bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5025: Dissecting the dynamics of anti-PD1 immunotherapy in preclinical tumor models
Authors: Sriram Venkataraman , Bigler Michael E. , Cherwinski Holly , Murphy Erin , McClanahan Terrill K. , Phillips Joseph H. 
Published: May 2015

Abstract
MK-3475 is an antagonistic humanized IgG4 anti-PD1 antibody currently in late stage clinical development for the treatment of cancer. MK-3475 exerts its anti-tumor effect through blocking the interaction of the immune inhibitory molecule PD-1 with its ligands. MK-3475 does not bind to mouse PD-1. Therefore, we generated a surrogate antibody, mDX400 for use in preclinical rodent models. In multiple syngeneic tumor models, treatment with mDX400 murinized anti-mouse antibody results in complete and durable tumor regression. We have used mDX400 as a mouse equivalent of MK-3475 to aid in our understanding of the cellular and molecular dynamics of anti-PD1 immunotherapy.
In the current study, we examined peripheral and intratumoral lymphoid compartments pre- and post-mDX400 treatment. The data indicated that:
1. Anti-tumor efficacy was primarily driven by the level of PD-1 receptor blockade in tumor, but not blood.
2. An altered molecular signature, including significant upregulation of genes involved in monocyte, B- and T-cell activation and differentiation, was observed post-treatment in the tumors, but not peripheral blood or draining lymph nodes, of responding animals.
3. Tumor-specific immune memory was evident, as assessed by ultrahigh-throughput DNA sequencing of TCR CDR3 region, following successful treatment with mDX400.
These data provide insights into the molecular dynamics following anti-PD1 immunotherapy and will guide hypothesis generation for biomarkers to inform our clinical strategy. In addition, the cellular and molecular pathways that predominate in preclinical tumor models insensitive to anti-PD1 immunotherapy are being evaluated. These types of studies may inform us on potential therapies that can be combined with MK-3475 to expand the therapeutic benefit of this biologic.
Citation Format: Venkataraman Sriram, Michael E. Bigler, Holly Cherwinski, Erin Murphy, Terrill K. McClanahan, Joseph H. Phillips. Dissecting the dynamics of anti-PD1 immunotherapy in preclinical tumor models. [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 5025. doi:10.1158/1538-7445.AM2014-5025
Abstract 5029: Comparative combination cancer immunotherapy with vaccination, checkpoint inhibition and TNFRSF stimulation
Authors: Schreiber Taylor H. , Schilling Neal , Deyev Vadim , Podack Eckhard R. 
Published: May 2015

Abstract
Therapeutic tumor immunity requires the presence and appropriate activation of tumor antigen specific CD8+ T cells and migration of activated tumor-antigen specific CD8+ T cells into a tumor microenvironment where immunosuppressive barriers have been eliminated. Antibody mediated blockade of CTLA-4 and PD-1 is a clinically effective strategy to dampen tumor mediated immunosuppression in a minority of patients with advanced cancer, and this approach may be potentiated through vaccination to prime additional CTL clones and through direct stimulation of T cell costimulatory molecules of the TNF superfamily. Here we provide a systematic comparison of anti-tumor vaccination with either heat shock protein gp96-Ig or traditional peptide/adjuvant vaccines given alone or in combination with CTLA-4 or PD-1 blockade and direct T cell costimulation via OX40, 4-1BB and TNFRSF25. Through the tracking of tumor-antigen specific CD4+ and CD8+ T cell responses, these studies demonstrate that both TNFRSF4 and TNFRSF25 independently and additively costimulate vaccine induced CD8+ T cell proliferation following both primary and secondary antigen challenge. In contrast, the activity of TNFRSF4 and TNFRSF25 were observed to be divergent in the costimulation of CD4+ T cell immunity. Interestingly, antigen-specific cellular and humoral responses were uncoupled upon secondary immunization, which was dramatically effected by the presence of OX40, 4-1BB or TNFRSF25 costimulation. When combined with checkpoint inhibition in therapeutic murine orthotopic tumor models, synergistic anti-tumor activity was observed with various triple combinations with vaccine, checkpoint inhibition and T cell costimulation. These studies highlight the complementary activity of vaccination, checkpoint inhibition and direct T cell costimulation, which may guide the application of combination immunotherapy for effective anti-tumor immunity.
Citation Format: Taylor H. Schreiber, Neal Schilling, Vadim Deyev, Eckhard R. Podack. Comparative combination cancer immunotherapy with vaccination, checkpoint inhibition and TNFRSF stimulation. [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 5029. doi:10.1158/1538-7445.AM2014-5029
Abstract 5034: The antitumor immune response generated by radiation therapy may be limited by tumor cell adaptive resistance and can be circumvented by PD-L1 blockade
Authors: Dovedi Simon J. , Lipowska-Bhalla Graznya , Cheadle Eleanor , Poon Edmund , Morrow Michelle , Stewart Ross , Wilkinson Robert , Honeychurch Jamie , Illidge Timothy 
Published: May 2015

