bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C12: Cancer navigation programs: Identifying barriers and addressing health disparities in Appalachia
Authors: Dwyer Sharon , Rohan Elizabeth , White Dana , Stockton Eric , Castro Georgina , Wilson Reda , White Carol , Dignan Mark
Published: February 2019

The Appalachian region includes 13 states comprising 420 counties, beginning in the north in southern New York and following the Appalachian Mountains to Mississippi. The region has unique natural beauty and a heterogeneous population that shares distinct cultural characteristics but with high rates of unemployment, low income, and high rates of chronic disease, including cancer. Patient Navigation (PN) can address barriers and enhance access to cancer screening and care through the use of individual navigators who are sensitive to the needs, interests, and values of the community. Although there are numerous PN training programs available, there are no known programs specific to the Appalachian population. An electronic survey was distributed in 2011 and again in 2015/16 to better understand the cancer navigation programs in all 13 states of the Appalachian states and how they serve the regional population. In both waves of the survey over 150 responses were received from navigators, program directors, and supervisors. Survey results identify where cancer navigation programs take place (hospitals, health centers, and cancer centers), which health professionals fill the role of navigators (social workers, nurses, health educators), where navigation programs reside in health organizations (breast care centers, infusion centers, social services, and cancer centers), what aspects of the cancer continuum are addressed (prevention, screening, treatment to survivorship), and what range of services are provided by navigation programs (from education, referrals, to financial and spiritual support). A summary and comparison of quantitative data will be reported supplemented with qualitative findings and open-ended responses.

Citation Format: Sharon Dwyer, Elizabeth Rohan, Dana White, Eric Stockton, Georgina Castro, Reda Wilson, Carol White, Mark Dignan. Cancer navigation programs: Identifying barriers and addressing health disparities in Appalachia [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C12.
Abstract C32: [Advocate Abstract:] Survivorship and African American women diagnosed with MBC
Authors: Florence Yvonne McLean
Published: February 2019

The poster will highlight the state of survival for African American women diagnosed with MBC.

Citation Format: Yvonne McLean Florence. [Advocate Abstract:] Survivorship and African American women diagnosed with MBC [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C32.
Abstract C51: Definitive radiation therapy for cervical cancer: Race as a risk factor for delayed completion, preliminary findings
Authors: Petersen Shariska , Davydov Dmitry , Davydova Yafa , FitzGerald Michael , Buekers Thomas
Published: February 2019

Objective: To assess whether racial disparities exist in time to completion of external beam pelvic radiation therapy and brachytherapy in cervical cancers treated with definitive chemoradiation.

Methods: A retrospective analysis was conducted on all cervical cancer patients treated with definitive radiotherapy between 2006 and 2016. Analyses were performed according to the following distinct definitions of wait times: interval from pathologic diagnosis of cervical cancer to (1) initiation of radiation therapy, (2) completion of external beam radiation therapy, and (3) completion of brachytherapy. The duration of external beam radiation therapy and brachytherapy was also calculated.

Results: A total of 50 women underwent primary external beam pelvic radiation therapy for cervical cancer at our institution over a 10-year period. Of 50 women, 21 self-identified as White, 25 as African-American (AA), and 4 as Hispanic. Due to small numbers, Hispanic women were excluded. Thus, a total of 46 patients were analyzed. The average age was 52 years for both White and AA women in this cohort.

Mean days to initiation of radiation therapy was 42.5 days: 33.7 days (median 32 days) among White patients versus 49.8 days (median 40 days) for AA patients (p-value 0.058). Mean days from diagnosis to completion of pelvic radiation therapy was 81.4 days: 70.9 days (median 69 days) among White patients versus 90.3 days (median 84 days) among AA (p-value 0.026). Mean days from diagnosis to completion of brachytherapy were noted to be 87.1 days for White patients and 103.7 days for AA patients (p-value 0.035). The duration of ERBT and brachytherapy was 57.2 for White patients and 56.6 for AA patients (p-value 0.818).

Conclusion: African-American patients experienced delays to initiating radiation therapy, which resulted in delays to completing external beam radiation and brachytherapy. However, there was no difference in the duration of treatment between groups. Therefore, we conclude that once patients begin treatment, they complete treatment within the similar time frame of 57 days regardless of race. Studies to determine the effect of delayed initiation on survival outcomes are under way. Directed patient navigation programs may be helpful to decrease the delay to initiating radiation therapy for African-American patients.

Citation Format: Shariska Petersen, Dmitry Davydov, Yafa Davydova, Michael FitzGerald, Thomas Buekers. Definitive radiation therapy for cervical cancer: Race as a risk factor for delayed completion, preliminary findings [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C51.
Abstract C60: The role of psychosocial predictors in HBV screening behavior among Vietnamese Americans
Authors: Lee Minsun , Zhu Lin , Wang Min Qi , Wei Zhengyu , Tan Yin , Nguyen Minhhuyen , Ogunwobi Olorunseun O. , Ma Grace X.
Published: February 2019

Objectives: Given the substantial disparity in hepatitis B virus (HBV) infection among Vietnamese Americans, it is important to understand what intervention components facilitate behavioral change. In this study, we evaluated the influence of psychosocial factors on HBV screening.

