Current Key Areas of Research

The Program in Cancer Immunology and Immunotherapy brings together experts in the fields of immunobiology, medicine, and oncology to explore the interaction between the immune system and cancer.

Building on their findings, program members are advancing new strategies that use the exquisite specificity of the body's natural defenses to destroy tumors with minimal toxicity to healthy tissues.

Program researchers work between the lab and the clinic investigating the cellular arms of the immune system for new treatment opportunities. Their efforts are advancing the areas of:

1. Experimentations, including therapeutic treatments with chemically-modified peptide-based vaccines that enforce the tumor-bearing animal’s immune defenses to attack the autologous/transplantable cancer cells.
2. Glucocorticoid-guided immune pathways on cytokine-dependent NK-cell activation and homeostasis.
3. NK cell-based adoptive therapies aiming at the involvement of innate immunity in cancer therapeutics directly but also indirectly at the interface of induction of adaptive antitumor immune responses.
4. The potential of small molecule inhibitors and other effector molecules as therapeutic agents in combination with peptide-based vaccines.
5. Gene-regulation of mesenchymal cell differentiation and regulation of tumor cell growth within the tumor stroma.
6. The role of HLA alleles as prognostic biomarkers in prostate cancer.
7. Intratumoral immune landscape and peripheral biomarkers for head and neck cancer.
8. TCR-Vβ variability and preexisting immunity in non-small cell lung cancer.

Research Projects

Infrastructure for systems biology Europe-Greece/Clinical Genomics. The CIIC is part of a consortium which participates in a multicenter translational study for identifying biomarkers for chronic diseases also including cancer. Such biomarkers detected in biological fluids and various types of cells will be useful acting as prognostic and predictive, but also as targets for therapeutic interventions.

Identification of immunogenic peptides to act as novel vaccine candidates from prostate cancer tumor specimen. The CIIC collaborates with IMMATICS a biotech company in Tuebingen Germany for the isolation and identification of tumor peptides from surgically excised prostate tumor specimens. These peptides are going to be tested for prevention and therapy of experimental tumors in mice before entering in phase I clinical trials.

Expression of CRD-BP, TET1 and TET2 in human mesenchymal cells from various sources
This project aims at investigating the role of the above genes in proliferation and metastatic potential of tumor cells. These genes but also other metabolites which belong to the molecular pathways dominated by the above genes may be used as therapeutic targets in combination with other signal transduction inhibitors.

Regulation of NK cell growth and function by glucocorticoids (GCs). In this project we are investigating the role of GCs on the function and expansion potential of NK cells. In particular, we are interested in testing whether GCs enhance NK cell proliferation and also protect NK cells from cytokine-induced cell death without compromising their functional potential. To this end, we investigate how and if GCs affect the phenotype of NK cells in terms of NK cell activating receptors, maturation markers and chemokine receptors, in order to obtain info-rmation on the differential effects of GCs on different subpopulations of circulating NK cells and their possible impact on their clinical use in cancer treatment.

Identification of immune cells infiltrating tumors and in the peripheral blood as prognostic/predictive biomarkers in breast cancer. In this project we propose to explore the prognostic impact of tumor-infiltrating lymphocytes as well as macrophages in patients with breast carcinoma (BC). Our studies will include for the first time (i) prospective analyses to identify this immune profile in patients with newly-diagnosed BC with clinical follow-up and (ii) comparative quantification and phenotyping of circulating T lymphocytes responding to tumor antigens overexpressed in BC. We will compare peripheral with intra-tumoral immune markers for longitudinal follow-up. In addition, we will perform retrospective analyses to correlate the infiltrating immune phenotypes with clinical outcome in patients with BC who were treated between 2000 and 2008.

Identification of novel prognostic biomarkers for prostate cancer. In this project we aim at validating novel biomarkers for prostate cancer which were detected in our previous studies using a HER-2/neu peptide for vaccinating patients with prostate cancer (Perez SA et al Cancer Res. 2010). These include HLA alleles (HLA-A2 and HLA-A24), serum factors TGFβ and IFNγ as well as circulating CD8+ T lymphocytes specifically recognizing HLA-A2- and HLA-A24-restricted HER-2/neu and PSA peptides.

