bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 633: Induction of ADCC resistance profoundly alters tumor cell phenotype and stress response
Authors: Aldeghaither Dalal S. , Murray Joseph C. , Roth Sarah M. , Fertig Elana J. , Tang Shaojun , Jablonski Sandra A. , Weiner Louis M. 
Published: July 2017

Abstract
Antibody dependent cellular cytotoxicity (ADCC) is one mechanism by which monoclonal antibodies (mAb) work. In addition to ADCC, mAbs act on their target by causing signal perturbation and complement activation. Cetuximab is an EGFR targeting mAb used to target EGFR overexpression and amplification seen in many types of cancer. While mechanisms of resistance to EGFR targeted therapy have been extensively studied, resistance to ADCC has not, mainly due to the lack of ADCC-resistance models for study. To address this limitation we established a model system for anti-EGFR ADCC using NK92-CD16V effector cells, cetuximab, and the high EGFR-expressing squamous cell carcinoma cell line A431. Continuous A431 exposure to ADCC yielded an ADCC resistant phenotype (ADCCr) that exhibits a stable phenotype in the absence of continued ADCC selection. We have explored: ADCCr cell gene expression profile, NK cell activation, metabolic signature and subsequent RPPA analysis to further understand the causes and properties associated with this resistance. This ADCCr cell line has a distinctive transcriptional profile highlighted by overexpression of histone- and interferon-related genes, reduced sensitivity to antimetabolites, DNA-intercalating and ABC transporter-regulated cytotoxic agents. Intense ADCC selection causes epigenetic modification and stress response characterized by the transcriptional overexpression of PCAF (KAT2B), which initiates histone hyper-acetylation and epigenetic changes, inducing DNA replication arrest, DNA damage and stress responses that activate checkpoint signaling in the cell cycle. The pharmacologic inhibition of KAT2B reverses the ADCCr phenotype. Immune checkpoints such as PD-L1 do not modulate ADCC in this model system. These results shed light on new mechanisms of ADCC resistance and inform future combinatorial treatments for mAb therapy. We are exploring the possibility that stress response mechanisms are responsible for resistance for diverse selection pressures imposed by immune synapse-mediated cytotoxic attack.
Citation Format: Dalal S. Aldeghaither, Joseph C. Murray, Sarah M. Roth, Elana J. Fertig, Shaojun Tang, Sandra A. Jablonski, Louis M. Weiner. Induction of ADCC resistance profoundly alters tumor cell phenotype and stress response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 633. doi:10.1158/1538-7445.AM2017-633
Abstract 64: Meditope SnAP-body technology facilitates enhanced internalization and in vivo efficacy of antibody therapeutics
Authors: Forster Karin , Gardiner Elisabeth , Hsieh Stephanie 
Published: July 2017

Abstract
Meditope Biosciences has developed a way to use SnAP technology to promote internalization of antibody receptor complexes through a novel construct called a SnAP-body. Meditope’s SnAP platform functionalizes monoclonal antibodies to bind to specific meditope peptides; this property can be used to directly facilitate receptor crosslinking when meditope-enabled antibodies are bound to cell surface receptors. SnAP-bodies are self-crosslinking meditope-enabled antibodies which permit a meditope peptide to specifically interact with a meditope-enabled antibody at the cell surface upon antigen engagement. Antigen-antibody complex formation through the specific contact of the SnAP-bodies and their cognate epitopes on the target antigen can increase clustering or co-localization of a cell surface antigen on a cell, which can promote enhanced internalization of the SnAP-body. The increased internalization can be used to clear or reduce the concentration of a cell surface antigen from the surface of a target cell or tumor. Enhancing internalization can increase the efficacy of antibody-based therapeutics, and in the case of antibody-drug conjugates, which require receptor internalization to deliver cytotoxic payloads, can reduce the amount of drug necessary to achieve a therapeutic effect. In vitro studies of SnAP-body binding to cell surface antigens demonstrate accelerated internalization of the antibody. In vivo, this translates into enhanced efficacy. The ability to see equivalent efficacy in the absence of toxin suggests a unique role for SnAP-body constructs in cancer therapeutics, especially in cases where lack of efficacy for a specific target is correlated with poor receptor internalization.
Citation Format: Karin Forster, Elisabeth Gardiner, Stephanie Hsieh. Meditope SnAP-body technology facilitates enhanced internalization and in vivo efficacy of antibody therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 64. doi:10.1158/1538-7445.AM2017-64
Abstract 640: Subsets of HLA alleles are capable of binding neoantigens derived from mutations within cancer driving genes such as KRAS and EGFR
Authors: Nguyen Andrew , Sanborn J Zachary , Vaske Charles J. , Rabizadeh Shahrooz , Niazi Kayvan , Soon-Shiong Patrick , Benz Steve 
Published: July 2017