Methods: The study sample consists of 1,716 Vietnamese participants in our HBV intervention trial, recruited from 36 community-based organizations in Pennsylvania, New Jersey, and New York City between 2009 and 2014. Using Health Belief Model and Social Cognitive Theory, we measured self-efficacy, knowledge, perceived barriers, perceived benefits, perceived severity, and risk susceptibility. Analysis of covariance (ANCOVA) was used to compare pre- and post-intervention changes of psychosocial variables. Structural equation modeling (SEM) was used to explore the direct and indirect effects of the psychosocial variables on HBV screening.

Results: Knowledge, self-efficacy, perceived benefits, and perceived barriers were directly associated with HBV screening, with knowledge having the strongest effect. Perceived severity and risk susceptibility had indirect association with HBV screening through other variables. Indirect paths among the 6 psychosocial variables were also identified.

Conclusions: To promote HBV screening among Vietnamese Americans, intervention efforts should focus on increasing knowledge, self-efficacy, and perceived benefits; decreasing perceived barriers; and account for the dynamic cognitive processing.

Citation Format: Minsun Lee, Lin Zhu, Min Qi Wang, Zhengyu Wei, Yin Tan, Minhhuyen Nguyen, Olorunseun O. Ogunwobi, Grace X. Ma. The role of psychosocial predictors in HBV screening behavior among Vietnamese Americans [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C60.
Abstract C62: Sub-Saharan African immigrant men's knowledge and support related to cervical cancer screening: A qualitative descriptive study
Authors: Adegboyega Adebola , Hatcher Jennifer
Published: February 2019

Background: Cervical cancer screening disparity puts sub-Saharan African immigrant women at an increased risk for development of invasive cervical cancer. Several studies have identified various factors influencing cervical cancer screening use among sub-Saharan African immigrants in the United States. One of such factors is the role of spousal support; African men are often the gatekeepers of health for their families and have significant influence on the health-seeking behavior of their wives/female partners. However, limited research exists on men's knowledge and support related to Pap screening. Thus, we conducted a qualitative descriptive study to assess knowledge and support related to Pap screening among sub-Saharan African immigrant men in Lexington, Kentucky.

Method: In-depth individual interviews using semistructured guide were conducted with 21 sub-Saharan African immigrant men who were married or in committed relationships. Data were audio recorded, transcribed verbatim, and analyzed using content analysis.

Results: The average age of the study participants was 36 ± 9; 53% have lived in the US for more than 5 years; 88% were college educated; 43% make more than $50,000 annually; and 62% were married. General knowledge of Pap screening, cervical cancer, and HPV's role in the etiology of cervical cancer was minimal. Men showed the desire to support their wives/female partners to have a Pap screening. All participants preferred to be carried along and informed about their wives' decision to have a Pap screening in order to provide any support that might be needed. The narratives related to health care providers' gender preference varied among men; several men showed preference for a female health care provider for Pap screening services for their wives/female partners while others showed no preference.

Conclusions: These findings underscore the importance of men's support in promoting Pap screening among sub-Saharan African immigrant women. Men should be included in cervical cancer prevention efforts to leverage their support. Thorough understanding of African family dynamics, cultural norms, and values related to preventive health care seeking is essential to the design and implementation of interventions for improving Pap screening among sub-Saharan African immigrant women.

Citation Format: Adebola Adegboyega, Jennifer Hatcher. Sub-Saharan African immigrant men's knowledge and support related to cervical cancer screening: A qualitative descriptive study [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C62.
Abstract C79: Examining the role of cultural competence in mammography adherence: Perceptions of African American residents of Harris County, Texas
Authors: Hall Marla B. , Guidry Jeffrey J. , Jones Lovell A.
Published: February 2019

Breast cancer mortality has affected African American women at a disproportionate rate. There are various factors contributing to this outcome, with medical mistrust identified as a significant determinant of screening adherence. The purpose of this research was to assess how perceptions of health professionals' cultural competence influenced African American women's barriers to and receipt of mammograms. To recruit participants, researchers first identified locations with large proportions of African American persons. This included grocery stores, local community centers, churches, strip malls, hair salons, and restaurants. At each site, significant efforts were made to personally interact with community members. Personal interaction included, as often as possible, matching the race/ethnicity and gender of the research team member with the potential participant. Sixty-one African American women residing in Harris County, Texas, shared their views within a series of focus groups. Participants noted various factors associated with mammography compliance. Firstly, lack of professionalism among clinicians and clerical staff caused a decrease in health care services utilization and procedural adherence. In addition, cultural insensitivity and discriminatory behavior strengthened attitudes of medical mistrust. Therefore, improving patient–provider communication, through culturally appropriate capacity building initiatives, is a beneficial strategy to facilitate healthful engagement of medically underserved and racial/ethnic minority populations.