Determination of genomic and transcriptomic prognostic bio-signatures in head and neck cancer. By relying on previous clinical findings from our studies, this proposal aims to identify prognostic and predictive biomarkers in H&N by evaluating: (a) the molecular profile of cancer cells through the study of genes that participate in basic cellular homeostatic mechanisms (such as cell cycle regulation and maintenance of genetic integrity), (b) the immunological profile of patients in combination with the immunological response to the disease.

Immune and Molecular circulating biomarkers for the selection of cancer patients for immunotherapy. This project will evaluate a combination of both molecular and immune biomarkers in the blood, in an attempt to select the candidates, for immunotherapy, cancer patients and, more especially the: (i) Pre-existing (PreI) immunity against a panel of tumor-associated antigens, (ii) clonality of TCR-Vβ, and (iii) a platform of blood tumor mutational burden (bTMB). The dynamics of these biomarkers, as well as their combinations will be evaluated in sequential blood samples during treatment with ICIs. For these purposes, patients with unresectable, stage III, PD-L1(+) NSCLC, who receive maintenance treatment with durvalumab after concurrent definitive chemoradiotherapy, in the context of the standard clinical practice, will be enrolled and will be evaluated for: PreI using an ELISpot assay based on the IFNγ production by CD8+ cells; TCR clonality using RNA sequencing and bTMB of tumor cell DNA using NGS. The results of the current project will be used to develop predictive platforms of biomarkers based on a) the IFNγ production by CD8+ cells upon stimulation with a panel of tumor-associated antigens, b) TCR-Vβ repertoire and c) bTMB.

