bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4928: Relationship between protein biomarkers of potential chemotherapy response and microsatellite status, tumor mutational burden, and PD-L1 expression in patients with cancer
Authors: Nikanjam Mina , Arguello David , Gatalica Zoran , Barkauskas Donald A. , Kurzrock Razelle 
Published: August 2019

Abstract
Introduction: Chemotherapy and checkpoint inhibitor immunotherapies are increasingly used in combinations. We determined associations between the presence of anti-PD-1/PD-L1 therapeutic biomarkers and protein markers of potential chemotherapy response.
Methods: Data was extracted from a clinical-grade testing database (Caris Life Sciences; Feb 2015 - Nov2017): immunotherapy response markers (microsatellite instability high (MSI-H) and tumor mutation burden-high (TMB-H) (by next generation sequencing (NGS)) and PD-L1 protein expression (immunohistochemistry); and protein chemotherapy response markers (ERCC1, TOPO1, TOP2A, TS, TUBB3, RRM1, and MGMT; immunohistochemistry). Relationships were determined by the Mantel-Haenszel chi-squared test or Fischer’s exact tests.
Results: Overall, 28,034 patients (40 tumor types) were assessed. MSI-H was found in 3.3% of patients, TMB-H, 8.4%, and PD-L1 expression in 11.0% of patients. Based on concurrent biomarker expression, combinations of immunotherapy with platinum (ERCC1 negativity) or with doxorubicin, epirubicin, or etoposide (TOP2A positivity), have a higher probability of response while combinations with irinotecan or topotecan (TOPO1 positivity), with gemcitabine (RRM1 negativity), and fluorouracil, pemetrexed, or capecitabine (TS negativity) may be of less benefit. The potential for immunotherapy and taxane (TUBB3 negativity) combinations is present for MSI-H but not TMB-H or PD-L1-expressing tumors; for temozolomide and dacarbazine (MGMT negative), PD-L1 is frequently co-expressed, but MSI-H and TMB-H are not associated.
Conclusion: Protein markers of potential chemotherapy response along with NGS for immunotherapy response markers can help support rational combinations as part of a precision oncology approach.
Citation Format: Mina Nikanjam, David Arguello, Zoran Gatalica, Donald A. Barkauskas, Razelle Kurzrock. Relationship between protein biomarkers of potential chemotherapy response and microsatellite status, tumor mutational burden, and PD-L1 expression in patients with cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4928.
Abstract 4949: Immunological ignorance is an enabling feature of the oligo-clonal T cell response to melanoma neoantigen
Authors: Linette Gerald P. , Carreno Beatriz M. , Skidmore Zackary L. , Hundel Jasreet , Griffith Obi L. , Griffith Malachi , Magrini Vincent , Mardis Elaine R. 
Published: August 2019

Abstract
The impact of intratumor heterogeneity (ITH) and the neoantigen landscape on T cell immunity is poorly understood. ITH is a widely recognized feature of solid tumors and poses distinct challenges related to the development of effective therapeutic strategies, including cancer immunotherapy. Cutaneous melanoma is characterized by C-&gt;T transitions caused by UV exposure which leads to a large mutational burden encoding putative neoantigens. Here, we performed ultra-deep DNA sequencing of multiple metastases from melanoma patients and observed ubiquitious sharing of clonal and subclonal single nucleotide variants (SNV) encoding putative HLA class I restricted neoantigen epitopes among tumors. MEL66, a reference melanoma patient with a large mutational burden (53 SNV/Mb), provided six resected metastases for study. The spontaneous T-cell response features an oligo/monoclonal T cell-receptor (TCR) repertoire which targets a few clonal neoantigens; most neoantigen-specific T cell clones ignore the tumor. CD8+ T cells to additional HLA class I restricted neoantigens can be elicited by DC vaccination (NCT03092453) with tumor-encoded amino acid substituted (mutated) peptides resulting in a diverse, high frequency TCR repertoire. Isolation of T cell clones by limiting dilution from blood and TIL permits functional validation regarding neoantigen-specificity. Gene transfer of paired abTCR heterodimers specific for clonal neoantigens confirmed correct clonotype assignments based on high throughput CDR3 sequencing. Additional melanoma patients with 2-6 resected metastases were investigated and similar observations were found. Our observations implicate ineffective neoantigen cross-presentation as the basis for immunological ignorance. We postulate that therapeutic vaccination is required to increase the breadth and diversity of neoantigen-specific CD8+ T cells as an adjunct to checkpoint inhibitor treatment for cancer.
Citation Format: Gerald P. Linette, Beatriz M. Carreno, Zackary L. Skidmore, Jasreet Hundel, Obi L. Griffith, Malachi Griffith, Vincent Magrini, Elaine R. Mardis. Immunological ignorance is an enabling feature of the oligo-clonal T cell response to melanoma neoantigen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4949.
Abstract 495: All-in-one flow cytometry staining panel for immune-cell profiling in syngeneic tumor models
Authors: Weber Holger , Beshay Janette , Obodozie Cynthia 
Published: August 2019