Citation Format: Marla B. Hall, Jeffrey J. Guidry, Lovell A. Jones. Examining the role of cultural competence in mammography adherence: Perceptions of African American residents of Harris County, Texas [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C79.
Abstract IA13: Understanding cancer disparities in mortality and survivorship and social and built environments
Authors: Shariff-Marco Salma
Published: February 2019

Neighborhoods have been shown to influence health outcomes through a number of pathways--environmental exposures, material deprivation (e.g., inadequate housing), psychosocial mechanisms (e.g., stress and social support), health behaviors (e.g., physical activity, smoking, diet), and access to resources--factors that likely impact mortality and survivorship after a cancer diagnosis. Using data from the California Neighborhoods Data System to characterize the social and built environments, this presentation will include findings from two studies examining associations between neighborhood and cancer mortality as well as health-related quality of life across diverse populations. In addition, this presentation will highlight methods for characterizing the social and built environments for cancer outcomes studies, including the use of latent class analyses for developing neighborhood archetypes. Assessing the impact of the social and built environments on cancer outcomes is the first step towards accounting for and addressing neighborhood context in cancer-survivorship trajectories.

Citation Format: Salma Shariff-Marco. Understanding cancer disparities in mortality and survivorship and social and built environments [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA13.
Abstract IA39: Explaining the obesity paradox in cancer: The role of muscle
Authors: Caan Bette
Published: February 2019

Although overweight and obesity, assessed by body mass index (BMI), are reliably related to an increased risk of cancer, data on the relationship between BMI and cancer prognosis are inconsistent. An emerging literature suggests that the relationship between BMI and cancer survival is often U-shaped and that overweight, and in some cases mild obesity, may not increase risk and might even offer protection. This is termed the “obesity paradox” and has been demonstrated in patients with lymphoma, leukemia, colorectal, endometrial, thyroid, and renal cancers.

Reasons provided to explain the obesity paradox in cancer include methodologic biases such as reverse causality, confounding, detection bias, or collider bias. Yet others posit that the association reflects true benefits of a higher BMI, including extra nutritional reserves, greater muscle mass, a lower likelihood of dose-limiting toxicity, and less aggressive tumors, each of which may be independently associated with better prognosis.

We will present evidence of the obesity paradox in breast and colorectal cancer. We will also present data on the importance of adequate muscle reserves to optimal cancer outcomes and explain how muscle may explain the U-shaped relationship between BMI and survival in these cancers. We will show that BMI is not an accurate measure of either adiposity or muscle, especially among cancer survivors. We will illustrate that when BMI is used to measure body size, an obesity paradox can emerge because “overweight” patients often have higher levels of protective muscle but lack adiposity levels sufficient to increase their risk of mortality.

Citation Format: Bette Caan. Explaining the obesity paradox in cancer: The role of muscle [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA39.
Abstract A12: Non-small cell lung tumor-derived autoantibodies can distinguish benign from malignant pulmonary nodules
Authors: Lastwika Kristin J. , Kargl Julia , Zhang Yuzheng , Zhu Xiaodong , Shelley David , Lo Edward , Wu Wei , Pipavath Sudhakar N. , Kinahan Paul E. , Houghton A. McGarry , Lampe Paul D.
Published: February 2019

High-risk smokers are currently being screened with low-dose CT imaging after the National Lung Screening Trial demonstrated a 20% reduction in lung cancer mortality. Unfortunately, small pulmonary nodules are a common finding in smokers (present in 25-50%), with very few (<2.5%) nodules ultimately determined to be cancer. We observed a 4-fold increase in lung tumor-associated B cells compared to normal lung and hypothesized that lung-tumor derived autoantibodies could be useful biomarkers for malignant nodule diagnosis. We first discovered 13 IgG or IgM autoantibodies found in both non-small cell lung tumor and peripheral plasma (n=10) on a large (~17,000) protein array. These autoantibodies were predominantly absent in plasma from patients with benign nodules (n=10). In the plasma from an expanded nodule positive cohort (n=250) we validated 3/13 autoantibodies on a targeted protein array and 5/13 autoantibodies on a high-density antibody array. By using both antibody arrays (to measure antigen-autoantibody complexes) and protein arrays (to measure free autoantibody), we obtained a comprehensive picture of malignant nodule-associated autoantibodies. When we combine our top two autoantibodies (one free and one complexed with antigen) with two features from CT images, they yield an AUC = 0.92 (72% sensitivity at 90% specificity). These observations indicate that our noninvasive autoantibody biomarkers can increase the diagnostic accuracy of pulmonary nodules identified by CT imaging.

