docrates Cancer Center , Helsinki , Finland.

Background: Prostate cancer (PCa) patients with metastatic disease often suffer from skeletal pain and urinary retention impairing their quality of life. Prophylactic radiotherapy to bone metastases planned concomitantly with primary PCa radiotherapy could enable more precise control of combined dose in healthy tissues when compared to sequential palliative treatment.

Materials And Methods: Volumetric modulated arc therapy (VMAT) was planned for 14 PCa patients with primary bone metastases. The bone planning target volume (PTVbone) was contoured together with the PTVs of prostate (pr), pelvic lymph nodes (ln) and seminal vesicles (sv). Another virtual plan was calculated excluding PTVbone for dose volume histogram (DVH) comparison. DVHs were additionally compared to a set of actual VMAT treatment plans of a control cohort of 13 high risk PCa patients treated with PTVpr, PTVsv and PTVln. The prescribed doses varied between 42 and 76 Gy for PTVbone.

Results: Recommended healthy tissue tolerances (Quantec) were not exceeded except for one patient's rectum V50Gy value. Rectum doses did not increase significantly due to the inclusion of PTVbone. For bladder, there was a slight increase for V65Gy and V50Gy (2.7% and 7.4%). The DVHs of metastatic and non-metastatic patients were comparable. There were no differences in the PTVpr DVH parameters, while mean PTVln dose increased by 3.7 Gy-4.4 Gy due to the increased treatment volume related to PTVbone. All side effects were
Conclusions: VMAT offers a good optimization tool for adding extra PTVs to the radiotherapy plan. Radiotherapy of bone metastases concomitantly with irradiation of the primary prostate tumor is a safe and well-tolerated approach and deserves to be studied in a randomized setting.
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http://dx.doi.org/10.3109/0284186X.2014.962665DOI Listing
June 2015

Radionuclide Treatment with 153Sm-EDTMP is Effective for the Palliation of Bone Pain in the Context of Extensive Bone Marrow Metastases: A Case Report.

Asia Ocean J Nucl Med Biol 2014 ;2(2):131-4

Department of Medical Oncology, Docrates Cancer Center, Helsinki, Finland.

Radionuclide therapy is widely used as an effective modality in the management of bone pain. The main indication for this treatment is symptomatic bone metastases, confirmed by bone scintigraphy. We present a case of small cell lung cancer (SCLC) stage T4N2M1b, with a good metabolic response to systemic therapy and radiotherapy of the primary tumor and locoregional disease, which became metabolically less active and remarkably smaller in size (reduction to 1/6 of the original volume). In spite of the good overall response, the patient developed a syndrome with severe bone pain and had progression in the bone marrow metastases, confirmed by (18)F-FDG PET/CT. The patient received (153)Sm-EDTMP treatment with a good clinical response. However, in the whole body bone scan with the therapeutic dose, there was no visual evidence of bone metastasis. Retrospectively, by drawing the region of interest, it was possible to identify one metastatic site. The possible mechanisms of the efficacy of this treatment modality, in this specific setting, are also discussed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937698PMC
July 2016

A single-institution experience with bevacizumab in the treatment of metastatic colorectal cancer and in conjunction with liver resection.

Onco Targets Ther 2014 1;7:1177-84. Epub 2014 Jul 1.

Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland ; Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland.

Background: Bevacizumab is active in the treatment of metastatic colorectal cancer (mCRC). However, efficacy of bevacizumab has predominantly been evaluated on selected patients with relatively good performance status and minor comorbidities. We evaluated the efficacy and safety of bevacizumab in unselected patients with mCRC, some of whom underwent liver resection.

Material And Methods: All patients with inoperable mCRC, fit for combination chemotherapy (n=180), who were initially not resectable, not included into studies and without contraindications to bevacizumab, and initiated on bevacizumab at the Helsinki University Central Hospital between April 2004 and December 2005 were included (n=114). Most (n=70) received 5-fluorouracil/leucovorin/irinotecan plus bevacizumab as first-line therapy. The remainder (n=44) of the patients received bevacizumab in combination with oxaliplatin or irinotecan with or without 5-fluorouracil or capecitabine. Minimum follow-up was 7 years. Treatment response was evaluated every 8-10 weeks according to RECIST criteria.