Abstract
Background: Immunoncology has shown great promise as a low toxicity tool to combat several cancers. Use of checkpoint inhibitors against PD1 or CTLA4 unlocks the immune system’s ability to recognize tumor antigens and, more specifically, neoantigens caused by random mutations within cancers. The vast majority of neoantigens consist of private mutations unique to a patient’s tumor genome, but several cancers harbor recurrent mutations. Mutations in the KRAS gene, such as p.G12V, occur in roughly 25% of colorectal cancers. Mutations in EGFR occur in 10% and 35% of patients with non-small cell lung cancer in the US and East Asia, respectively. Even more prevalent are mutations within the TP53 tumor suppressor gene, with roughly 23000 unique protein variants reported to date. If these mutations in cancer driving genes are so prevalent in cancers, why are neoantigens against these targets not more readily available?
Results: We collected recurrent mutations across a variety of cancer driving genes such as KRAS, EGFR, TP53 and MYC and performed binding analysis using netMHC 3.4 to see which HLA alleles are capable of binding specific cancer mutations such as KRAS p.G12V. Using this method, we report all possible HLA alleles capable of binding these recurrent mutations within cancer genes. We further performed 3-dimensional modeling to determine whether complexes created by the HLA alleles and cancer neoepitopes are stable.
Conclusions: Several HLA alleles are capable of binding recurrent cancer mutations. These include both MHC Class 1 and Class 2 alleles. The variation in alleles capable of binding commonly mutated genes such as EGFR may explain the difference in prevalence of these mutations between geographic populations. Determining whether a certain HLA allele confers resistance to common cancer gene mutations may lead to identification of immune cells within these populations that can recognize neoantigens from commonly mutated cancer genes.
Citation Format: Andrew Nguyen, J Zachary Sanborn, Charles J. Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Patrick Soon-Shiong, Steve Benz. Subsets of HLA alleles are capable of binding neoantigens derived from mutations within cancer driving genes such as KRAS and EGFR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 640. doi:10.1158/1538-7445.AM2017-640
Abstract 649: Emigrant pre-REP tumor infiltrating lymphocytes profoundly differ from remnant T-cells
Authors: Simpson-Abelson Michelle R. , Mosychuk Christopher , Fardis Maria , Lotze Michael T. 
Published: July 2017