Abstract
Radiation therapy (RT) is administered to around 50% of all cancer patients making it one of the most important cancer treatments. In addition to the direct cytoreductive effect of RT there is increasing evidence that radiation-induces immunogenic tumor cell death. Despite the immunogenicity of RT-induced tumor cell death, RT delivered to tumours in the clinic rarely generates therapeutic systemic anti-cancer immune responses or ‘abscopal effects’.
Here we show that tumor infiltrating CD8+ cytotoxic T lymphocytes (CTL) have increased expression of PD-1 following RT in vivo. Moreover, our data demonstrate that treatment of established syngeneic tumors with RT leads to upregulation of tumor cell expression of PD-L1 in vivo but not when cells are irradiated in vitro. Using depleting antibodies we determined that the depletion of CD8+ T cells but not CD4+ T cells or NK cells could abrogate this RT-induced increase in tumor cell expression of PD-L1 in vivo. Furthermore, silencing of IFNγR1 using ShRNA confirmed that this process was dependent on CD8+ T cell production of IFNγ suggesting an adaptive upregulation of PD-L1 following RT occurs in response to CTL activation. This novel finding suggests that the immunogenicity of RT may be limited via the PD-L1/PD-1 signalling axis and may contribute to treatment failure.
We next sought to determine whether blockade of the PD-1/PD-L1 signalling axis could enhance the therapeutic response to RT. Our study demonstrates that administration of either an anti-PD-1 or anti-PD-L1 mAb in combination with RT leads to substantially improved survival when compared to either monotherapy alone with approximately 60% of treated mice undergoing a complete response. In addition, our data reveal that combination therapy generates long-term immunological memory in mice that have undergone complete response protecting against tumor rechallenge.
This is the first report to our knowledge that demonstrates adaptive resistance through the upregulation of tumour cell PD-L1 expression in response to an RT-induced CTL response. This study demonstrates the potential for enhancing the efficacy of conventional RT through blockade of the PD-1/PD-L1 axis and warrants clinical evaluation.
Citation Format: Simon J. Dovedi, Graznya Lipowska-Bhalla, Eleanor Cheadle, Edmund Poon, Michelle Morrow, Ross Stewart, Robert Wilkinson, Jamie Honeychurch, Timothy Illidge. The antitumor immune response generated by radiation therapy may be limited by tumor cell adaptive resistance and can be circumvented by PD-L1 blockade. [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 5034. doi:10.1158/1538-7445.AM2014-5034
Abstract 5036: Blockade of the CD39 immunoregulatory pathway by monoclonal antibodies
Authors: Bastid Jeremy , Dejou Cécile , Giustiniani Jérôme , Cochaud Stéphanie , Alberici Gilles , Bensussan Armand , Eliaou Jean-François , Bonnefoy Nathalie 
Published: May 2015

Abstract
The CD39/ CD73/ adenosine pathway is an important regulator of effector immune cell response. We previously demonstrated that, in human cancer specimen, CD39 is expressed by infiltrating regulatory T cells, tumor cells and the tumor associated stroma. CD39 enzymatic activity decreases peritumoral ATP, a potent tumor cell toxicity and immunogenic inducer, and generates immunosuppressive adenosine that binds adenosine receptors and inhibits CD4, CD8 T cell and NK cell responses. We and other demonstrated that CD39-mediated decrease of extracellular ATP and increase of adenosine promote tumor progression and immune escape as well as resistance to chemotherapy-induced immune response. We therefore generated several CD39 blocking monoclonal antibodies and present here the latest developments of these antibodies. We provide evidence that CD39 blocking antibodies restore the proliferation of CD4 and CD8 T cells inhibited by melanoma cells expressing CD39 and increase the generation of CD8 cytotoxic T cells against CD39+ melanoma cells. We also demonstrated that CD39+ lymphoma cells are less sensitive to NK cell cytotoxic activity than CD39- lymphoma cells, and that CD39-blocking monoclonal antibodies increase NK-mediated lysis of CD39+ lymphoma cells but not CD39- lymphoma cells. In conclusion, CD39 blocking antibodies may represent a novel immunotherapy strategy for inhibiting regulatory T cells and tumor cell-mediated immunosuppression. The results presented here support the ongoing development of CD39 blocking monoclonal antibodies as potential anticancer drugs to restore antitumor immune response.
Citation Format: Jeremy Bastid, Cécile Dejou, Jérôme Giustiniani, Stéphanie Cochaud, Gilles Alberici, Armand Bensussan, Jean-François Eliaou, Nathalie Bonnefoy. Blockade of the CD39 immunoregulatory pathway by monoclonal antibodies. [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 5036. doi:10.1158/1538-7445.AM2014-5036
Abstract 5038: Telomere length linking social contexts and cancer risk in Mexican Americans
Authors: Han Lixia , Zhao Hua , Strom Sara , Daniel Carrie R. , Chang David , Zhang Hui , Ye Yuanqing , Gu Jian , Chow Wong-Ho , Wu Xifeng 
Published: May 2015