Abstract
Checkpoint inhibitor treatment has become a common therapy of various cancer types; however, clinical data indicate that only few patients respond to this regimen due to attenuated anti-tumor immune response. Thus, it has been recognized as important to consider the immune response already during preclinical drug development to anticipate such clinical drawbacks and investigate the changes of immune cell populations after treatment. Flow cytometry is widely used for this kind of analysis. However, a comprehensive analysis of numerousness immune cell populations in one tumor is a major challenge when only limited material is available due to small tumor size of e.g. a tumor responding to the treatment or analysis at an early tumor developmental stage. A staining panel that allows the analysis of all major immune cell populations in a single staining would be a major advantage.
Here we present an all-in-one flow cytometry panel based on 15 colors which permits the differentiation of the main immune cell populations in the tumor, such as T cells (CD4+, CD8+, Treg), NK cells, macrophages (M1/M2), MDSCs (neutrophils, M-MDSCs) and dendritic cells. To demonstrate the value of the panel, the immune cell content of CT26wt tumors was compared after subcutaneous, orthotopic or intra-mammary fat pad implantation. During tumor growth profiling of the immune population is performed every 4 days, starting at day 7 after implantation when tumor volume is still very small (50 - 100 mm3). A comprehensive overview is given with valuable insight into the immune biology of the tumor over time and with respect to different tumor sizes.
The established all-in-one staining panel allows the direct comparison of immune cell populations with a single staining which improves the development of new immune-modulating drug candidates.
Citation Format: Holger Weber, Janette Beshay, Cynthia Obodozie. All-in-one flow cytometry staining panel for immune-cell profiling in syngeneic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 495.
Abstract 4961: Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12
Authors: Uribe-Herranz Mireia , Bittinger Kyle , Rafail Stavros , Pierini Stefano , Guedan Sonia , Bushman Frederic , June Carl , Facciabene Andrea 
Published: August 2019

Abstract
Adoptive T cell therapy (ACT) is a promising new modality for malignancies. Here, we report that adoptive T cell efficacy in tumor-bearing mice is significantly affected by differences in the native composition of the gut microbiome or treatment with antibiotics, or by heterologous fecal transfer. Depletion of bacteria with vancomycin decreased the rate of tumor growth in mice from The Jackson Laboratory receiving ACT, whereas treatment with neomycin and metronidazole had no effect, indicating the role of specific bacteria in host response. Vancomycin treatment induced an increase in systemic CD8α+ DCs, which sustained systemic adoptively transferred antitumor T cells in an IL-12-dependent manner. In subjects undergoing allogeneic hematopoietic cell transplantation, we found that oral vancomycin also increased IL-12 levels. Collectively, our findings demonstrate an important role played by the gut microbiota in the antitumor effectiveness of ACT and suggest potentially new avenues to improve response to ACT by altering the gut microbiota.
Citation Format: Mireia Uribe-Herranz, Kyle Bittinger, Stavros Rafail, Stefano Pierini, Sonia Guedan, Frederic Bushman, Carl June, Andrea Facciabene. Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4961.
Abstract 4962: Repurposing bazedoxifene to suppress gastrointestinal cancer growth
Authors: Thilakasiri Pathum , Nero Tracy , Parker Michael W. , Ernst Matthias , Chand Ashwini L. 
Published: August 2019