Results: Median age was 59.6 years (range 35-79); male/female ratio was 54%/46%; World Health Organization performance status 0/1/2-3 was 33%/55%/11%, respectively; and the number of metastatic sites, one/two/three or more, was 31%/21%/48%, respectively. Median duration of bevacizumab therapy was 7.8 months (range 0.5-70.5 with pauses). In first-line (n=40), response rate (RR) was 62%, progression-free survival (PFS) 11.7 months, and overall survival (OS) 22.1 months. In second-line (n=43), RR was 44%, PFS 8.7 months, and OS 18.7 months. In later lines (n=31), RR was 14%, PFS 6.7 months, and OS 14.2 months. Ten patients with initially unresectable liver metastases became operable and R0 resection was achieved in 90% (9/10 resections). In 23% (7/31) of operated metastases, no vital tumor cells were found in histologic examination. Operative morbidity was low: two mild infections, no increased bleeding tendency was noticed, and no impaired wound healing occurred.

Discussion: Bevacizumab-containing combination therapy was effective with acceptable tolerability in an unselected mCRC patient population in which liver resections could be safely performed.
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http://dx.doi.org/10.2147/OTT.S63739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085307PMC
July 2014

Antiviral and antitumor T-cell immunity in patients treated with GM-CSF-coding oncolytic adenovirus.

Clin Cancer Res 2013 May 14;19(10):2734-44. Epub 2013 Mar 14.

Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.

Purpose: Multiple injections of oncolytic adenovirus could enhance immunologic response. In the first part of this article, the focus was on immunologic aspects. Sixty patients previously naïve to oncolytic virus and who had white blood cells available were treated. Thirty-nine of 60 were assessed after a single virus administration, whereas 21 of 60 received a "serial treatment" consisting of three injections within 10 weeks. In the second part, we focused on 115 patients treated with a granulocyte macrophage colony-stimulating factor (GM-CSF)-coding capsid chimeric adenovirus, CGTG-102.

Results: Following serial treatment, both increase and decrease in antitumor T cells in blood were seen more frequently, findings which are compatible with induction of T-cell immunity and trafficking of T cells to tumors, respectively. Safety was good in both groups. In 115 patients treated with CGTG-102 (Ad5/3-D24-GMCSF), median overall survival was 111 days following single and 277 days after serial treatment in nonrandomized comparison. Switching the virus capsid for avoiding neutralizing antibodies in a serial treatment featuring three different viruses did not impact safety or efficacy. A correlation between antiviral and antitumor T cells was seen (P = 0.001), suggesting that viral oncolysis can result in epitope spreading and breaking of tumor-associated immunologic tolerance. Alternatively, some patients may be more susceptible to induction of T-cell immunity and/or trafficking.

Conclusions: These results provide the first human data linking antiviral immunity with antitumor immunity, implying that oncolytic viruses could have an important role in cancer immunotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-2546DOI Listing
May 2013

Oncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus: assessment of safety and immunologic responses in patients.

Cancer Res 2012 Apr 9;72(7):1621-31. Epub 2012 Feb 9.

Cancer Gene Therapy Group, Transplantation Laboratory, Haartman Institute and Finnish Institute of Molecular Medicine, University of Helsinki, Helsinki, Finland.

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.
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http://dx.doi.org/10.1158/0008-5472.CAN-11-3001DOI Listing
April 2012

Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial.

J Clin Oncol 2009 Dec 2;27(34):5685-92. Epub 2009 Nov 2.

Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.

Purpose: Docetaxel has not been compared with vinorelbine as adjuvant treatment of early breast cancer. Efficacy and long-term safety of a short course of adjuvant trastuzumab administered concomitantly with chemotherapy for human epidermal growth factor receptor 2 (HER2) -positive cancer are unknown.

Patients And Methods: One thousand ten women with axillary node-positive or high-risk node-negative breast cancer were randomly assigned to receive three cycles of docetaxel or vinorelbine, followed in both groups by three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Women with HER2-positive cancer (n = 232) were further assigned to either receive or not receive trastuzumab for 9 weeks with docetaxel or vinorelbine. The median follow-up time was 62 months after random assignment.

Results: Women assigned to docetaxel had better distant disease-free survival (DDFS) than those assigned to vinorelbine (hazard ratio [HR] = 0.66; 95% CI, 0.49 to 0.91; P = .010). In the subgroup of HER2-positive disease, patients treated with trastuzumab tended to have better DDFS than those treated with chemotherapy only (HR = 0.65; 95% CI, 0.38 to 1.12; P = .12; with adjustment for presence of axillary nodal metastases, HR = 0.57; P = .047). In exploratory analyses, docetaxel, trastuzumab, and FEC improved DDFS compared with docetaxel plus FEC (HR = 0.32; P = .029) and vinorelbine, trastuzumab, and FEC (HR = 0.31; P = .020). The median left ventricular ejection fraction of trastuzumab-treated patients remained unaltered during the 5-year follow-up; only one woman treated with trastuzumab was diagnosed with a heart failure.