Abstract
Social contexts have a strong impact on chronic disease risk, including cancer, but how these influences “get under the skin” remains unclear. We hypothesize that telomere length may serve as the molecular link between social contexts and cancer risk. Using quantitative real-time PCR, we measured relative telomere length (TL) on baseline whole blood DNA samples collected from 6,574 participants of the ongoing Mano-a-Mano Mexican American Cohort study. We found that TL decreased linearly with increasing age (P-trend&lt;0.001). In multivariable-adjusted Cox proportional-hazard regression models, longer TL was directly associated with a 2.66-fold increased risk of all-cancer incidence (95% CI= 1.40-5.03). TL was positively associated with several acculturation-related variables. For example, participants with a higher acculturative score with greater stays in the US had a longer TL among participants older than the median age of 38 (P=0.05 and 0.04, respectively). Participants born in the US and with at least a high school education were also more likely to have a longer TL. Among the modifiable risk factors, TL was inversely associated with sedentary or sitting time among women (P=0.01) and among young participants (P=0.01). In other chronic diseases, we found that longer TL was associated with diabetes and gallbladder disease in older participants (P=0.04 and 0.01, respectively). Our results suggest that TL may mediate the relationship between acculturation and related risk factors such as physical inactivity, education, and cancer risk among Mexican Americans. This is our first step in a continuum of research focused on understanding how social and behavioral disparities influence biological pathways in cancer development.
Citation Format: Lixia Han, Hua Zhao, Sara Strom, Carrie R. Daniel, David Chang, Hui Zhang, Yuanqing Ye, Jian Gu, Wong-Ho Chow, Xifeng Wu. Telomere length linking social contexts and cancer risk in Mexican Americans. [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 5038. doi:10.1158/1538-7445.AM2014-5038
Abstract 5042: Using a statewide collaborative approach to improve tobacco cessation referral rates for cancer patients
Authors: Severson Jane , Baca Hilary , Blayney Douglas , Brown Karen , Galiyas Grayce , Minasian Mara , Schmidt Joan , Schulze Anna , Warren Graham 
Published: May 2015

Abstract
Purpose:
Though tobacco use by cancer patients is associated with poor therapeutic outcomes, most oncologists do not regularly provide tobacco cessation support for cancer patients. The purpose of this study was to determine if dedicated statewide services could substantially enhance delivery of evidence based cessation support to broad cancer patient populations across many oncology clinics.
Methods:
The Michigan Oncology Quality Consortium (MOQC) collaborated with the Michigan Department of Community Health and the Michigan Cancer Consortium to identify and address tobacco cessation support that could be improved for cancer patients. A statewide Tobacco Cessation Demonstration Project was developed to reduce patient barriers to access by increasing education, identifying all cancer patients who use tobacco, referring them to the Michigan Tobacco Quitline, and providing funding for free Quitline telephone counseling services and nicotine replacement therapy for cancer patients. Reported are results in 19 clinical practices.
Results:
Implementation of this project resulted in tobacco assessments in more than 98% of patients and increased tobacco cessation referral rates for participating practices from 15% in May 2013 to over 60% in July and September of 2013 (p &lt; .001). Total statewide referrals to the Quitline increased by between 32% and 60% over the first 6 months, with an increasing proportion of patients (between 31% and 50%) being cancer patients referred by MOQC participating sites.
FebMarAprMayJunJulAugSepOctTotal Michigan # Referrals140153153202233245238220210MOQC # Referralsn/an/an/a628812397104102MOQC Referrals % of Total Michigann/an/an/a31%38%50%41%47%49%
Conclusions:
Reducing patient barriers to access to tobacco cessation services and supplying clinic teams with scientific evidence, standard workflows, and lean tools improved the referral rate to a tobacco cessation program for oncology patients. Critical factors for success included strong physician leadership, adoption of an auto referral process, and front line staff accountability for identifying all patients who use tobacco and assessing their tobacco cessation status at subsequent clinic visits.
Citation Format: Jane Severson, Hilary Baca, Douglas Blayney, Karen Brown, Grayce Galiyas, Mara Minasian, Joan Schmidt, Anna Schulze, Graham Warren. Using a statewide collaborative approach to improve tobacco cessation referral rates for cancer patients. [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 5042. doi:10.1158/1538-7445.AM2014-5042
Abstract 5056: Perceptions related to breast cancer prevention and behavioral practices in underserved women participated in a CBPR intervention
Authors: Rahman Saleh M. M. , Harris Cynthia M. , Mitchell Miaisha , Soliman Karam F. 
Published: May 2015