Citation Format: Kristin J. Lastwika, Julia Kargl, Yuzheng Zhang, Xiaodong Zhu, David Shelley, Edward Lo, Wei Wu, Sudhakar N. Pipavath, Paul E. Kinahan, A. McGarry Houghton, Paul D. Lampe. Non-small cell lung tumor-derived autoantibodies can distinguish benign from malignant pulmonary nodules [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A12.
Abstract A18: Diagnostic and prognostic utility of urinary creatine riboside for early stage non-small cell lung cancer
Authors: Oike Takahiro , Kanke Yasuyuki , Parker Amelia , Haznadar Majda , Krausz Kristopher W. , Bowman Elise D. , Robles Ana I. , Gonzalez Frank J. , Harris Curtis C.
Published: February 2019

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR02) of the Conference Proceedings.

Citation Format: Takahiro Oike, Yasuyuki Kanke, Amelia Parker, Majda Haznadar, Kristopher W. Krausz, Elise D. Bowman, Ana I. Robles, Frank J. Gonzalez, Curtis C. Harris. Diagnostic and prognostic utility of urinary creatine riboside for early stage non-small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A18.
Abstract B05: Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma
Authors: Chung Chaeuk , Lee Daehye
Published: February 2019

Developments of EGFR-TKI and immunotherapy targeting the PD1/PD-L1 pathway are considered the most important medical breakthroughs in lung cancer treatment. Nowadays, third-generation EGFR TKI is widely used for T790M positive first and second EGFR-TKI resistant lung cancer patients. Immunotherapy is powerful option for lung cancer patients without drug targets and chemotherapy-resistant patients. It also has changed the concept of conventional anticancer therapy in the point of regulating tumor microenvironment. There are many studies linking these two important pathways. Recent studies demonstrated that PD-L1 expression is significantly correlated to the mutation status of EGFR, and activation of EGFR signaling can also induce the expression of PD-L1. However, the real linker between PD-L1 and EGFR signaling remains to be revealed. Our previous study revealed that the Hippo pathway effector YAP confers EGFR-TKI resistance in lung adenocarcinoma, and inhibition of YAP restores sensitivity to EGFR-TKIs. Thus, we examined whether PD-L1 is relevant in terms of conferring EGFR-TKI resistance and whether YAP directly regulates the expression of PD-L1 in this context. First, we compared the expression levels of PD-L1 and YAP between EGFR-TKI-resistant PC9 cells and the parental PC9 adenocarcinoma cells. The expression levels of both YAP and PD-L1 were markedly higher in the EGFR-TKI-resistant cells compared to the parental cells, suggesting differential expression pattern between two cell types. YAP knockdown significantly decreased the expression of PD-L1 in the EGFR-TKI-resistant cells, while YAP overexpression increased the expression of PD-L1 in the parental PC9 cells. Then, our results revealed that YAP regulates the transcription of PD-L1, and the YAP/TEAD complex binds to the PD-L1 promoter. Surprisingly, knockdown of PD-L1 was sufficient to decrease cell proliferation and wound healing in the EGFR-TKI-resistant PC9 cells. These data suggest a PD1-independent oncogenic function of PD-L1. The Hippo effector YAP plays a crucial role in linking the PD-L1 and EGFR-TKI resistance by directly regulating the expression of PD-L1 in lung cancer. Targeting PD-L1 directly or via YAP could provide an effective therapeutic strategy for EGFR-TKI-resistant lung

Citation Format: Chaeuk Chung, Daehye Lee. Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B05.
Abstract B06: Targeted radiopeptide therapy re188-P2045 to treat neuroendocrine lung cancer
Authors: Adams Chris , Shinto Ajit , Saif Wasif
Published: February 2019

Background: Despite the recent success of checkpoint inhibitors, there continues to be a significant medical need for lung cancer therapies that can be directed to the patients most likely to respond. Somatostatin receptor subtype 2 (SSTR2) is the most widely upregulated subtype in both small and non-small cell lung cancers and is also expressed in tumoral (but not mature) blood vessels. Peptide-targeted radiotherapy has advantages over traditional targeted therapies in that targeted tumor cells as well as surrounding cancer cells and supporting stroma are selectively killed. This study was conducted to determine the ability of Rhenium Re 188 P2045, a radiolabeled somatostatin analog specific for SSTR2 to both image (to select the most appropriate patients) and treat lung and neuroendocrine cancer patients who overexpress somatostatin receptors.

Methods: In an open-label, single-arm study, refractory lung cancer and metastatic neuroendocrine patients to standard-of-care therapy were identified by image analysis using Rhenium Re 188 P2045, a radiolabeled somatostatin analog. Twenty-five patients received the imaging dose of 10uCi of Re188 and 265ng of peptide by intravenous injection. Three patients were selected based on high SSTR expression levels to receive 30uCi of Re188 P2045 as a therapeutic dose 14 days after imaging. Patients were followed for 8 weeks post treatment.