List of Research Studies and Funding Sources

1. SFS Programme, NATO Scientific Affairs Division. Development of Immunodiagnostics in Greece (1987-1993), 700.000$
2. Commission of the European Community. Medical Research Division "Cellular and Molecular Strategies for Immunotherapy of Cancer" , 324.000 EURO
3. European Community. Mediterannean Programmes. "Production of monoclonal antibodies against normal and leukemic lymphocytes", 180.000 Euro
4. EPET 2 (General Secretariat of Research and Technology), 300.000 Euro (1996-1999)
5. Production of immunodiagnostic assays for the detection of hepatitis B and HIV 1,2. NATO Scientific Affairs Division 1995-2000, BF 6.000.000
6. DG XVI through "PEP Attica". Development of Cancer Vaccines, 700.000 Euro (1996-2000)
7. The European Commission through the General Secretariat of Research in Greece. Cancer Immunotherapy: Genetic modification of T lymphocytes and CD34+ stem cells with tumor specific chimeric receptors, 900.000 Euro (1998-2001)
8. The European Commission through the General Secretariat of Research in Greece. Isolation and genetic manipulation of CD34+ stem cells for therapeutic use in BM transplantation, 800.000 Euro (1999-2001)
9. The European Commission through 3^rd Operational Program PEP of Attica (MIS 59605). Production of vaccines against cancer, 2.220.000 Euro (2001-2009)
10. The General Secretariat of Research and Technology in the framework of ΕPΑΝ II ”Cancer immunotherapy: genetical modification of T lymphocytes and CD34+ progenitors with tumor antigen-specific chimeric receptors”; code no.97EKBAN2-19; period:1998-2002, 1.000.000 Euro
11. The General Secretariat of Research and Technology in the framework of EPAN II “Use of Biosensors for the study of immunogenicity of tumor cells”; code no. 97-EL-34; period 1999-2003, 700.000 Euro
12. The General Secretariat of Research and Technology in the framework of EPET “Modifications in the expression of genes and proteins in tumor cell lines overexpressing HER-2/neu”; code no. YB/3; period: 2003-2007, 1.000.000 Euro
13. Bilateral Research Programmes between Greece and Germany funded by the General Secretariat of Research and Technology “Isolation and identification of immunogenic peptides eluted from tumor cells to be used in cancer immunotherapy” code no. GRI-0606-097; period :1997-2000, 70.000 Euro
14. Bilateral Research Programmes between Greece and Germany funded by the General Secretariat of Research and Technology “ Generation of CD4+ T lymphocyte lines and clones recognizing immunogenic epitopes of HER-2/neu. Analysis of their role in the induction cytotoxic reactions against HER-2/neu overexpressing tumor cell lines” code no. GRI-037099; period: 1999-2002, 70.000 Euro
15. The General Secretariat of Research and Technology in the framework of PENED “Production of natural killer cells genetically modified to recognize HER-2/neu overexpressing tumor cells” code no. 01ED55; period 2002-2005, 100.000 Euro
    The General Secretariat of Research and Technology in the framework of PENED “Immunotherapy against HER-2/neu⁺ tumors”; code no. 03ED113; period :2005-2009, 100.000 Euro
16. The European Commission in the framework of BIOMED II (CIIC, collaborarting partner), “EUCAPS” code no. BMH4-CT98-3058; period: 1998-2002, 100.000 Euro
17. The European Commission in the framework of QLRT-2001-00668; period: 2002-2005, 150.000 Euro
18. The European Commission in the framework of Quality of Life and Management of Living Resources (CIIC, collaborarting partner), “ ENACT” code no. LSHC-CT-2004 503306; period 2005-2008, 150.000 Euro
19. Phase I clinical study on vaccinating prostate cancer patients with an Ii-Key/HER-2/neu vaccine (code no. after approval from National Organization of Medicines : IS-107-01-06). Funded by Generex SA, 250.000 Euro
20. Phase II clinical study on vaccinating breast cancer patients with 2 different Ii-Key/HER-2/neu vaccines (code no. after approval from National Organization of Medicines : IS-52/01-03-07). Funded by Generex SA, 550.000 Euro
21. Phase I study on cellular immunotherapy with infusions of activated natural killer cells in non-small lung cancer (code no. code no. after approval from National Organization of Medicines : IS-89/01/06)
22. Antigen Express Inc. In vitro and in vivo antitumor activities induced by Ii-Key/HER-2/neu(776-790) hybrid peptide. 1996-until now, 600.000 Euro
23. ROCHE Hellas funded project: Effect of Trastuzumab therapy on the frequency of circulating regulatory T cells in HER-2/neu overexpressing breast cancer patients (2006-2007), 22.250 Euro
24. EISAI funded project (ONT-IIS-0018-07): A Pre-Clinical Study for the Combined Immunotherapy of Lung Cancer by Elimination of Suppressor Cells Prior to NK Cell Adoptive Transfer (2008-2010), 23.805 USD
25. ROCHE Hellas funded project: Combination of Trastuzumab therapy with HER-2/neu peptide vaccination in disease free HER-2/neu overexpressing breast cancer patients for prevention of recurrence (2008-2010), 20.000 Euro
26. ROCHE Hellas funded project: Do shedded HER-ECD and/or HER-2/neu+ apoptotic bodies complexed with trastuzumab induce effective T cell responses? (2009-2010), 16.660 Euro
27. Bilateral Research Programmes between Greece and Germany funded by the European Commission: “Immune signatures within the tumor and in the peripheral blood as prognostic/predictive biomarkers in breast cancer (acronym: ISPEBREAST)” (2013-2015), 250.000 Euro.
28. General Secretariat of Research and Technology in the framework of EYDE ETAK – EDK – PANEL II (Research- Create - Innovate) “Establishment of novel prognostic and predictive biomarkers for prostate cancer”; code no. T1EDK-01404; period: 2018 - 2021, 676.800 Euro.
29. General Secretariat of Research and Technology in the framework of EYDE ETAK – EDK – PANEL II (Research- Create - Innovate) “Identification of genomic and transcriptomic prognostic biosignatures for head and neck cancer (acronym BIOKAKETRA, project code T2EDK-03266; period: 2021 - 2023, 755.000 Euro.
30. General Secretariat of Research and Technology in the framework of EYDE ETAK – EDK – PANEL II (Research- Create - Innovate) “Immunological and Molecular Biomarkers in Peripheral Blood for the Selection of Cancer Patients for Immunotherapy (acronym B- PREIMMUN, project code T2EDK-02218; period: 2021 - 2023, 645.200 Euro.