Gene expression analysis of tumors demonstrates an induction of Th1 type immune response following intratumoral administration of ONCOS-102 in refractory solid tumor patients
Majumder et al. Journal for ImmunoTherapy of Cancer
Gene expression analysis of tumors demonstrates an induction of Th1 type immune response following intratumoral administration of ONCOS- 102 in refractory solid tumor patients
Mamun Majumder 0 3 4
Ashwini Kumar 0 3 4
Caroline Heckman 0 3 4
Matti Kankainen 0 3 4
Sari Pesonen 0 2 4
Elke Jäger 0 1 4
Julia Karbach 0 1 4
Timo Joensuu 0 4 6
Kalevi Kairemo 0 4 6
Kaarina Partanen 0 4 6
Tuomo Alanko 0 4 6
Akseli Hemminki 0 4 5
Charlotta Backman 0 2 4
Kasper Dienel 0 2 4
Mikael von Euler 0 2 4
Tiina Hakonen 0 2 4
Juuso Juhila 0 2 4
Tuuli Ranki 0 2 4
Lotta Vassilev 0 2 4
Antti Vuolanto 0 2 4
Magnus Jaderberg 0 2 4
0 From Society for Immunotherapy of Cancer 29th Annual Meeting National Harbor , MD, USA. 6-9 November 2014
1 Krankenhaus Nordwest , Frankfurt/M. , Germany
2 Oncos Therapeutics , Helsinki , Finland
3 Institute for Molecular Medicine Finland , Helsinki , Finland
4 Authors' details
5 Cancer Gene Therapy Group, University of Helsinki , Helsinki , Finland
6 Docrates Cancer Center , Helsinki , Finland
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Advanced tumors are often immunosuppressive.
Intratumoral administration of adenovirus activates Toll-like
receptor signalling leading to production of
pro-inflammatory cytokines and activation of the innate immune
system. Oncolytic adenovirus causes immunogenic cancer
cell death and creates a danger signal at tumors, thus
undermining immunological tolerance towards tumors.
The release of tumor antigens from dying cancer cells
results in priming of a potent anti-tumor immune
response. This effect may be enhanced by the local
production of immunostimulatory molecules coded by the
virus. We present results of gene expression analysis of
tumors from a Phase I study with ONCOS-102, an
oncolytic adenovirus coding for GMCSF, in 12 patients with
refractory solid tumors.
A total of 9 intratumoral injections of ONCOS-102 were
given to each patient. Biopsies were collected at baseline
and 1 and 2 months after treatment initiation. RNA was
extracted from fresh-frozen biopsies using standard
methods. Gene expression profiling was carried out using the
Illumina BeadChip platform. Data was normalized by
quantile method, probes presenting the same genes were
averaged, and the batch effects were adjusted using
ComBat pipeline, as implemented in Chipster (http://chipster.
csc.fi/). Finally, log2 fold-changes were computed by
subtracting baseline data from after treatment data. Network
and pathway analyses were conducted through the use of
2Oncos Therapeutics, Helsinki, Finland
Full list of author information is available at the end of the article
IPA (Ingenuity ®Systems, www.ingenuity.com). A cutoff
value of 2-fold expression change was used to filter
differentially expressed genes and run core analysis to identify
underlying signaling networks and deregulated molecules.
A significant enrichment of genes involved in immune
cell trafficking, inflammatory response and antigen
presentation were detected post treatment. A mesothelioma
patient showed a prominent post-treatment induction of
MAGE3-specific CD8+ T-cells in peripheral blood in
IFNg ELISPOT. Furthermore, a late decrease in
metabolic activity was observed in PET imaging 7.5 months
after treatment initiation during the follow-up period,
measured as a 47% decrease in total lesion glycolysis in
comparison to the imaging at 6 months. In the same
patient, upstream regulators driving differentially
expressed genes detected in the post treatment biopsy
included cytokines (INFG, TNF, IL1B, CCL2, CXCL10,
IL-17A, CD40LG), enzymes (FN1, NOS2, PTGS2,
PARP9), growth factors (BMP2, LEP), kinases (CHUK,
CRKL, IKBKB, IKBKG, ITK, STK11, SYK),
transcriptional regulators (IRF1, NFATC2, NFKBIA, STAT1,
STAT3, ZEB1, RELA), and transmembrane receptors
(B2M, CD40, IL6R, TLR2-4, TNFSF1B). Likely, these
events collectively induced a higher CD8+ mediated
cytotoxic T cell response (GZMB, PRF1) post treatment.
Detailed analysis per patient will be presented at the
meeting.
Consent
Written informed consent was obtained from the patient
for publication of this abstract and any accompanying
images. A copy of the written consent is available for
review by the Editor of this journal.
doi:10.1186/2051-1426-2-S3-P230
Cite this article as: Majumder et al.: Gene expression analysis of tumors
demonstrates an induction of Th1 type immune response following
intratumoral administration of ONCOS-102 in refractory solid tumor
patients. Journal for ImmunoTherapy of Cancer 2014 2(Suppl 3):P230. (...truncated)