Results: The imaging study revealed a high density of expression of the somatostatin receptor in the lungs of patients. Patients in the imaging and therapeutic treatment groups reported no adverse advents or signs of toxicity. The image analysis using Re188 P2045 was compared to CT images and demonstrated accurate detection of lung and neuroendocrine tumor lesions. The patients who received R188 P2045 at the therapeutic dose had a 25% reduction in tumor mass based on image analysis versus typical results of stable disease from standard of care. The images obtained using Re188 P2045 were of sufficiently high quality to enable identification of receptor expression at the tumor site as shown in Figures 1 and 2 (figures not available).

Conclusions: Rhenium Re 188 P2045, a radiolabeled somatostatin analog, may be used to both identify and treat lung and neuroendocrine cancer tumors. The ability to image and dose patients with the same targeted molecule enables a personalized medicine approach, and this highly targeted patient therapy may significantly improve treatment of tumors that overexpress somatostatin receptors.

Citation Format: Chris Adams, Ajit Shinto, Wasif Saif. Targeted radiopeptide therapy re188-P2045 to treat neuroendocrine lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B06.
Abstract B09: Evaluating transcription factor networks as targets for the treatment of small cell lung cancer
Authors: Pozo Karine , Kollipara Rahul K. , Minna John D. , Gazdar Adi F. , Johnson Jane E.
Published: February 2019

Achaete-scute homolog 1 (ASCL1) is a transcription factor that is highly expressed in most small cell lung cancer (SCLC) tumors and cell lines and is critical for their proliferation. Inhibiting ASCL1 transcriptional activity may thus be a valid therapeutic strategy for SCLC. However, transcription factors (TFs) have been historically difficult to target. Given that TFs belong to complex regulatory networks, we propose to identify and target multiple components within an ASCL1-transcriptional network rather than ASCL1 alone. We have previously detected ASCL1-bound genomic regions associated with the active chromatin epigenetic mark, H3K27Ac in SCLC cells. Here we report the identification of an ASCL1-containing transcriptional network in SCLC cells and evaluate its targeting by the transcriptional inhibitor, mithramycin. We conducted chromatin immunoprecipitation (ChIP) by immunoprecipitating the H3K27Ac chromatin mark from NCI-H2107 and NCI-H69 SCLCs (5X107 cells) nuclear lysates with10 μg H3K27Ac antibodies (Abcam-Ab4729), and sequenced ChIP libraries on an Illumina High-Seq2000. Further characterization using siRNA transfections, immunoblotting and MTS-cell proliferation assays were conducted following standard procedures. We found 82 overlapping TF genes, including lineage-specific TF genes for ASCL1, Forkhead box protein A2 (FOXA2), and nuclear factor 1 B-type (NFIB), associated with the active chromatin epigenetic marks H3K27Ac in SCLC cell lines. This suggests that ASCL1, FOXA2, and NFIB may belong to the same transcriptional network. siRNA-mediated knockdown of ASCL1 leads to decreased FOXA2 levels, but it has no effect on NFIB levels, implicating ASCL1 as a transcriptional regulator of FOXA2 but not NFIB. Mithramycin stops cell proliferation and reduces ASCL1, FOXA2 but not NFIB protein levels. In conclusion, our studies identify the beginning of a transcriptional network necessary for SCLC proliferation in which ASCL1 regulates FOXA2. Targeting multiple TFs within a network with mithramycin can stop cell proliferation and as such suggests a therapeutic strategy for SCLC. Because of the importance of NFIB in mediating metastatic behavior of SCLC, these data indicate that approaches other than targeting ASCL1 and use of mithramycin will be needed to target NFIB.

Citation Format: Karine Pozo, Rahul K. Kollipara, John D. Minna, Adi F. Gazdar, Jane E. Johnson. Evaluating transcription factor networks as targets for the treatment of small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B09.
Abstract IA24: Are tumors predictable? Inherited immune variation constrains tumor evolution
Authors: Marty Rachel , Kaabinejadian Saghar , Rossel David , Slifker Michael J. , Haar Joris Van de , Engin Hattice Billur , Prisco Nicola de , Ideker Trey , Hildebrand William H. , Font-Burgada Joan , Carter Hannah
Published: February 2019

