TY  - JOUR
A1  - Ranki, Tuuli
A1  - Pesonen, Sari
A1  - Hemminki, Akseli
A1  - Partanen, Kaarina
A1  - Kairemo, Kalevi
A1  - Alanko, Tuomo
A1  - Lundin, Johan
A1  - Linder, Nina
A1  - Turkki, Riku
A1  - Ristimäki, Ari
A1  - Jäger, Elke
A1  - Karbach, Julia
A1  - Wahle, Claudia
A1  - Kankainen, Matti
A1  - Backman, Charlotta
A1  - Euler, Mikael von
A1  - Haavisto, Elina
A1  - Hakonen, Tiina
A1  - Heiskanen, Raita
A1  - Jaderberg, Magnus
A1  - Juhila, Juuso
A1  - Priha, Petri
A1  - Suoranta, Laura
A1  - Vassilev, Lotta
A1  - Vuolanto, Antti
A1  - Joensuu, Timo
T1  - Phase I study with ONCOS-102 for the treatment of solid tumors – an evaluation of clinical response and exploratory analyses of immune markers
T2  - Journal for ImmunoTherapy of Cancer
N2  - 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
KW  - Immunotherapy
KW  - in situ vaccine
KW  - Cytotoxic CD8+ T cell
KW  - Anti-tumor immunity
KW  - Intratumoral
KW  - Oncolytic adenovirus
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/40218
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-402188
VL  - 4
IS  - 17
SP  - 1
EP  - 18
PB  - BioMed Central
CY  - London
ER  -