Abstract
Adoptive T cell therapy with autologous tumor infiltrating lymphocytes (TIL) provides up to 56% objective response rates and a complete response in 24% of patients with metastatic melanoma. The process of generating TIL from resected tumor involves morcellating the tumor into 1-3 mm3 fragments and expanding TIL in the presence of Interleukin 2 (IL-2) in a pre-Rapid Expansion Protocol (pre-REP). During the ‘pre-REP’, tumor-resident immune cells emigrate (eTIL) and proliferate. The length of the pre-REP varies between 11-21 days, depending on cell growth. Residual tumor fragments (remnants) are discarded and the expanded eTIL are subjected to a Rapid Expansion Protocol (REP) with irradiated PBMC feeders, anti-CD3 and IL-2. Viable cells remaining in the tumor remnants (rTIL) following the pre-REP were investigated to assess their function and phenotype. We evaluated and compared the rTIL and eTIL in melanoma, breast, renal, pancreatic, lung and colorectal tumors (n=9). Tumor rTIL are consistently phenotypically distinct from eTIL, as determined by differential expression of various markers (Table 1). The fundamental differences in rTIL were: Increased CD69+ (7 fold MFI in CD4+) (p&lt;.001); diminished LAG3 (2 fold MFI in CD8) (p&lt;.05); TIM3 (3 and 2 fold MFI in CD8 and CD4 respectively) (p&lt;.05/.01); CD154 (3 fold MFI in CD4) (p&lt;.01); and CD56 (5%) (p&lt;.05). Surprisingly, a REP of rTIL and eTIL resulted in comparable expansion. The phenotypic signature of TIL was sustained post-REP with fidelity of the individual expression of LAG3, Tim3, and CD28. These studies have identified significant differences in the biology of cell populations in terms of tissue-resident T cells and the signals associated with emigration and retention. These data provide additional insights on the individual TIL populations that could be utilized for adoptive T-cell therapy in patients and raise important questions about the nature of tissue-resident T cells in sites of chronic inflammation such as tumor.
Table 1:Tumor resident remnant T cells are phenotypically distinct from emigrating T cells (N=9)Marker ExpressionLAG3 (CD8/ CD4) MFITim3 (CD8/ CD4) MFIPD-1 (CD8/ CD4) %CD69 (CD8/ CD4) MFICD154 (CD8/ CD4) MFICD28 (CD8/ CD4) MFICD57 (CD8/ CD4) %CD56%eTIL507/ 1442832/ 175636.95/ 471320/ 15431498/ 37511163/ 503618.76/ 19.65.615rTIL209/ 106877/ 74242.8/ 483437/ 223.41034/ 1167458.3/ 27959.16/8.51.027*P-values(CD8/ CD4) 0.05/ 0.210.05/ 0.010.38/ 0.890.11/ 0.0010.55/ 0.010.05/ 0.110.05/ 0.060.05 _______
Citation Format: Michelle R. Simpson-Abelson, Christopher Mosychuk, Maria Fardis, Michael T. Lotze. Emigrant pre-REP tumor infiltrating lymphocytes profoundly differ from remnant T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 649. doi:10.1158/1538-7445.AM2017-649
Abstract 650: B lymphocytes promote upregulation of an IL-1-NfkB dependent signaling and increase invasiveness of triple negative breast cancer
Authors: Flynn Nicole , Somasundaram Rajasekharan , Sims-Mourtada Jennifer 
Published: July 2017

Abstract
Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that progresses quickly from a non-invasive carcinoma in situ to an invasive state. Chronic inflammation associated to humoral immune responses has been found to promote aggressiveness in a number of solid tumor types. In breast cancer, B lymphocytes are associated with microinvasive disease and correlate with expression of inflammatory genes. The purpose of our work is to study the impact of B lymphocytes on the tumor microenvironment and increased invasiveness of TNBC cells. Through real-time PCR, we demonstrate that co-culture of B lymphocytes and TNBC cells leads to increased mRNA levels of IL1β and its downstream target interleukin 8 (IL8) in both B lymphocytes and in TNBC cells. Western Blot analysis shows that co-culture also leads to increased phosphorylation of p65, indicating IL-1 β activation of NFκB signaling. Additionally, co-culture of B lymphocytes with TNBC cells leads to increased expression of matrix metalloproteinases (MMPs) and cellular invasion through a matrigel invasion chamber. Gelatin zymography reveals increased functional MMP2 and MMP9 in tumor cell supernatant following co-culture with B lymphocytes. To complement our in vitro studies, we examined the presence of CD20+ B cells and expression of inflammatory cytokines IL-1β and IL-8 by immunohistochemistry in serial sections of tissue microarrays from patients with estrogen receptor (ER) positive and negative ductal carcinoma in situ (DCIS) and invasive carcinoma. Large areas of densely populated B cells were observed in ER-DCIS and in invasive TNBC compared to ER+ DCIS. Furthermore, in ER- DCIS and TNBC, both B lymphocytes and tumor cells are found to express IL1β whereas IL8 is found more specifically to be expressed by tumor cells. Our findings support the hypothesis that B lymphocytes promote a chronic inflammatory environment leading to increased invasion of TNBC cells.
Citation Format: Nicole Flynn, Rajasekharan Somasundaram, Jennifer Sims-Mourtada. B lymphocytes promote upregulation of an IL-1-NfkB dependent signaling and increase invasiveness of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 650. doi:10.1158/1538-7445.AM2017-650
Abstract 651: Evaluation of the expression and function of TIM-3 relative to PD-1 in human tumors
Authors: McEachern Kristen , Ghosh Srimoyee , Zhao Yonghong , Zhang Qiyao , Zhang Norman , Jenkins David W. 
Published: July 2017