Recent studies have characterized the extensive somatic alterations that arise during cancer, and various studies have probed rare inherited mutations that lead to early-onset cancer syndromes. However, little is understood about the role of genetic background in “sporadic” adulthood cancers. The somatic evolution of a tumor may be significantly affected by inherited polymorphisms carried in the germline. The region encoding the Major Histocompatibility Complex Class I (MHC-I) is one of the most variable regions in the human population. MHC-I is a molecule that exposes the intracellular protein content of a cell on the cell surface, allowing T cells to detect mutated or foreign peptides. Each individual carries six MHC-I alleles that define the set of peptides that can be effectively presented for immune surveillance. We hypothesized that individual variation in MHC-I could create personal gaps in immune surveillance, generating individual-specific susceptibility for cells to acquire specific oncogenic mutations. We tested this hypothesis through the development and application of a residue-centric patient presentation score to 1,018 recurrent oncogenic mutations in 9,176 cancer patients. This analysis found that cancer-causing mutations were more likely to be observed when a patient’s genotype-based scores suggested poor MHC-I based presentation of those mutations. Mutations that were poorly presented by most patients were also more likely to reach high frequency among tumors. Thus the landscape of oncogenic mutations observed in clinically diagnosed tumors is shaped by MHC-I genotype-restricted immunoediting during tumor formation, and individual MHC-I genotype provides information about the mutations likely to emerge in tumors that develop later in life.

Citation Format: Rachel Marty, Saghar Kaabinejadian, David Rossel, Michael J. Slifker, Joris Van de Haar, Hattice Billur Engin, Nicola de Prisco, Trey Ideker, William H. Hildebrand, Joan Font-Burgada, Hannah Carter. Are tumors predictable? Inherited immune variation constrains tumor evolution [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA24.
Abstract IA29: Circulating Tumor Cells: A liquid biopsy for SCLC with multiple applications
Authors: Dive Caroline
Published: February 2019

Circulating Tumor Cells (CTCs) are relatively prevalent in SCLC compared to other tumor types and present several research opportunities in a disease where tumor biopsy is challenging, and notably so when repeated sampling is required.

Pre-treatment CTC number by the CellSearch platform (CS-CTCs) is prognostic for overall survival and in most patients decreases significantly after cycle 1 of platinum-based chemotherapy. The prevalence and wide dynamic range of CS-CTC numbers makes them an ideal pharmacodynamic biomarker, and their prevalence affords assay development and implementation as a predictive biomarker in upcoming trials of novel treatments. Recently we showed that chemotherapy response could be predicted via single CTC sequencing to generate a CTC copy number signature (Carter et al., Nat Med 2017).

SCLC patients’ CTCs are also highly tumorigenic in immune-compromised mice (Hodgkinson et al., Nat Med 2014). CDX mirror patient tumor histology and chemotherapy response. The resultant CTC-derived explant models (CDX) can be generated not only at baseline but also from the same patient at disease progression, allowing studies of the almost universal acquired chemotherapy resistance and insights into the rapid evolution of this dismal disease. CDX are used for therapy testing and biomarker development that can be translated to CTC-based biomarkers in the clinic. CDX allow exploration of SCLC biology as we recently exemplified by the identification of vasculogenic mimicry and its likely role in metastasis (Williamson et al., Nat Commun 2016). CDX tumors can be disaggregated and propagated in culture for more rapid treatment screening and can be genetically manipulated for function testing hypotheses ex vivo and in vivo. Finally, SCLC CTCs can now be cultured directly from the patient sample, offering the potential for real-time treatment testing. In summary, SCLC CTC research can now make a valuable contribution to the worldwide efforts to molecularly profile this recalcitrant tumor at all stages of disease progression and to discover, develop, and implement new treatments for much-needed improved patient outcomes.

Citation Format: Caroline Dive. Circulating Tumor Cells: A liquid biopsy for SCLC with multiple applications [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA29.
Abstract A008: Neoadjuvant nivolumab, gemcitabine and cisplatin in muscle-invasive bladder cancer: Study update
Authors: Gupta Shilpa , Weight Christopher J. , Agarwal Neeraj , Gupta Sumati , Konety Badrinath , Gibb Ewan , Davicioni Elai , Thyagarajan Bharat , Sonpavde Guru
Published: February 2019

Background: Cisplatin-based neoadjuvant chemotherapy in muscle-invasive bladder cancer (MIBC) improves survival which correlates with pathologic response (PaR) at radical cystectomy (RC). Immunotherapy with checkpoint inhibitors has improved outcomes in advanced bladder cancer and immunotherapy is synergistic with chemotherapy. Our ongoing trial is aimed at studying the efficacy and safety of nivolumab (N)with gemcitabine-cisplatin (GC) as neoadjuvant therapy for MIBC (NCT03294304). Methods: This is a single-arm, multicenter phase II study for patients with MIBC eligible for neoadjuvant GC and planned for RC. Forty-one patients will be treated with N+ GC every 21 days for 4 treatment cycles over 12 weeks followed by RC. The primary endpoint is PaR. Key inclusion criteria are presence of MIBC (predominantly urothelial carcinoma) with clinical stage T2-T4a and N≤1 disease (solitary lymph node measuring < 2 cm) and M0 and deemed eligible for radical cystectomy, ECOG PS of 0 or 1, Cr Cl ≥ 50 ml/min, adequate organ function, eligible to receive GC and no contraindications to receiving N. Patients will receive C (70mg/m2) IV on D1, G (1000mg/m2) on D1,D8 and N (360 mg) IV on D8 every 21 days for 4 cycles followed by radical cystectomy within 6-8 weeks. Secondary objectives are to determine safety of combination of N+GC in pts with MIBC prior to RC and PFS. The correlative objectives include: 1) correlation of whole-genome sequencing (WGS) of the pre-treatment bladder cancer biopsy with PaR; 2) correlation of molecular subtypes of bladder cancer using Genomedx to evaluate whether addition of N alters the response to neoadjuvant GC; 3) correlation of PD-L1 expression in tumor tissue at baseline with PaR; 4) Nanostring pancan immune panel gene expression will be studied at baseline and at RC. At the time of submission of this abstract, 12/41 pts. have been enrolled and the combination has not resulted in any added toxicities or immune-related AEs so far. There were no delays in RC. PaR and correlative analysis is ongoing in enrolled pts. and further enrollment is ongoing.

