CTLA-4 blockade: therapeutic potential in cancer treatments

Enhancing or prolonging T-cell activation by monoclonal antibodies (mAbs) blocking negative signaling receptors such as CTLA4 is one approach to overcoming tumor-induced immune tolerance. Ipilimumab and tremelimumab inhibit CTLA4, prolonging antitumor immune responses and leading to durable anti-tumor effects. Treatment with these mAbs has demonstrated clinically important and durable tumor responses and disease control rates in patients with unresectable advanced melanoma. Durable objective responses have been reported across a spectrum of doses and schedules, with relative safety in this patient population. Although the phase III tremelimumab melanoma study was closed for “futility”, the 1-year survival rate of >50% for tremelimumab and the median survival of 11.7 months (compared with 10.7 months for chemotherapy) are notable. Results of the phase III studies testing CTLA4-blockade with ipilimumab are eagerly anticipated. The further development of these agents includes testing in the neoadjuvant melanoma setting (ipilimumab) as well the adjuvant high-risk melanoma setting (ipilimumab). Future progress with CTLA-4 blockade therapy will also likely come from the use of combinations of agents that target several critical regulatory pathways of the immune system and modulate the immune response in the host in a synergistic and controlled fashion

Scaling of the CKM Matrix in the 5D MSSM

We discuss a five-dimensional Minimal Supersymmetric Standard Model compactified on a $S^1/Z_2$ orbifold, looking at, in particular, the one-loop evolution equations of the Yukawa couplings for the quark sector and various flavor observables. Different possibilities for the matter fields are discussed, that is, where they are in the bulk or localised to the brane. The two possibilities give rise to quite different behaviours. By studying the implications of the evolution with the renormalisation group of the Yukawa couplings and of the flavor observables we find that, for a theory that is valid up to the unification scale, the case where fields are localised to the brane, with a large $\tan\beta$, would be more easily distinguishable from other scenarios.Comment: 12 pages, 8 figures, Extra comments adde

Melanoma antigen-specific effector T cell cytokine secretion patterns in patients treated with ipilimumab

Additional file 1. Summary of Luminex cytokine measurements

Anomaly mediated SUSY breaking scenarios in the light of cosmology and in the dark (matter)

Anomaly mediation is a popular and well motivated supersymmetry breaking scenario. Different possible detailed realisations of this set-up are studied and actively searched for at colliders. Apart from limits coming from flavour, low energy physics and direct collider searches, these models are usually constrained by the requirement of reproducing the observations on dark matter density in the universe. We reanalyse these bounds and in particular we focus on the dark matter bounds both considering the standard cosmological model and alternative cosmological scenarios. These scenarios do not change the observable cosmology but relic dark matter density bounds strongly depend on them. We consider few benchmark points excluded by standard cosmology dark matter bounds and suggest that loosening the dark matter constraints is necessary in order to avoid a too strong (cosmological) model dependence in the limits that are obtained for these models. We also discuss briefly the implications for phenomenology and in particular at the Large Hadron Collider.Comment: 37 pages, 20 figures, 1 tabl

Future perspectives in melanoma research. Meeting report from the “Melanoma Bridge. Napoli, December 2nd-4th 2012”

Recent insights into the genetic and somatic aberrations have initiated a new era of rapidly evolving targeted and immune-based treatments for melanoma. After decades of unsuccessful attempts to finding a more effective cure in the treatment of melanoma now we have several drugs active in melanoma. The possibility to use these drugs in combination to improve responses to overcome the resistance, to potentiate the action of immune system with the new immunomodulating antibodies, and identification of biomarkers that can predict the response to a particular therapy represent new concepts and approaches in the clinical management of melanoma. The third “Melanoma Research: “A bridge from Naples to the World” meeting, shortened as “Bridge Melanoma Meeting” took place in Naples, December 2 to 4th, 2012. The four topics of discussion at this meeting were: advances in molecular profiling and novel biomarkers, combination therapies, novel concepts toward integrating biomarkers and therapies into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage, and the knowledge gained from the biology of tumor microenvironment across different tumors as a bridge to impact on prognosis and response to therapy in melanoma. This international congress gathered more than 30 international faculty members who in an interactive atmosphere which stimulated discussion and exchange of their experience regarding the most recent advances in research and clinical management of melanoma patients

PD-1 and Tim-3 Regulate the Expansion of Tumor Antigen-Specific CD8+ T Cells Induced by Melanoma Vaccines

Although melanoma vaccines stimulate tumor antigen (TA)-specific CD8+ T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we evaluated the character of vaccine-induced CD8+ T cells with regard to the inhibitory T cell co-receptors PD-1 and Tim-3 in metastatic melanoma patients who were administered tumor vaccines. The vaccines included incomplete Freund's adjuvant (IFA), CpG oligodeoxynucleotide (CpG) and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V, either by itself or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid TA-specific CD8+ T-cell responses detected ex vivo, however, TA-specific CD8+ T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8+ T cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8+ T cells at the time of vaccine administration correlated inversely with their expansion in vivo. Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8+ T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antitumor T cell responses and increase the likelihood of clinical responses in advanced melanoma patients