Abstract
The interleukin (IL)6 family of inflammatory cytokines, characterized by the shared use of the gp130 receptor, supports the progression of solid cancers. Specifically, gp130 signaling becomes rate limiting for the growth of gastrointestinal tumors arising from oncogenic driver mutations in Apc, but remains dispensable for the homeostatic renewal of the gastrointestinal mucosa. In the present study we investigate the effects of the selective estrogen receptor modulator bazedoxifene, clinically approved for the treatment of osteoporosis, as a putative small molecule inhibitor of gp130 receptor oligomerization and activation. We assessed the effects of bazedoxifene on IL6 and IL11-dependent STAT3 activation and cell proliferation in gastric and colon cancer cell lines. In patient-derived colon cancer organoid cultures, we assessed bazedoxifene effects on IL11-dependent growth. The gp130Y757F, Lgr5CreERT2- or Cdx2CreERT2-driven Apc flox mouse models of gastrointestinal cancer, were used to examine the effects of bazedoxifene on tumour growth. In silico modeling suggests that the inhibitory activity of bazedoxifene is due to its ability to mimic the interaction between the Site III interface of gp130 receptor and the tryptophan-157 in IL6, or tryptophan-168 in IL11 cytokine. We show that bazedoxifene interferes with IL6 and IL11-dependent proliferation of BAF/03 cells. Bazedoxifene suppresses gastric tumor growth in gp130Y757F mice irrespective of their gender, in which tumors arise through excessive IL11-dependent STAT3 signaling. Strikingly, in sporadic colon cancer models based on aberrant activation of the β-catenin/canonical WNT pathway, bazedoxifene treatment also reduces tumor burden in mice following conditional ablation of the Apc suppressor gene using the Lgr5CreERT2- or Cdx2CreERT2-driver alleles. Consistent with our observation that nuclear accumulation of β-catenin remains unaffected in colonic tumors of bazedoxifene-treated mice, bazedoxifenetreatment of human SW480 colon cancer cells harboring mutant APC did not affect canonical WNT signaling, but suppressed IL11-dependent STAT3 signaling. Our findings provide compelling proof-of-concept for the repurposing of bazedoxifene for the treatment of gastrointestinal cancers that arise from bona fide oncogenic driver mutations.
Note: This abstract was not presented at the meeting.
Citation Format: Pathum Thilakasiri, Tracy Nero, Michael W. Parker, Matthias Ernst, Ashwini L. Chand. Repurposing bazedoxifene to suppress gastrointestinal cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4962.
Abstract 4970: Establishment of a patient-derived platform for preclinical immunooncology studies using autologous tumor and TIL coculture
Authors: Hinada Kaede , Garland Dennis , Nair Dileep , Hu Yong , Broudy Thomas 
Published: August 2019

Abstract
The use of tumor infiltrated lymphocytes (TILs) as an adoptive cell transfer therapy to treat cancer has been conducted in clinic trials for more than two decades. TIL therapy in combination with added immunotherapy treatments, such as IL-2 or anti-CTLA4, has further improved clinical response rates. Isolated from a patient’s own tumor specimen, TILs that recognizes tumor-specific known or unknown antigens can be expanded and infused back to tumor-bearing patients to attack autologous cancer cell populations. Despite the progress in clinical research, preclinical and translational models of autologous tumor/TIL coculture have been difficult to establish.
This study has established autologous tumor/TIL coculture methods directly from patient tumor specimens. Models were established from BioDuro’s viably cryopreserved tumor & TIL bank, containing more than 100,000 patient biospecimens. Each patient specimen contains a heterogeneous population of cells types, including tumor, TILs and TAFs (tumor associated fibroblasts). These cell populations were expanded under specific growth conditions to then serve as components for the patient-derived coculture systems established.
In this study, TILs and monocytes from a cohort of patient tumor specimens (including kidney, melanoma and lung) were analyzed. Leukocytes, T cells, monocytes and B cells were marked with CD45, CD3, CD14, CD20. Patients’ samples were also tested for PD-1 expression levels. The results show significant individual variation on cell subpopulations and PD-1 expression. Established methods were used for expansion of TILs, supporting either CD4 or CD8 phenotypes. Autologous cancer cells were expanded at the same time. TILs and tumor cells were co-cultured and high content fluorescent image cytometry was used to monitor tumor cell killing. This study found that autologous patient-matched TILs showed preferential tumor cell killing compared to patient-unmatched TILs. This response was observed in a dose dependent fashion.
In summary, the BioDuro biobank of viable tumor and TIL patient specimens served as a large and powerful immunooncology resource to establish patient-derived autologous tumor/TIL coculture assays. These assays, and the ability to readily study larger populations of cancer patients, provide a powerful in vitro platform to test immunooncology drug candidates.
Citation Format: Kaede Hinada, Dennis Garland, Dileep Nair, Yong Hu, Thomas Broudy. Establishment of a patient-derived platform for preclinical immunooncology studies using autologous tumor and TIL coculture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4970.
Abstract 4971: Dominant negative PD 1 armored CAR T cells induce remission in refractory diffuse large B-cell lymphoma (DLBCL) patients
Authors: Chen Tong 
Published: August 2019

