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Baxevanis C.N.,Cancer Immunology and Immunotherapy Center | Voutsas I.F.,Cancer Immunology and Immunotherapy Center | 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. Source


Tsavaris N.,National and Kapodistrian University of Athens | Voutsas I.F.,Cancer Immunology and Immunotherapy Center | Kosmas C.,Metaxa Cancer Hospital | Gritzapis A.D.,Cancer Immunology and Immunotherapy Center | Baxevanis C.N.,Cancer Immunology and Immunotherapy Center
Investigational New Drugs | Year: 2012

Background Bevacizumab, a monoclonal antibody (mAb) targeting vascular endothelial growth factor (VEGF), has produced promising results when combined with chemotherapy in the treatment of advanced colorectal cancer (CRC). The aim of the present study was to define the immunological profile of metastatic CRC patients at baseline and following chemotherapy with either irinotecan/5- fluorouracil/leucovorin (IFL) alone or IFL in combination with.bevacizumab (B-IFL). Methods Peripheral blood mononuclear cells (PBMCs) obtained from healthy donors (HD) (n=20) and patients (n=40) were tested for T-cell proliferation in the autologous mixed lymphocyte reaction (auto-MLR), and cytokine production following stimulation with anti-CD3 mAb. Results,PBMCs obtained from CRC patients prior to treatment exhibited lower auto-MLR responses and low production of IL-2, IFN-γ, IL-12 and IL-18 cytokines, whereas IL-4 and IL-10 cytokines were increased as compared to HD (p<0.001, for all parameters) following in vitro stimulation with anti-CD3 mAb. During treatment, and in particular in week 12 of evaluation, IL-2 (p <0.001 for both IFL and B-IFL groups), IFN-γ (p<0.001 for IFL and p=0.001 for B-IFL), IL-12 (p<0.001 for both IFL and B-IFL) and IL-18 (p<0.001 for both IFL and B-IFL) production, as well as auto-MLR responses increased (p< 0.001 for both IFL and B-IFL), whereas IL-4 (p<0.001 for IFL and p=0.001 for B-IFL) and IL-10 [p<0.001 for IFL and p=0.067 (non-significant) for B-IFL] production decreased over baseline in the two treatment groups, yet their respective values never reached those of HD. Moreover, IL-2, IFN-γ production, and auto-MLR were higher in the B-IFL over the IFL treatment group (p<0.001, p<0.04, p<0.001, respectively). Conclusion Our study demonstrates that the abnormal immune parameters observed inmetastatic CRC patients at presentation can substantially improve during treatment with either IFL or B-IFL. The immune parameters examined can provide a sensitive and valuable tool for monitoring immune function in CRC patients, and could be applied as surrogate markers predicting treatment-related outcome. © Springer Science+Business Media, LLC 2010. Source


Perez S.A.,Cancer Immunology and Immunotherapy Center | Von Hofe E.,Antigen Express Inc. | Kallinteris N.L.,Antigen Express Inc. | Gritzapis A.D.,Cancer Immunology and Immunotherapy Center | And 3 more authors.
Cancer | Year: 2010

The use of synthetic peptides as vaccines aimed at the induction of therapeutic CD8-positive T-cell responses against tumor cells initially experienced great enthusiasm, mostly because of advances in vaccine technology, including design, synthesis, and delivery. However, despite impressive results in animal models, the application of such vaccines in humans has met with only limited success. The therapeutic activity of vaccine-stimulated, tumor-specific, CD8-positive T cells can be hampered through the physical burden of the tumor, tolerance mechanisms, and local factors within the tumor microenvironment. Recently, accumulating evidence has suggested that combining a peptide-based therapeutic vaccination with conventional chemotherapy can uncover the full potential of the antitumor immune response, increasing the success of immunotherapy. In addition, therapeutic vaccination in the preventive setting has been extremely effective in eliciting antitumor responses in preclinical tumor models and has demonstrated good promise clinically in patients with minimal residual disease. The rationale behind preventive vaccination is that patients with minimal tumor burden still have a fully competent immune system capable of developing robust antitumor responses. Finally, therapeutic CD8-positive T-cell peptide vaccines have been improved by coimmunization with T-helper epitopes expressed on long peptides. © 2010 American Cancer Society. Source


Gritzapis A.D.,Cancer Immunology and Immunotherapy Center | Voutsas I.F.,Cancer Immunology and Immunotherapy Center | Baxevanis C.N.,Cancer Immunology and Immunotherapy Center
Cancer Immunology, Immunotherapy | Year: 2012

Disrupting tumor-mediated mechanisms suppressing host immunity represents a novel approach to tumor immunotherapy. Depletion of regulatory T cells (Tregs) increases endogenous anti-tumor immunity and the efficacy of active immunotherapy in experimental tumor models. HLA-A2.1/HLA-DR1 (A2.1/DR1) x BALB-neuT +(neuT +) triple transgenic mice represent an improvement over neuT + mice for evaluating vaccination regimens to overcome tolerance against HER-2/neu. We questioned whether depletion of Tregs with Denileukin diftitox (Ontak) enhances the efficacy of a therapeutic vaccine consisting of HER-2(85-94) (p85) CTL and HER-2(776-790) (p776) Th peptides against the growth of TUBO.A2 transplantable tumor in male A2.1/DR1 x neuT + Tg mice. While the therapeutic vaccine primed the tumor-reactive CD8 + CTLs and CD4 + effector T lymphocytes (Teffs) compartment, inducing activation, tumor infiltration, and tumor rejection or delay in tumor growth, treatment with Ontak 1 day prior to vaccination resulted in enhanced CD4 + and CD8 + T-cell-mediated vaccine-specific immune responses in the periphery. This was closely associated with greater infiltration and a striking change in the intratumor balance of Tregs and vaccine-specific CTLs/Teffs that directly correlated with markedly enhanced antitumor activity. The data suggest that Tregs control both CD4 + and CD8 + T-cell activity within the tumor, emphasize the importance of the intratumor ratio of vaccine-specific lymphocytes to Tregs, and demonstrate significant inversion of this ratio and correlation with tumor rejection during Ontak/vaccine immunotherapy. © Springer-Verlag 2011. Source


Baxevanis C.N.,Cancer Immunology and Immunotherapy Center | Papamichail M.,Cancer Immunology and Immunotherapy Center | Perez S.A.,Cancer Immunology and Immunotherapy Center
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. Source

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