Saint Savas Cancer Hospital

Athens, Greece

Saint Savas Cancer Hospital

Athens, Greece
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Baxevanis C.N.,Saint Savas Cancer Hospital | Perez S.A.,Saint Savas Cancer Hospital
Vaccines | Year: 2015

The significant contribution of host immunity in early tumorigenesis has been recently recognized as a result of our better understanding of the molecular pathways regulating tumor cell biology and tumor-lymphocyte interactions. Emerging evidence suggests that disseminated dormant tumor cells derived from primary tumors before or after immune surveillance, are responsible for subsequent metastases. Recent trends from the field of onco-immunology suggest that efficiently stimulating endogenous anticancer immunity is a prerequisite for the successful outcome of conventional cancer therapies. Harnessing the immune system to achieve clinical efficacy is realistic in the context of conventional therapies resulting in immunogenic cell death and/or immunostimulatory side effects. Targeted therapies designed to target oncogenic pathways in tumor cells can also positively regulate the endogenous immune response and tumor microenvironment. Identification of T cell inhibitory signals has prompted the development of immune checkpoint inhibitors, which specifically hinder immune effector inhibition, reinvigorating and potentially expanding the preexisting anticancer immune response. This anticancer immunity can be amplified in the setting of immunotherapies, mostly in the form of vaccines, which boost naturally occurring T cell clones specifically recognizing tumor antigens. Thus, a promising anticancer therapy will aim to activate patients’ naturally occurring anticancer immunity either to eliminate residual tumor cells or to prolong dormancy in disseminated tumor cells. Such an endogenous anticancer immunity plays a significant role for controlling the balance between dormant tumor cells and tumor escape, and restraining metastases. In this review, we mean to suggest that anticancer therapies aiming to stimulate the endogenous antitumor responses provide the concept of the therapeutic management of cancer. © 2015 by the authors; licensee MDPI, Basel, Switzerland.

Katsara O.,Saint Savas Cancer Hospital | Mahaira L.G.,Saint Savas Cancer Hospital | Iliopoulou E.G.,Saint Savas Cancer Hospital | Moustaki A.,Saint Savas Cancer Hospital | And 6 more authors.
Stem Cells and Development | Year: 2011

Mesenchymal stem cells (MSCs) are a very important adult stem cell population with a multitude of potential applications in regenerative medicine. The thorough characterization of the bone marrow MSC (BM-MSC) population derived from the BALB/c species was essential, considering the significance of the murine model amongst animal models. In the present study, we examined the effect of gender, age, and in vitro culture on the basic properties (proliferation, differentiation, and immunosuppressive potential) of BM-MSCs. We found a decline in the progenitor frequencies from the BM of adult mice, lower MSC frequencies in all female donors, and an increase in the BM-MSC proliferation rate upon in vitro propagation. We also examined BM-MSCs for the expression of the 3 major embryonic stem cell transcription factors, Oct3/4, Sox-2, and Nanog, as well as 2 mRNA binding proteins, coding region determinant binding protein/insulin-like growth factor 2 mRNA binding protein 1 (Crd-bp/Imp1) and Deleted in azoospermia-like (Dazl), which are expressed in primitive stem cells, umbilical cord blood-hematopoietic stem cells and amniotic fluid stem cells, respectively. Further, it has been reported that these 2 genes are critical for embryonic development. In this study, therefore, we report, for the first time, the expression of Crd-bp/Imp1 and Dazl in BM-MSCs. Dazl, Oct3/4, and Sox2 were detected in relatively low levels in contrast to Crd-bp/Imp1, its major target c-Myc, as well as Nanog, which were expressed redundantly, irrespective of sex, donor age, or in vitro passaging. These findings could further support the extrinsic theory of aging of the MSC population and the potential implication of embryonic genes in adult stem cell physiology. © Copyright 2011, Mary Ann Liebert, Inc.

