J D Wolchok

..Further research is warranted to establish how immunotherapeutic agents can be combined with conventional agents, with each other or with molecularly targeted agents such as vemurafenib, to further optimise clinical outcomes...

..Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer...

..The observation of two partial responses has led to a phase II study to evaluate treatment with high dose paracetamol alone or in combination with BCNU...

..These results show that immunity to TRP-2 following DNA immunization uses an IFN-gamma-dependent Th1 pathway, but immunity to gp75/TRP-1 is down-regulated by IFN-gamma...

..Mouse and human TYR DNA vaccines were found safe and induced CD8(+) T-cell responses in 7 of 18 patients. T cells recognizing a native TYR peptide had a phenotype consistent with that of effector memory cells...

..New approaches to melanoma are emerging. This review summarizes developments over the past 12 months...

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..Novel criteria for the evaluation of antitumor responses with immunotherapeutic agents are required...

..Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma...

..These findings support the hypothesis that ipilimumab-treated patients with advanced melanoma have similar outcomes regardless of their HLA-A*0201 status...

..Autoimmunity uses similar mechanisms as tumor immunity, but tumor immunity and autoimmunity can uncouple. These studies open up strategies for active immunization against cancer...

..Metastatic disease is a common sequela for which few effective treatment options exist. Studies show that xenogeneic tyrosinase DNA vaccination yields immune responses and prolongation of survival in dogs with oral malignant melanoma...

..e., antibody versus CD8(+) T cell. However, both pathways led to tumor immunity and identical phenotypic manifestations of autoimmunity...

..One patient had an increase in CD8+ IFN-gamma+ cells. This xenogeneic immunization strategy was safe and associated with minimal toxicity. There was also evidence of immune response...

..Most interestingly, the onset of antibody induction in these three dogs coincides with observed clinical responses and may suggest a means to account for their long-term tumor control and survival...

..In conclusion, our data suggest that KGF can function as a potent vaccine adjuvant after allo-BMT through its effects on posttransplantation T-cell reconstitution...

..To further define the optimal vaccination strategy, we conducted a pilot clinical trial comparing i.m. injection with particle-mediated epidermal delivery (PMED)...

..Monoclonal antibodies should be tested as vaccine adjuvants in the treatment of cancer...

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..However, fusion constructs with Vp22 gave a strong CD4 response to B16 melanoma and the OmpA response is MHC-II dependent. Both adjuvant fusion constructs stimulated CD4 and CD8 responses otherwise diminished in old mice...

..These data provide an immunologic rationale for the efficacy of anti-CTLA-4 therapy and call for immunotherapeutic designs that combine NY-ESO-1 vaccination with CTLA-4 blockade...

..Responding T cells had an effector memory cell phenotype. Polyfunctional T cells were also demonstrated. At a median of 31 months follow-up, median survival has not been reached. Human GM-CSF DNA was found to be a safe adjuvant...

..The current Phase II study examined the efficacy and safety of this combination in chemotherapy-naive patients with brain metastases...

..HER2/neu is frequently overexpressed in breast cancer. In a mouse model, vaccination with HER2/neu DNA elicits antibodies that confer partial protection against tumor challenge...

..Therefore large fusion vector panels such as those presented here can provide information to promote the successful advancement of gene-based vaccines...

..Further, precursor frequency as an isolated variable can be exploited to augment efficacy of clinical vaccine strategies designed to activate any antigen-specific CD8(+) T cells...

..We are currently conducting a phase I trial of human and mouse PSMA DNA vaccines in patients with recurrent prostate cancer, based on preclinical experiments described below...

..These studies provided the rationale for a trial of xenogeneic DNA vaccination in CMM using the human tyrosinase gene...

..These data demonstrate that this approach can serve as the basis of epitope-engineering against cancer and intracellular pathogens...

..These findings provide further support for the continued development of agonist anti-GITR mAbs as an immunotherapeutic strategy for cancer...

..Vitiligo (autoimmune hypopigmentation) can be mediated by T cells, FcgammaR+macrophages and/or complement...

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..Therefore, the efficacy and safety of temozolomide in combination with pegylated IFN-alpha-2b in patients with metastatic melanoma without brain metastases was investigated...

..Although initial clinical trials have shown the safety and immunological efficacy of vaccines for melanoma, the true clinical benefit of these strategies will only be revealed in large randomised trials...

..A secondary objective was to test the feasibility of obtaining adequate tissue before and after treatment for genetic testing...

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..We hypothesized that expression of methylguanine methyltransferase (MGMT) in the tumor would correlate with drug resistance to TMZ...

..We reviewed a contemporary, single-institution experience to evaluate the natural history of stage-IV melanoma metastatic to the lung and identify factors predictive of survival...

..The immunogram - a newly described graphical synthesis of treatment data and immune correlates in individual patients - may help us to confirm, reject or formulate new hypotheses regarding the mechanism of anti-CTLA-4 activity...