Citation Format: Shilpa Gupta, Christopher J. Weight, Neeraj Agarwal, Sumati Gupta, Badrinath Konety, Ewan Gibb, Elai Davicioni, Bharat Thyagarajan, Guru Sonpavde. Neoadjuvant nivolumab, gemcitabine and cisplatin in muscle-invasive bladder cancer: Study update [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A008.
Abstract A015: Cellular immunomonitoring for personalized adoptive cellular therapy trial ACTolog® (IMA101-101)
Authors: Mendrzyk Regina , Ulges Alexander , Demberg Thorsten , Stephens Geoffrey , Reinhardt Carsten , Walter Steffen , Maurer Dominik
Published: February 2019

Adoptive cellular therapy (ACT) has dramatically changed the landscape of immunotherapy; however, only a small proportion of solid tumor patients have benefited from these advances due to i) heterogeneity of tumor antigen expression, ii) tumor escape (e.g., only one target is addressed), or iii) off-target toxicities (e.g., expression of targets on normal tissues). ACTolog® concept, utilizing antigen specific T-cells (IMA101), identified by the Immatics’ proprietary XPRESIDENT® technology, is intended to overcome these limitations by introducing multiple novel tumor targets. ACTolog® is a personalized ACT approach in which autologous T-cell products are manufactured against the most relevant tumor target peptides for individual patients whose tumors are positive against a predefined target warehouse. Target positive tumors are identified by qPCR. Expression levels predictive for antigen presentation are determined by mass spectrometry. Autologous T-cells against ACTolog targets are in vitro primed in the presence of IL-21 followed by HLA tetramer-guided cell sorting and expansion prior to infusion. IMA101-101 is a first-in-human clinical trial in HLA-A*02:01 positive patients with relapsed or refractory solid tumors using the multitargeted ACTolog® approach in which up to four products with different tumor target-specificities are manufactured and infused for each patient. We developed two flow cytometric phenotyping assays that allow us to determine the frequency of target-specific cells in the final product and persisting cells in the blood as well as to deeply characterize the memory marker expression (CD45RA, CCR7, CD27, CD28, CD45RO, CD62L, CD57, CD127) and immune checkpoint expression (CD137, LAG-3, PD-1, TIGIT, TIM-3) of target-specific cells. Product characterization and initial persistence data of the three first treated patients revealed a high prevalence of persisting target-specific cells in the blood until 2 months after infusion as well as a favorable phenotype of target-specific cells. At the conference 6 months’ data for one patient will be available and presented.

Citation Format: Regina Mendrzyk, Alexander Ulges, Thorsten Demberg, Geoffrey Stephens, Carsten Reinhardt, Steffen Walter, Dominik Maurer. Cellular immunomonitoring for personalized adoptive cellular therapy trial ACTolog® (IMA101-101) [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A015.
Abstract A026: Novel electroporation method for quick CAR-T-cell manufacture
Authors: Chen Jian , Xia Xiaofeng
Published: February 2019

CAR-T-cells are currently manufactured for clinical use by infection of human T-cells with viral vectors containing the CAR gene. T lymphocytes have to be stimulated and expanded ex vivo because the viral vectors infect fresh natural lymphocytes very poorly. The viral vector approach is extremely expensive due to the high cost of virus production and the high cost of long-term cell expansion that could take 10-14 days in a GMP facility. The viral vector approach also has a huge biologic downside: ex vivo expanded T-cells become bulky and lose efficacy against tumor cells. The use of electroporation technology in CAR-T-cell manufacturing has attracted increasing interests for its low cost and the wide range of applications, including transposon based stable CAR expression, transient expression and genome editing. However, actual clinical use of electroporation technology in CAR-T has been difficult and several clinical trials have met significant problems due to the poor transfection efficiency and decreased T-cell survival with traditional electroporation methods. Through theoretical analysis of the other existing electroporation technologies, we found that they all have problems in electrophysical design. The problems include physical design of devices, electrical pulse selection, and buffer composition. With a redesigned electroporation system, we can now achieve very high transfection efficiency for T-cells while maintaining cell survival. For Sleeping Beauty transposon-based CAR expression, we found that over a period of two to three weeks the efficiency can get to 60% to 90% with fasT-cell proliferation. The protein expression time after electroporation is very short. For simple GFP plasmids we can observe GFP expression after only 30 minutes. Unlike viral vectors, electroporation works well on fresh natural T-cells, thereby eliminating the need for expensive cell expansion and virus production altogether and cutting the huge economic burden of CAR-T therapy. By reinfusion of more natural T-cells, the antitumor efficacy of CAR-T-cells could be improved while the side effects of cytokine release syndrome could be minimized.