Abstract
While immunotherapies directed against PD-1 and PD-L1 have proven effective across multiple indications, there is still a large unmet medical need for therapies for patients who do not respond or who develop acquired resistance during the course of treatment. There are several emerging hypotheses to explain the lack of response, including the overall presence and localization of immune cells, as well as the up-regulation of additional T-cell checkpoints, including TIM-3 in tumor infiltrating lymphocytes. To investigate the potential role of TIM-3, we set out to evaluate the expression and function of TIM-3 and the relationship to PD-1 in several systems. Firstly, we developed a flow cytometry methodology to enumerate T-cell, including CD4 and CD8 positive cells, as well as other immune cell populations in a panel of human tumor samples, including non-small cell lung cancer (NSCLC). In these samples, we investigated the expression profiles of TIM-3 and PD-1 in both T-cell and non-T-cell populations. In addition, we performed complementary genomic studies to explore gene expression profiles of not only the bulk tumor samples but also of isolated PD1 positive/TIM-3 negative versus PD1 and TIM-3 double positive cell populations. The profiling identified tumors with a range of tumor infiltrating lymphocyte content and also differences in PD1 and TIM-3 expression. It was found that in addition to T-cells, TIM-3 was expressed on myeloid cell populations and furthermore, that there were distinct differences in the gene expression profiles of PD1 single positive versus PD1 and TIM-3 double positive cells. Building on the expression studies, the functional role of Tim-3 in T-cells and also on myeloid-derived cells was explored. Taken together, these studies provide further evidence for TIM-3 as an important immunological checkpoint and as a relevant therapeutic target for the treatment of cancer with the potential for biological effects in both the T-cell and myeloid compartments of the tumor microenvironment.
Citation Format: Kristen McEachern, Srimoyee Ghosh, Yonghong Zhao, Qiyao Zhang, Norman Zhang, David W. Jenkins. Evaluation of the expression and function of TIM-3 relative to PD-1 in human tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 651. doi:10.1158/1538-7445.AM2017-651
Abstract 66: Anthracycline-based antibody drug conjugates with potent immune-stimulatory functions
Authors: Beerli Roger R. 
Published: July 2017

Abstract
Antibody drug conjugates (ADCs) are highly potent and selective anti-tumor drugs, combining the specific targeting of monoclonal antibodies with the potency of small molecule toxic payloads. Here, we employed enzymatic, site-specific conjugation to generate homogenous ADCs based on a derivative of the highly potent anthracycline toxin PNU-159682 and a non-cleavable peptide linker, using the anti-HER-2 antibody trastuzumab (part of trastuzumab emtansine) and the anti-CD30 antibody cAC10 (part of brentuximab vedotin). Characterization of the resulting ADCs in vitro and in vivo showed that they were highly stable and exhibited potencies exceeding those of ADCs based on conventional tubulin-targeting payloads, such as trastuzumab emtansine and brentuximab vedotin. Anti-tumor activity in an immune-competent host involved activation of the immune system, as shown by evaluation of a trastuzumab-PNU ADC in a Kadcyla-resistant HER2-positive orthotopic breast cancer model. Depletion of CD8 T cells severely reduced the anti-tumor activity of the ADC, demonstrating an important role for T cells in driving tumor regression. Furthermore, when tumor free animals were re-challenged with the same tumor, tumor growth was entirely inhibited in the absence of any further ADC administration, indicating the development of an immunological memory. In summary, we present a novel ADC format endowed not only with highly potent cytotoxicity, but also effective immune-stimulatory functions.
Citation Format: Roger R. Beerli. Anthracycline-based antibody drug conjugates with potent immune-stimulatory functions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 66. doi:10.1158/1538-7445.AM2017-66
Abstract 667: Immunoprofiling circulating blood as a means to early detection of solid tumors
Authors: Kumar Amit , Gabrilovich Dimitry , Rauscher Frank J. , Dominguez George , Sholevar Cyrus , Roop John , Campisi Anthony , Polo Alexander 
Published: July 2017