Baxevanis C.N.,Saint Savas Cancer Hospital | Voutsas I.F.,Saint Savas Cancer Hospital | Tsitsilonis O.E.,National and Kapodistrian University of Athens
Immunotherapy | Year: 2013

Toll-like receptor (TLR) agonists possess remarkable properties, particularly with regard to dendritic cell activation, promoting Th1-type cytokine production and optimizing cytotoxic T-cell responses. Preclinical and clinical studies conducted to date show that TLR agonists can improve currently applied anticancer vaccination protocols. Although these have resulted in the US FDA approval of three TLR agonists for use in humans, their abundant application encounters limitations, principally due to dose-limiting toxicity evoking from systemic cytokine production. Here, using selected examples of clinical studies, we provide a concise review regarding the knowledge acquired thus far on the adjuvant use of TLR agonists as cancer vaccine components. We also provide evidence on the exploitation of a novel TLR agonist, prothymosin-α, which enhances the efficacy of tumor-reactive effectors without causing severe adverse effects. © 2013 Future Medicine Ltd.

Perez S.A.,Saint Savas Cancer Hospital | Kallinteris N.L.,Antigen Express Inc. | Bisias S.,Saint Savas Cancer Hospital | Tzonis P.K.,Saint Savas Cancer Hospital | And 6 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Active immunotherapy is emerging as a potential therapeutic approach for prostate cancer. We conducted the first phase I trial of an Ii-Key/HER-2/neu(776-790) hybrid peptide vaccine (AE37) with recombinant granulocyte macrophage colony-stimulating factor as adjuvant in patients with HER-2/neu+ prostate cancer. The primary end points of the study were to evaluate toxicity and monitor patients' immune responses to the vaccine. Experimental Design: Thirty-two HER-2/neu+, castrate-sensitive, and castrate-resistant prostate cancer patients were enrolled. Of these, 29 patients completed all six vaccination cycles with AE37. Immunologic responses in the total patient population were monitored by delayed-type hypersensitivity and IFN-γ ELISPOT and intracellular staining. Regulatory T-cell (Treg) frequency and plasma HER-2/neu and transforming growth factor-â levels were also determined. Immunologic responses were also analyzed among groups of patients with different clinical characteristics. Local/systemic toxicities were monitored throughout the study. Results: Toxicities beyond grade 2 were not observed. Seventy-five percent of patients developed augmented immunity to the AE37 vaccine and 65% to the unmodified AE36 peptide as detected in the IFN-γ-based ELISPOT assay. Intracellular IFN-γ analyses revealed that AE37 elicited both CD4+ and CD8+ T-cell responses. Eighty percent of the patients developed a positive delayed-type hypersensitivity reaction to AE36. Additionally, significant decreases could be detected in circulating Treg frequencies, plasma HER-2/neu, and serum transforming growth factor-β levels. Patients with less extensive disease developed better immunologic responses on vaccination. Conclusion: AE37 vaccine is safe and can induce HER-2/neu-specific cellular immune responses in patients with castrate-sensitive and castrate-resistant prostate cancer, thus emphasizing the potential of AE37 to target HER-2/neu for the immunotherapy of prostate cancer. ©2010 AACR.

Baxevanis C.N.,Saint Savas Cancer Hospital | Anastasopoulou E.A.,Saint Savas Cancer Hospital | Voutsas I.F.,Saint Savas Cancer Hospital | Papamichail M.,Saint Savas Cancer Hospital | Perez S.A.,Saint Savas Cancer Hospital
Expert Review of Molecular Diagnostics | Year: 2015

In order to be optimally efficacious, therapeutic cancer vaccines must induce robust tumor-specific CD8+ cytotoxic T cells, which are responsible for tumor cell lysis. Unlike cytotoxic drugs, which act directly on the tumor, cancer vaccines demonstrate new kinetics involving the generation of specific cellular immune responses, which need to be translated into antitumor responses to delay tumor progression and improve survival. These delayed kinetics of action establish a new concept of benefit in the long term, which implies a slow down in tumor growth rates, than a marked reduction in tumor size. Therefore, there is a significant need to identify intermediate biomarkers so that clinical responses can be evaluated in a timely manner. Therapeutic vaccination as a modality for cancer treatment has received significant attention with multiple clinical trials demonstrating improvements in overall survival. Significant challenges to this modality remain, including increasing vaccine potency and minimizing treatment-related toxicities and identifying prognostic and predictive biomarkers of clinical benefit that may guide to select and optimize the therapeutic strategies for patients most likely to gain benefit. © 2015 Informa UK, Ltd.