Citation Format: Jian Chen, Xiaofeng Xia. Novel electroporation method for quick CAR-T-cell manufacture [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A026.
Abstract A048: Targeting the tumor microenvironment to enhance immunotherapy against cancer
Authors: Slaney Clare Y. , Oliver Amanda J. , Kershaw Michael H.
Published: February 2019

Immunotherapies that harness the immune system against cancer are an attractive proposition for cancer treatment. While there have been some promising successes, only a small fraction of patients obtain clinical benefit. It has become clear that the immunosuppressive tumor microenvironment (TME) is a major obstacle for immunotherapies, because the TME suppresses immune responses, leading to reduced efficacy. We previously demonstrated that the site of tumor growth is a major determinant in sculpting the organ-specific TME, and thus predisposes treatment efficacy (1). In this project, we hypothesize that the TME of visceral tumors is more immunosuppressive than those of the tumors growing elsewhere. We investigated in murine models the difference in the TME in breast cancer growing orthotopically and the same breast cancer growing in the common metastatic sites, such as the lungs. Our findings showed that the breast cancer growing in the lungs was resistant to immunotherapies such as anti-PD1 and anti-CTLA-4, whereas the breast cancer growing orthotopically could be completely eradicated even when the cancer burden was greater. Through an institutional prospective community-based rapid autopsy program (CASCADE), we obtained genetically matched metastases and surrounding tissues from several sites in the same breast cancer patients and investigated the TME from these tumors using novel technologies such as RNAseq and multiplex immunohistochemistry. Strikingly, the TMEs from the same organs in different patients have similar immune gene expression profiles and in contrast, TMEs from the same patient differ greatly in different organs. Together, our research demonstrates an organ-specific difference between TMEs that leads to different responses to therapies. We anticipate that further study of how cancer cells sculpt the TME at different sites will greatly enhance our understanding of the TME and provide promising targets to enhance current immunotherapies, especially for patients who do not respond to existing therapies. Reference: 1. Devaud C., et al. Molecular Therapy 2014;22:18-27.

Citation Format: Clare Y. Slaney, Amanda J. Oliver, Michael H. Kershaw. Targeting the tumor microenvironment to enhance immunotherapy against cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A048.
Abstract A055: Lineage–tracing reveals a unique contribution of embryonic macrophages to NSCLC progression
Authors: Casanova Maria
Published: February 2019

Macrophages are the professional phagocytes of the innate immune system required to remove cellular debris and maintain tissue homeostasis. However, they can also play a role in the pathophysiology of many diseases. In non-small-cell lung carcinoma (NSCLC), macrophages constitute one of the major leukocyte subsets founds in tumors and contribute to immunosuppression by releasing growth factors, inhibiting immune T-cell surveillance, and enhancing angiogenesis, among other mechanisms. Importantly, macrophages in the lung can arise from embryonic or from adult hematopoietic precursors derived from the bone marrow (BM). This dual source of phagocytes has long been ignored and their contribution to tumor progression and response to immunotherapy has remained largely unexplored. Here we propose to analyze the role of macrophages during early and late stages of NSCLC. Using lineage-tracing murine models, tumor spheroids, and high-dimensional techniques to capture macrophage heterogeneity within the lesions (scRNAseq), we found that embryonic macrophages are progressively excluded from the tumor mass, whereas BM-derived ones are evenly distributed. Depletion of embryonic macrophages in a pretumor implantation setting diminishes tumor size and metastasis and leads to an increase in T-cell infiltration and antitumor activity, whereas elimination of tissue-resident macrophages post-tumor implantation does not impact tumor burden or immunity. Importantly, early human NSCLC lesions (stage I) show reduced macrophage infiltrates within the tumor microenvironment, which correlate with poor T-cell infiltration. Our findings suggest that macrophage ontogeny plays a pivotal role in tumor immunity. In this context, we aim to develop novel immunotherapies that harness embryonic macrophages to prevent tumor progression during early phases of lung cancer.

Citation Format: Maria Casanova. Lineage–tracing reveals a unique contribution of embryonic macrophages to NSCLC progression [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A055.