7 research outputs found

    Rationale for a multimodality strategy to enhance the efficacy of dendritic cell-based cancer immunotherapy

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    Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications — such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer — clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of antitumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of precision cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted—and personalized—approach combining DC-based vaccination with adjunctive strategies

    CD4 +

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    Vaccination strategies incorporating the immunodominant HLA-A2-restricted HER2/neu-derived peptide 369-377 (HER2(369-377)) are increasingly utilized in HER2/neu-expressing cancer patients. The failure of post-vaccination HER2(369-377)-specific CD8(+) T cells to recognize HLA-A2(pos)HER2/neu-expressing cells in vitro, however, has been attributed to impaired MHC class I/HLA-A2 presentation observed in HER2/neu-overexpressing tumors. We reconcile this controversy by demonstrating that HER2(369-377) is directly recognized by high functional-avidityHER2(369-377)-specific CD8(+) T cells—either genetically modified to express a novel HER2(369-377)-TCR or sensitized using HER2(369-377)-pulsed type 1-polarized dendritic cells (DC1)—on class I-abundant HER2(low), but not class I-deficient HER2(high), cancer cells. Importantly, a critical cooperation between CD4(+) T-helper type-1 (Th1) cytokines IFNγ/TNFα and HER2/neu-targeted antibody trastuzumab is necessary to restore class I expression in HER2(high) cancers, thereby facilitating recognition and lysis of these cells by HER2(369-377)-specific CD8(+) T cells. Concomitant induction of PD-L1 on HER2/neu-expressing cells by IFNγ/TNF and trastuzumab, however, has minimal impact on DC1-sensitized HER2(369-377)-CD8(+) T cell-mediated cytotoxicity. Although activation of EGFR and HER3 signaling significantly abrogates IFNγ/TNFα and trastuzumab-induced class I restoration, EGFR/HER3 receptor blockade rescues class I expression and ensuing HER2(369-377)-CD8(+) cytotoxicity of HER2/neu-expressing cells. Thus, combinations of CD4(+) Th1 immune interventions and multivalent targeting of HER family members may be required for optimal anti-HER2/neuCD8(+) T cell-directed immunotherapy

    Optimizing dendritic cell-based approaches for cancer immunotherapy

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    Dendritic cells (DC) are professional antigen-presenting cells uniquely suited for cancer immunotherapy. They induce primary immune responses, potentiate the effector functions of previously primed T-lymphocytes, and orchestrate communication between innate and adaptive immunity. The remarkable diversity of cytokine activation regimens, DC maturation states, and antigen-loading strategies employed in current DC-based vaccine design reflect an evolving, but incomplete, understanding of optimal DC immunobiology. In the clinical realm, existing DC-based cancer immunotherapy efforts have yielded encouraging but inconsistent results. Despite recent U.S. Federal and Drug Administration (FDA) approval of DC-based sipuleucel-T for metastatic castration-resistant prostate cancer, clinically effective DC immunotherapy as monotherapy for a majority of tumors remains a distant goal. Recent work has identified strategies that may allow for more potent "next-generation" DC vaccines. Additionally, multimodality approaches incorporating DC-based immunotherapy may improve clinical outcomes

    Dendritic cell-based vaccines: barriers and opportunities

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    Dendritic cells (DCs) have several characteristics that make them an ideal vehicle for tumor vaccines, and with the first US FDA-approved DC-based vaccine in use for the treatment of prostate cancer, this technology has become a promising new therapeutic option. However, DC-based vaccines face several barriers that have limited their effectiveness in clinical trials. A major barrier includes the activation state of the DC. Both DC lineage and maturation signals must be selected to optimize the antitumor response and overcome immunosuppressive effects of the tumor microenvironment. Another barrier to successful vaccination is the selection of target antigens that will activate both CD8(+) and CD4(+) T cells in a potent, immune-specific manner. Finally, tumor progression and immune dysfunction limit vaccine efficacy in advanced stages, which may make DC-based vaccines more efficacious in treating early-stage disease. This review underscores the scientific basis and advances in the development of DC-based vaccines, focuses on current barriers to success and highlights new research opportunities to address these obstacles

    Plasma-derived extracellular vesicle analysis and deconvolution enable prediction and tracking of melanoma checkpoint blockade outcome

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    Immune checkpoint inhibitors (ICIs) show promise, but most patients do not respond. We identify and validate biomarkers from extracellular vesicles (EVs), allowing non-invasive monitoring of tumor- intrinsic and host immune status, as well as a prediction of ICI response. We undertook transcriptomic profiling of plasma-derived EVs and tumors from 50 patients with metastatic melanoma receiving ICI, and validated with an independent EV-only cohort of 30 patients. Plasma-derived EV and tumor transcriptomes correlate. EV profiles reveal drivers of ICI resistance and melanoma progression, exhibit differentially expressed genes/pathways, and correlate with clinical response to ICI. We created a Bayesian probabilistic deconvolution model to estimate contributions from tumor and non-tumor sources, enabling interpretation of differentially expressed genes/pathways. EV RNA-seq mutations also segregated ICI response. EVs serve as a non-invasive biomarker to jointly probe tumor-intrinsic and immune changes to ICI, function as predictive markers of ICI responsiveness, and monitor tumor persistence and immune activation

    Racial disparities in the use of outpatient mastectomy

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    Background: Racial disparities exist within many domains of cancer care. This study was designed to identify differences in the use of outpatient mastectomy(OM) based on patient race. Methods: We identified patients in the American College of Surgeons National Surgical Quality Improvement Program Participant Use File (during the years 2007-2010) who underwent a mastectomy. The association between mastectomy setting, patient race, patient age, American Society of Anesthesiology physical status classification, functional status, mastectomy type, and hospital teaching status was determined using the chi-square test. A multivariable logistic regression analysis was developed to assess the relative odds of undergoing OM by race, with adjustment for potential confounders. Results: We identified 47,318 patients enrolled in the American College of Surgeons National Surgical Quality Improvement Program Participant Use File who underwent a mastectomy during the study time frame. More than half (62.6%) of mastectomies were performed in the outpatient setting. All racial minorities had lower rates of OM, with 63.8% of white patients; 59.1% of black patients; 57.4% of Asian, Native Hawaiian, or Pacific Islander patients; and 43.9% of American Indian or Alaska Native patients undergoing OM (P < 0.001). After adjustment for multiple confounders, black patients, American Indian or Alaska Native patients, and those of unknown race were all less likely to undergo OM (odds ratio [OR], 0.86; 95% confidence interval [CI], 0.80-0.93; OR, 0.55; 95% CI, 0.41-0.72; and OR, 0.70; 95% CI, 0.64-0.76, respectively) compared with white patients. Conclusions: Disparities exist in the use of OM among racial minorities. Further studies are needed to identify the role of cultural preferences, physician attitudes, and insurer encouragements that may influence these patterns of use. (C) 2014 Elsevier Inc. All rights reserved
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