Abstract
Anti-CD19 chimeric antigen receptor (CAR19) autologous T cell treatment has been demonstrated as effective therapy to relapse/refractory B cell leukemia and lymphoma. However, CAR T shows limited efficacy in treatment of solid tumor or challenging with immunosuppressive characters, such as PD-L1+/hi lymphomas.
PD-1/PD-L1 blockade have been shown as potentially effective anti-tumor therapies. We generated a lenti-vector incorporating an anti-CD19 secondary CAR molecule sequence with 4-1BB co-stimulatory domain and a dominant negative PD-1 sequence (Figure A). Compared with conventional CART cells, these ”armored” CART cells show enhanced capability of tumor killing after multiple-round challenging by PD-L1+CD19+ positive tumors, with a ”emory-like” phenotype(Figure B), suggesting dominant negative PD-1 molecule may protect CART cells from inhibition in tumor micro-environment.
Here we report 2 cases of refractory diffuse large B cell lymphomas (DLBCLs) successfully treated with this novel dominant negative PD-1 armored humanized anti-CD19 CART cells. These two patients all failed to achieve response after multiple rounds of chemotherapy and radiotherapy, and infused with autologous CAR T cells at 5.23×10^6/kg and 1.97×10^6/kg during disease progress. Both patients showed significantly tumor mass decrease and SUV max decline in PET/CT results with ongoing response. (From 34.48 to 3.89 at day 27, from 25.02 to 2.38 at day 31, respectively.) (Figure C).
Conclusion: These 2 cases revealed the significant anti-bulky lymphoma response of new type of CAR19 T cells with limited and tolerated cytokine release syndrome and central nervous system toxicity. This novel structure of dnPD1-hCAR19 may augment CART cells persistence in the patient after activation triggered by the lymphoma cells, suggesting that dnPD-1 molecule may enhance efficacy of CAR T cells in treatment of solid tumor. We are continuing to recruit more patients in clinical research.
Citation Format: Tong Chen. Dominant negative PD 1 armored CAR T cells induce remission in refractory diffuse large B-cell lymphoma (DLBCL) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4971.
Abstract 4976: Ex vivo functional characterization and in vivo efficacy validation of human CD40 agonistic antibodies in the human CD40 knock-in model (CD40 HuGEMM)
Authors: He Daniel Xianfei , Zheng Lei , Sun Ruilin , An Annie Xiaoyu , Fei Jian , Li Henry Qixiang , Ouyang Davy Xuesong 
Published: August 2019