Perez S.A.,Saint Savas Cancer Hospital | Anastasopoulou E.A.,Saint Savas Cancer Hospital | Papamichail M.,Saint Savas Cancer Hospital | Baxevanis C.N.,Saint Savas Cancer Hospital
Cancer Immunology, Immunotherapy | Year: 2014

A fundamental challenge in administering immunotherapies for cancer is the establishment of biomarkers that can predict patients’ responsiveness to treatment. In this study, our aim was to predict the immunologic and clinical responses of vaccination therapy with an Ii-key-modified HER-2/neu peptide (Ii-key/HER-2(776–790) or AE37), applied in our recent phase I study in patients with prostate cancer. To this end, we retrospectively analyzed our data derived from immunologic determinations before, during and after primary series of vaccinations with AE37, as well as after one AE37 booster injection. Using the obtained data, we then observed the relationship between the immunologic parameters and clinical outcome of patients. We found that preexisting levels of transforming growth factor beta (TGF-β) had an inverse correlation with in vivo and in vitro immunologic responses to the AE37 vaccine which were measured as delayed-type hypersensitivity (DTH) and interferon gamma (IFN-γ) production in response to the native HER-2(776–790) (or AE36) peptide, respectively. Patients with preexistent IFN-γ immunity to AE36 developed positive DTH reactions after primary vaccinations and booster. Moreover, we could detect a direct correlation between IFN-γ production and DTH reactions in response to AE36 challenge in our vaccinated patients. DTH reactions were a stronger indicator for patients’ overall survival (OS) than preexistent or vaccine-induced IFN-γ immunity. In contrast, we found that preexisting TGF-β levels were correlated with shorter patients’ OS. These retrospective analyses suggest that the above biomarkers at the time-points measured offer promise for evaluating immunologic and clinical responses to AE37-based vaccinations. © 2014, Springer-Verlag Berlin Heidelberg.

Moustaki A.,Saint Savas Cancer Hospital | Argyropoulos K.V.,Saint Savas Cancer Hospital | Baxevanis C.N.,Saint Savas Cancer Hospital | Papamichail M.,Saint Savas Cancer Hospital | Perez S.A.,Saint Savas Cancer Hospital
Cancer Immunology, Immunotherapy | Year: 2011

We have previously reported a synergistic effect between hydrocortisone (HC) and IL-15 on promoting natural killer (NK) cell expansion and function. In the present study, we extend our findings to methylprednisolone (MeP) and dexamethasone (Dex), thus ascribing to glucocorticoids (GCs) a general feature as positive regulators of IL-15-mediated effects on NK cells. We demonstrate that each GC when combined with IL-15 in cultures of peripheral blood (PB)-derived CD56 + cells induces increased expansion of CD56 +CD3 - cells displaying high cytolytic activity, IFN-γ production potential and activating receptor expression, including NKp30, NKp44, NKp46, 2B4, NKG2D and DNAM-1. Furthermore, GCs protected NK cells from IL-15-induced cell death. The combination of IL-15 with GCs favored the expansion of a relatively more immature CD16 low/neg NK cell population, with high expression of NKG2A and CD94, and significantly lower expression of KIR (CD158a and CD158b) and CD57, compared to IL-15 alone. IL-15-expanded NK cells, in the presence or absence of GCs, did not express CD62L, CXCR1 or CCR7. However, the presence of GCs significantly increased the density of CXCR3 and induced strong CXCR4 expression on the surface of NK cells. Our data indicate that IL-15/GC-expanded NK cells, apart from their increased proliferation rate, retain their functional integrity and exhibit a migratory potential rendering them useful for adoptive transfer in NK cell-based cancer immunotherapy. © 2011 Springer-Verlag.

Gritzapis A.D.,Saint Savas Cancer Hospital | Voutsas L.F.,Saint Savas Cancer Hospital | Lekka E.,Saint Savas Cancer Hospital | Papamichail M.,Saint Savas Cancer Hospital | Baxevanis C.N.,Saint Savas Cancer Hospital
Cancer Research | Year: 2010