Conclusion: Adjuvant treatment with docetaxel improves DDFS compared with vinorelbine. A brief course of trastuzumab administered concomitantly with docetaxel is safe and effective and warrants further evaluation.
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http://dx.doi.org/10.1200/JCO.2008.21.4577DOI Listing
December 2009

[Not Available].

Duodecim 2007 ;123(4):413-8

HYKS:n syöpätautien klinikka, HUS.

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April 2008

Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer.

N Engl J Med 2006 Feb;354(8):809-20

Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.

Background: We compared docetaxel with vinorelbine for the adjuvant treatment of early breast cancer. Women with tumors that overexpressed HER2/neu were also assigned to receive concomitant treatment with trastuzumab or no such treatment.

Methods: We randomly assigned 1010 women with axillary-node-positive or high-risk node-negative cancer to receive three cycles of docetaxel or vinorelbine, followed by (in both groups) three cycles of fluorouracil, epirubicin, and cyclophosphamide. The 232 women whose tumors had an amplified HER2/neu gene were further assigned to receive or not to receive nine weekly trastuzumab infusions. The primary end point was recurrence-free survival.

Results: Recurrence-free survival at three years was better with docetaxel than with vinorelbine (91 percent vs. 86 percent; hazard ratio for recurrence or death, 0.58; 95 percent confidence interval, 0.40 to 0.85; P=0.005), but overall survival did not differ between the groups (P=0.15). Within the subgroup of patients who had HER2/neu-positive cancer, those who received trastuzumab had better three-year recurrence-free survival than those who did not receive the antibody (89 percent vs. 78 percent; hazard ratio for recurrence or death, 0.42; 95 percent confidence interval, 0.21 to 0.83; P=0.01). Docetaxel was associated with more adverse effects than was vinorelbine. Trastuzumab was not associated with decreased left ventricular ejection fraction or cardiac failure.

Conclusions: Adjuvant treatment with docetaxel, as compared with vinorelbine, improves recurrence-free survival in women with early breast cancer. A short course of trastuzumab administered concomitantly with docetaxel or vinorelbine is effective in women with breast cancer who have an amplified HER2/neu gene. (International Standard Randomised Controlled Trial number, ISRCTN76560285.).
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http://dx.doi.org/10.1056/NEJMoa053028DOI Listing
February 2006

FGF-2 blocks TGF-beta1-mediated suppression of Bcl-2 in normal melanocytes.

Exp Dermatol 2005 Mar;14(3):202-8

Department of Dermatology, Helsinki University Central Hospital, University of Helsinki, PB160, 00029 HUS, Finland.

Normal melanocytes require growth support provided by the adjacent basement membrane. In contrast, nevus cells and melanoma cells survive in the dermis, and in vitro on a soft collagen gel. Transforming growth factor-beta1 (TGF-beta1) produced by melanocytes themselves induces apoptosis in normal melanocytes cultured on collagen gel, an effect that can be counteracted by fibroblast growth factor-2 (FGF-2). The purpose of this study was to investigate the mechanisms by which FGF-2 counteracts the apoptotic signals from TGF-beta1 in melanocytes cultured on collagen gel. We report that FGF-2 did not interfere with the signal transduction from the TGF-beta1 receptors to SMAD2/3 proteins. Instead, TGF-beta1 decreased the level of Bcl-2 in normal melanocytes cultured on collagen gel, and FGF-2 reversed the TGF-beta1-mediated reduction in the level of Bcl-2. In nevus and melanoma cells, TGF-beta1 was unable to induce a decrease in the level of Bcl-2, and treatment with FGF-2 did not cause an increase in the level of Bcl-2 in nevus or melanoma cells. In conclusion, our results suggest that a reduction in the level of the anti-apoptotic Bcl-2 is involved in the execution of apoptosis induced by TGF-beta1 in normal melanocytes cultured on collagen gel and that FGF-2 can prevent TGF-beta1 from causing this reduction.
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http://dx.doi.org/10.1111/j.0906-6705.2005.00277.xDOI Listing
March 2005
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