Abstract
Our goal was to evaluate whether profiling Myeloid Derived Suppressor Cells (MDSCs) in circulation correlated with the existence and stage of multiple, biopsy-verified solid tumor types and to evaluate whether such analyses could enable early detection. The tumor micro-environment (TME) is replete with numerous immune cells, and the type and concentration of such cells can provide prognostic information. The link between high concentrations of MDSCs and poor prognosis is most likely due to the immuno-suppressive effects of such cells. Some fraction of these cells spill into the blood stream. We utilized flow cytometry to phenotypically quantify subsets of MDSCs and other leukocytes in the circulation of biopsy-verified cancer patients, as well as in age and sex matched healthy donors. Our results indicate a marked increase in MDSC levels in the circulation of tumor patients relative to healthy donors. We have analyzed patients presenting over a dozen solid tumor types (lung, breast, ovarian, colon, melanoma, liver, thyroid, pancreatic, uterine, osteosarcoma, appendiceal, leiomyosarcoma, liposarcoma, and vulvar) and found notable differences in the immune-profiles of circulating blood in these patients. It appears that the immune response, as measured by our flow cytometry technique, is general for most tumor types. We will present correlations and inter-relations between different cell types and evidence of tumors. While our studies to date have been performed in an unblinded manner, we will present performance data (specificity and sensitivity) for our approach.
Citation Format: Amit Kumar, Dimitry Gabrilovich, Frank J. Rauscher, George Dominguez, Cyrus Sholevar, John Roop, Anthony Campisi, Alexander Polo. Immunoprofiling circulating blood as a means to early detection of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 667. doi:10.1158/1538-7445.AM2017-667
Abstract 672: Baseline serum albumin as a prognostic factor in patients with stage I and II colon adenocarcinoma
Authors: Onate-Ocana Luis F. 
Published: July 2017

Abstract
Background: Patients with stage I or II colon carcinoma (CC) have a significant risk of recurrence after adequately performed curative resection. Adjuvant chemotherapy has not improved recurrence or survival in such patients. In this study, a prognostic model in patients with stage I or II CC is presented.
Methods: Consecutive cases with CC treated at a cancer center in Mexico City from January 2008 to December 2014, with diagnosis of adenocarcinoma by colonoscopy and biopsy were included in this cohort. Patients were treated according to standard guidelines. Follow-up continued until June 2016; the Kaplan-Meier method and the Cox model were used to analyze the association of prognostic factors and overall survival (OS).
Results: 1,259 cases of CC were treated; only 496 patients have stage I and II CC and were included in the database: 234 women (47.2%) and 262 males (52.8%) and their mean age was 59.9 years (SD 14.9); 96, 339, 31 and 30 cases were pTNM stages I, IIa, IIb and IIc, respectively. Multivariate analysis of prognostic factors is depicted below. Predicted survival functions using this model, defined 4 risk groups that showed better prognostic value than simple TNM stages I-IIc.
Conlusion: BSA is an independent, significant, simple, cheap and widely available prognostic factor in patients with CC. BSA and other clinical factors add significant prognostic information to TNM classification. Feasibly, it can be used to develop multivariate prognostic models with clinical impact defining the use of adjuvant chemotherapy. The use of histopathological and immunohistochemical markers could improve the prognostic information of this model.
Multivariate análisis of prognostic factorsBetaSEpHR95% CIMale gender0.3550.1660.0321.4261.031-1.973Hemoglobin-0.0880.0380.020.9160.85-0.986Platelet count-0.0020.0010.0010.9980.996-0.999Neutrophil count0.0820.0280.0041.0851.027-1.147Albumin0.7820.2280.0012.1851.397-3.417Albumin/Globulin-1.6240.4880.0010.1970.076-0.513BMI-0.0420.0220.0510.9580.918-1.0TNM 0/I0.0541TNM IIa0.5540.2550.031.741.056-2.869TNM Iib0.7340.4040.0692.0830.944-4.597TNM IIc0.950.3670.012.5861.26-5.305Chemotherapy-0.7650.2&lt;0.00010.4650.315-0.688R0&lt;0.00011R10.2670.4750.5741.3060.515-3.311R20.9360.3480.0072.5511.29-5.044No Resection1.9360.288&lt;0.00016.9323.944-12.18Platelet/Lymphocute ratio0.0010.0010.081.0011.0-1.002
Citation Format: Luis F. Onate-Ocana. Baseline serum albumin as a prognostic factor in patients with stage I and II colon adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 672. doi:10.1158/1538-7445.AM2017-672