BALB/c mice transgenic (Tg) for the transforming rat neu oncogene (BALB-BeaT) are genetically predestined to develop mammary carcinogenesis in a process similar to that in humans. We crossed HLA-A2.1/HLADR1 (A2.1/DR1) Tg mice with BALB-neuT mice to generate A2.1/DR1 x BALB-newT triple Tg (A2.1/DR1 x neulT+) mice, which represent an improvement over BALB-neuT mice for evaluating vaccination regimens to overcome tolerance against HER-2/neu;. A vaccine formulation strategy, consisting of synthetic peptides from the rat HER-2/neu oncogene combined with granulocyte macrophage colony-stimulating factor, was highly effective in preventing the growth of established transplantable tumors in male A2.1/DR1 x neuT+ mice. Vaccination with HER-2(435-443) (p435) CTL peptide alone induced weak antitumor responses, which were characterized by increased numbers of regulatory T cells (Treg) and low numbers of vaccine-specific CD8+ CTL and helper T cells (Th). The administration of p435 plus HER-2(776-790) (p776; helper peptide) reversed this situation, inducing functionally active, peptide-specific CTL and Th. There was a striking change in the intratumoral balance of Tregs (decrease) and vaccine-specific Th (increase) that directly correlated with tumor rejection. Intratumoral administration of anti-FasL antibody promoted tumor growth. The decrease in Tregs (Fas+) was due to apoptosis induced by cell contact with Fas ligand+ (L)+ Th. Mice vaccinated with p435 plus p776 exhibited long-lasting antitumor immunity. Our vaccine regimen also significantly delayed the outgrowth of mammary carcinomas in female A2.1/DR1 x neuT+ animals. We provide a mechanism to overcome tolerance against HER-2/neu, which proposes a combined vaccination with two (Th and CTL) HER-2 peptides against HER-2/neu-expressing tumors. © 2010 American Association for Cancer Research.

Baxevanis C.N.,Saint Savas Cancer Hospital | Papamichail M.,Saint Savas Cancer Hospital | Perez S.A.,Saint Savas Cancer Hospital
Cancer Immunology, Immunotherapy | Year: 2015

Cancer vaccines as a modality of immune-based cancer treatment offer the promise of a non-toxic and efficacious therapeutic alternative for patients. Emerging data suggest that response to vaccination largely depends on the magnitude of the type I immune response generated, epitope spreading and immunogenic modulation of the tumor. Moreover, accumulating evidence suggests that cancer vaccines will likely induce better results in patients with low tumor burden and less aggressive disease. To induce long-lasting clinical responses, vaccines will need to be combined with immunoregulatory agents to overcome tumor-related immune suppression. Immunotherapy, as a treatment modality for prostate cancer, has received significant attention in the past few years. The most intriguing characteristics that make prostate cancer a preferred target for immune-based treatments are (1) its relative indolence which allows sufficient time for the immune system to develop meaningful antitumor responses; (2) prostate tumor-associated antigens are mainly tissue-lineage antigens, and thus, antitumor responses will preferentially target prostate cancer cells. But, also in the event of eradication of normal prostate epithelium as a result of immune attack, this will have no clinical consequences because the prostate gland is not a vital organ; (3) the use of prostate-specific antigen for early detection of recurrent disease allows for the initiation of vaccine immunotherapy while tumor burden is still minimal. Finally, for improving clinical outcome further to increasing vaccine potency, it is imperative to recognize prognostic and predictive biomarkers of clinical benefit that may guide to select the therapeutic strategies for patients most likely to gain benefit. © 2015, Springer-Verlag Berlin Heidelberg.

Baxevanis C.N.,Saint Savas Cancer Hospital | Papamichail M.,Saint Savas Cancer Hospital | Perez S.A.,Saint Savas Cancer Hospital
Expert Opinion on Biological Therapy | Year: 2013

Introduction: There is now accumulating evidence to suggest that intratumoral adaptive immune responses predict patient prognosis. The presence of tumor-infiltrating lymphocytes has been correlated with patients' disease-free and overall survival. Recent exciting studies of human colorectal cancers (CRCs) have underlined the significance of including immunological biomarkers as prognostic markers. Areas covered: This review covers recent literature which suggests that the type, density and location of immune cells within the colorectal tumors represent a better predictor of patient survival than the histopathological methods currently used to stage CRC. Expert opinion: Remarkably, the quantity, quality and spatial distribution of immune cells within the tumor has a greater prognostic value than the standard tumor staging based on tumor burden, infiltration of draining and regional lymph nodes by tumor cells, and evidence of metastases. In addition, such an immune classification may also have a predictive value. Thus, by increasing the knowledge of the immune events inside the tumors and by better understanding the immune architecture of these tumors as well as the functional programs of their constituents, there will certainly be a more complete idea of how tumors evade from immunosurveillance. This knowledge will help to identify new targets for the development of therapeutic strategies. © 2013 Informa UK, Ltd.

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