..This represents an example of intermolecular determinant recognition, but is not simply due to epitope spreading since antibodies against the antigen targeted by DNA vaccination are not typically detected...

..CD8(+) T-cell responses were readily induced in TLR4-deficient mice immunized with DNA depleted of LPS. LPS in DNA vaccines is not required for CD8(+) T-cell responses...

..Monitoring cellular immune responses is one prerequisite for the rational development of cancer vaccines...

..This HLA-matched APC line can be adapted to other HLA haplotypes, and has advantages for monitoring clinical trials of immunotherapy with limited availability of autologous APC and PBMC from patients...

..To further investigate the efficacy and safety of temozolomide plus thalidomide in patients with metastatic melanoma without brain metastases...

..Several immunologic endpoints have been proposed to correlate with clinical activity. This review will focus on the endpoints of immune monitoring described in studies to date and discuss future areas of additional work needed...

..In this review, we will discuss strategies to induce active immunity against melanoma...

..To present our single-institution experience with postoperative radiotherapy for mucosal melanoma of the head and neck...

..It gives a brief history and then discusses the proposed mechanism of action, preclinical and clinical studies, and methods of enhancing the immune responses induced by DNA vaccines...

..The patient's course and associated immunological monitoring and other laboratory data are presented in an immunogram, a way to visualize temporal associations between the multiple clinical and laboratory parameters...

..Immune modulation, such as inducing GITR signaling, is required to enhance CD8(+) T-cell responses to specific mutations and to lead to tumor rejection...

..Studies examining the molecular basis for immunogenicity of conserved paralogues are facilitating the development of new strategies to rationally design vaccines that trigger adaptive immune responses to cancer...

..These results establish the basis for clinical trials to test PSMA DNA vaccines in patients with solid tumors that either express PSMA directly or that depend on normal endothelial cells expressing PSMA for their continued growth...

..These results show that active immunization with xenogeneic DNA vaccines can induce CD8+ T cell-dependent immunity against CD20...

..Finally, this effect on vaccine-induced CD8(+) T-cell responses was partially independent of CD4(+) T cells (both helper and regulatory), consistent with a direct costimulatory effect on the effector CD8(+) cells themselves...

..Further studies are needed to establish the role of vaccination as viable postremission therapy for acute myeloid leukemia...

..These results demonstrate that DNA immunization against tissue-restricted Ags after allogeneic T cell-depleted HSCT can induce potent antitumor effects without causing GVHD...

..These are surprising observations, linking antibodies of the adaptive immune system to innate immune responses that drive epithelial carcinogenesis...

..Based on these pre-clinical studies, we suggest that anti-CTLA-4 should be tested with xenogeneic DNA vaccines against cancer and that special attention should be given to sequence and schedule of administration...

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..Further studies of these selected novel STS antigens are warranted to identify and characterize potential antigen targets expressed by STS...

..However, vaccination of patients with GD2-KLH has previously failed to induce a consistent relevant antibody response. We test here whether the use of GD2 lactone-KLH can overcome the low immunogenicity of GD2-KLH...

..Understanding the kinetics of response to ipilimumab will help clinicians to manage patients who may benefit from treatment. In this article, several cases that illustrate the kinetics of response to ipilimumab are discussed...

..The purpose of this study was to compare viral and plasmid DNA in combination vaccination strategies in the context of a tumor antigen...

..The low response rate among previously treated patients indicates that biochemotherapy is not useful as second-line therapy...

..These studies provided the impetus for development of a xenogeneic DNA vaccine program in CMM...

..CCS/MSP also has typical melanoma features, including immunoreactivity for S100 and HMB45, pigmentation, MITF-M expression, and a propensity for regional lymph node metastases...

..CONCLUSION: TMZ at this dose and schedule results in CD4(+) lymphopenia in a majority of patients that can result in OIs. Pneumocystis pneumonia prophylaxis should be considered for patients who develop sustained lymphopenia on TMZ...

..These results have implications for understanding early events in the immune response to DNA vaccines, and provide a basis for development of new approaches to cancer vaccines, including the use of cytokine genes as adjuvants...

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..Closer examination revealed that diminished intratumoral T reg cell levels resulted from hyperactivation and T reg cell-specific apoptosis. Thus, we propose that CTX and OX40 engagement represents a novel and rational chemoimmunotherapy...

..This review discusses the role of GITR as a potential target for immunomodulatory therapy, as well as the research involved in understanding the mechanisms of anti-GITR therapy and current progress in translation into the clinic...

..Crucial to these approaches is the discovery and understanding of the molecular identity of antigens and the mechanisms involved in tumor immunity. In this review, strategies to overcome immune ignorance and tolerance are discussed...

..Melanoma has the potential to spread to virtually any organ, including the gallbladder. The role of intervention in this rare entity must be based on a thorough appreciation of the underlying disease biology...

..This report will highlight the major scientific themes and advances of this most successful meeting, and provide a useful perspective on the current state of melanoma research, as well as where the field should be heading...