Abstract
CD40 receptor is a member of TNF-receptor superfamily, broadly expressed on the surface of antigen-presenting cells (APC) including B cells, dendritic cells (DC), macrophages, monocytes, and non-APC like platelets, endothelial cells and even some tumor cells. CD40 is essential for APC activation and signalling via ligation of CD40 ligand located on helper T cells and CD40 on APC to mediate licensing (activating) of APC. Ligation of CD40 on DCs, for example, can induce increased surface expression of costimulatory and MHC molecules, production of pro-inflammatory cytokines, and enhanced T cell activation. CD40 ligation on resting B cells can increase its antigen-presenting function and proliferation. In contrast to its critical role in the induction of effective innate and adaptive immune responses, CD40 signalling on certain malignant cells, particularly B cell lymphomas, triggers tumor apoptosis. The dual function of CD40 signalling provide unique opportunities for the use of agonistic CD40 antibodies in cancer immunotherapy. Indeed, several CD40 monoclonal antibodies are now in different stages of clinical development, some shown promising preliminary results in combination with other cancer immunotherapies. However, we are lacking preclinical models to evaluate efficacy of therapeutic CD40 agonistic antibodies, which usually don’t cross-bind to mouse targets. To fill this gap, we developed a human CD40 knock-in model (CD40 HuGEMM), of which mouse exon 2-5 are replaced by human counterparts. These KI mice express a chimeric CD40 with human extracellular domain & mouse trans-membrane and intracellular sequences. We have characterized the human CD40 expression of CD40 HuGEMM on a broad spectrum of mouse cells, such as lymphocytes, macrophages, DCs, and endothelial cells. In addition, we confirmed that human CD40 antibodies bind to the chimeric m/hCD40 recombinant protein, and lead to increased expression of MHCII on the B cells. Finally, the in vivo efficacy study indicates that human CD40 antibody treatment lead to robust anti-tumor response and contribute to better survival of the mice. Taken together, our CD40 HuGEMM provides a powerful preclinical model to assess the efficacy of the human-specific CD40 agonistic antibodies. It may also serve as a model for proof of concept studies of CD40 agonistic antibodies with other therapies.
Citation Format: Daniel Xianfei He, Lei Zheng, Ruilin Sun, Annie Xiaoyu An, Jian Fei, Henry Qixiang Li, Davy Xuesong Ouyang. Ex vivo functional characterization and in vivo efficacy validation of human CD40 agonistic antibodies in the human CD40 knock-in model (CD40 HuGEMM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4976.
Abstract 4977: Dynamic transcriptional programs controlling single NK cell killing dynamics
Authors: Hall Matthew S. , Decker Joseph T. , Grody Emanuelle I. , Blaisdell Rachel B. , Jeruss Jacqueline S. , Shea Lonnie D. 
Published: August 2019

Abstract
NK cells have a vast heterogeneity in function and phenotype in vivo and their healthy function is critical in the prevention of nascent cancers. NK cell-based immunotherapies, such as adoptive NK cell therapy, are emerging and greater insights into the mechanism of NK cell activation could increase their efficacy. In vitro cytotoxicity assays have revealed that a small subset of NK cells kill the majority of cancer target cells, yet little is known about the dynamic state or triggers of these highly cytotoxic cells. Here, we present methodology for discovery of the molecular precursors and drivers of single NK cell killing events. We study the NK-92 cell line both as a model of primary NK cells and to gain direct insights for improving NK-92 based adoptive cell therapies. In our method, we first performed single cell RNA sequencing on NK-92 cells seeded sparsely on a monolayer of HeLa cancer cells along with a control NK-92 cell population. Clustering cells by principal component analysis revealed groups of NK cells that upregulated genes associated with NK cell cytotoxicity in the HeLa cell activated sample that are absent in the control group. Landmark genes associated with the cytotoxic NK cell clusters included PRF1, GZMK, and ITGB2. Utilizing live cell imaging, we identified categories of dynamic functional phenotypes in NK-92 cells exposed to a HeLa cell monolayer including non-motile and non-killing, highly motile but non-killing, single killing, serial killing, and exhausted. In order to link the systems-level single cell gene expression data to functional NK cell behaviors, we next performed high content live cell imaging of NK-92 cells bearing cas9-based endogenous genetic reporters as they surveilled and killed HeLa cells. Utilizing a custom analysis algorithm, we tracked the motility and killing activity of individual NK-92 cells, and correlated this activity to the dynamic gene expression. Next, we aim to identify the causality and sequence of transcriptional changes associated with NK cell killing and extend our results to the analysis of the critical transcription factor networks governing dynamic NK cell functional phenotypes. We note that the single cell functional discovery strategy that we have shown can be applied more broadly to other model systems of the cancer microenvironment.
Citation Format: Matthew S. Hall, Joseph T. Decker, Emanuelle I. Grody, Rachel B. Blaisdell, Jacqueline S. Jeruss, Lonnie D. Shea. Dynamic transcriptional programs controlling single NK cell killing dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4977.