The impact of patient age on breast cancer risk prediction models

BackgroundThe impact of age on breast cancer risk model calculations at the population level has not been well documented

Abstract 4079: Reversal of immune evasion mediated by HER2 requires both humoral and cellular HER-2 targeted immune interventions

Abstract Objectives: HER2 over-expression in breast cancer is associated with a poor prognosis and HER2 is an intense target of immunotherapy with both humoral and T cell -base approaches. HER2 expression is also known to facilitate the escape of tumor cells from immune surveillance by down-regulating MHC class I, resulting in a reduced sensitivity to CTL lysis. Restoring tumor cell MHC Class I expression and reversing their immune evasion are therefore important strategies in the design of immunotherapy against HER2 expressing tumors. In this study we investigated the effects of monoclonal antibody trastuzumab and T help-1 associated cytokines IFN-γ and TNF-A on HLA Class I expression and the susceptibilities to CTL lysis of human HER2 expressing tumor cell lines. Methods: Breast cancer cell lines MCF7, SKBR3, BT474 and ovarian cancer cell line SKOV3 were treated with trastuzumab only, combination of IFN-γ and TNF-A or trastuzumab with IFN-γ and TNF-A. Cell surface expressions of HLA ABC were examined by flow cytometric analysis. The susceptibility of tumor cells to HER2 specific CD8+ T cell recognition and CTL lysis were assessed by measurement of CD8+ T cell IFN-γ secretion and flow cytometric analysis respectively. Results: Th1 cytokines IFN-γ and TNF-A dramatically increased HLA ABC expressions on all tumor lines compared to untreated cells, [ MCF7 (p=0.04); SKBR3 (p=0.02); SCOV3 (p=0.02) and BT474 (p=0.04)], while trastuzumab alone showed little impact on HLA ABC up-regulation. When treated with a combination of trastuzumab, IFN-γ and TNF-A tumor cells displayed synergistically enhanced HLA ABC expression [MCF7 (p=0.02); SKBR3 (p=0.004); SKOV3 (0.006) and BT474 (p=0.03)]. We observed that IFN-γ and TNF-A treatment was able to remarkably increase CD8+ T cell recognition and CTL lysis of low and intermediate HER2 expressing tumors [ MCF7(p=0.03) and SKOV3(0.02)], but not High HER2 tumor[ SKBR3(p=0.07)]. Only a combined treatment of trastuzumab, IFN-γ and TNF-A rendered SKBR3 susceptible to a significant killing by CTL (p=0.02). To investigate the impact of other HER family members EGFR and HER3 on MHC class I expression , HER2 over-expressing breast cancer cell lines BT474 and SKBR3 were pre-treated with EGF or Heregulin, then subjected to IFN-γ and TNF-A treatments. Activation of HER1 and HER3 signaling made HER2 over-expressing cells resistant to the effect of MHC class I up-regulation by IFN-γ and TNF-A. Conclusion: Both humoral and cellular immune HER-2 targeted interventions are required to reverse immune escape mediated by HER2; in addition to targeting HER2, targeting HER1 and HER3 signaling elements should also be included in order to abrogate the cross talk between HER family members and more effectively inhibit the HER2 signaling pathway. Citation Format: Shuwen Xu, Jessica Cintolo, Jashodeep Datta, Cinthia Rosemblit, Erik Berk, Julia Terhune, Elizabeth Fitzpatrick, Brian Czerniecki. Reversal of immune evasion mediated by HER2 requires both humoral and cellular HER-2 targeted immune interventions. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4079. doi:10.1158/1538-7445.AM2014-407

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

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 +

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

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

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

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

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