Abstract
Objective: To assess perceptions, knowledge, behavioral practices in breast cancer screening among uninsured and underinsured women in Leon and Gadsden Counties in Florida.
Methods: Women recruited through Community Outreach and Preventive Services (COPS) Core of a P20 Center of Excellence for Cancer Research, Training and Community Service were surveyed as a part of preliminary evaluation (N=107).
Results: Participants ranged in age from 25 to 72 years, predominantly 50-59 years old (33%). Among these women 76% reported having a previous mammogram; however, only 21.7% have reported having a mammogram one year ago. Though 83% reported having a Clinical Breast Examination (CBE), about 24% reported having a CBE three years ago. About 66% women had a recent health care visit and about 10% reported health care visit one to two years ago. Perceived Barriers appeared to be significant factor in screening decision making process. Majority women considered not having enough money as a barrier (49%), however, 97% women agreed that no matter how expensive it is they would receive a mammogram if her doctor had ordered them. Women's knowledge about breast cancer and screening mammogram was relatively poor (mean score = 8 /17).
Conclusion: Though prevalence of screening mammogram has increased, however, financial barrier is still a significant factor in women's decision making process for screening mammogram. Intervention should target social disparity areas to improve screening utilization in underserved women.
Citation Format: Saleh M. M. Rahman, Cynthia M. Harris, Miaisha Mitchell, Karam F. Soliman. Perceptions related to breast cancer prevention and behavioral practices in underserved women participated in a CBPR intervention. [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 5056. doi:10.1158/1538-7445.AM2014-5056
Abstract 5058: MTHFR and health behaviors: A meta-analysis of epigenetic risks for breast cancer prevention
Authors: Gonzales Mildred Crisostomo , Shiao S. Pamela , Lie Amanda 
Published: May 2015

Abstract
Purpose: Breast cancer is the most common malignancy and the second leading cause of cancer death among women worldwide. Methylenetetrahydrofolate reductase (MTHFR) is one of the most studied low penetrant genes that are critical for methylation pathways for deoxyribonucleic acid (DNA) repair and normal cellular development. Methylation pathways are affected by health behaviors such as folate intake, alcohol consumption, and tobacco smoking. While there were several meta-analyses on the associations of MTHFR gene variations and BC, by far, no meta-analysis has been noted on the associations of health behaviors and MTHFR gene variations, with breast cancer.
Procedure: PubMed databases were searched by using a combination of key words including “breast cancer”, “MTHFR”, “folate”, “alcohol”, “smoking”, and “health determinants”. Initial search resulted 135 articles from 1999 to 2013. Studies were reviewed for case-control studies, and scored for quality using the standard rating indicators from Quality of Reporting of Meta-analyses. Repeated data from same authors and those with poor quality scores were excluded. Inter-rater reliabilities on data coding and quality scores were established for the selection of studies.
Findings: Preliminary results included 55 studies for a total of 22,077 breast cancer cases and 25,419 controls including 27 studies with Whites, 21 studies with Asians, and 7 studies with mixed Euramericans. Twelve studies included MTHFR gene counts with folate intake levels for 8,032 cases and 10,482 controls; 5 studies with alcohol consumption for 3,068 cases and 5,157 controls; and 5 studies with tobacco smoking status for 909 cases and 1233 controls. Preliminary analysis indicated that MTHFR 677CT was associated with increased risk of BC (P &lt; 0.005). The results also suggested that low folate intake, heavy alcohol consumption, and tobacco smoking contributed to increased risks for BC.
Conclusion: Investigating the epigenetic risks including healthy life style factors in relation to gene variations has the potential to explain the influence of health behaviors on carcinogenesis. Translating the results from the meta-analysis of health behaviors in relation to epigenetics can provide meaningful insights on the prevention of breast cancer. The findings from the meta-analysis per various race-ethnicity groups can be useful for future development of culturally sensitive and personalized interventions to prevent and reverse breast cancer by promoting the healthy methylation pathways for cancer prevention.
Citation Format: Mildred Crisostomo Gonzales, S. Pamela Shiao, Amanda Lie. MTHFR and health behaviors: A meta-analysis of epigenetic risks for breast cancer prevention. [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 5058. doi:10.1158/1538-7445.AM2014-5058