tbuckley/cabot-search huggingface dataset:
Abstract 2178: Expansion of tumor-specific tumor-infiltrating lymphocytes (TIL) from head and neck tumors
Authors: Luz Nagle, Amy Mackay Weber, MacLean Hall, Matthew Beatty, J. Trad Wadsworth, Caitlin McMullen, Krupal Patel, Kathryn Vorwald, Christine Chung, Shari Pilon-Thomas
Journal: Cancer Research (2020)

Abstract Background: Until recently, treatment options for patients with head and neck cancer include a combination of surgery, chemotherapy and radiation. Although the combined use of these treatment options modestly improves survival, combination therapy increases toxicity. Overall survival of these treatment regimens for patients with advanced head and neck cancer is just over 10 months. Even with the newly approved and vastly more tolerable use of anti-PD-1 immunotherapy, survival is only extended by 3-5 months. In comparison, adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has improved the median overall survival in patients with metastatic melanoma to 52 months. The goal of this study was to test the feasibility of expanding tumor-reactive TIL from head and neck tumors for the development of a clinical trial. Methods: Primary tumors were resected from 20 head and neck cancer patients. Tumors were minced into small fragments (1-3 mm3) and plated in high dose IL-2. After 4 weeks, expanded TIL were phenotyped by flow cytometry and tested for tumor reactivity by IFN-gamma production after co-culture of TIL with autologous tumor digest. IFN-gamma levels were determined by ELISA. Reactive TIL were expanded using a rapid expansion protocol (REP). Results: The mean expansion of TIL per fragment was 1.96 × 106. From 20 primary tumors, seven were contaminated and discarded. TIL were successfully expanded from 11/13 (85%) evaluable tumors. The phenotype of expanded TIL consisted of CD3− CD56+ NK cells and CD3+ T cells. Tumor-specific reactivity was analyzed for seven samples. TIL expanded from three (43%) tumors were predominantly CD8+ and were reactive against autologous tumor as determined by IFN-gamma ELISA. Expansion of TIL during REP resulted in an average 600-fold increase in cell numbers (range of 61 - 1,774 fold) and led to the depletion of NK cells and an increase of CD3+ T cells. Conclusions: In this study, we have demonstrated the feasibility of growing tumor-reactive TIL from head and neck tumors. This study raises the potential for the implementation of ACT with TIL for the treatment of head and neck cancer patients. Citation Format: Luz Nagle, Amy Mackay Weber, MacLean Hall, Matthew Beatty, J. Trad Wadsworth, Caitlin McMullen, Krupal Patel, Kathryn Vorwald, Christine Chung, Shari Pilon-Thomas. Expansion of tumor-specific tumor-infiltrating lymphocytes (TIL) from head and neck tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2178.
Abstract 6223: Combination of BCL-2/BCL-xL dual inhibitor APG-1252 and chemotherapeutics overcomes resistance to osimertinib in EGFR mutant NSCLC in preclinical models
Authors: Ran Tao, Guangfeng Wang, Douglas D. Fang, Guoqin Zhai, Yuanbao Li, Jing Lv, Miaoyi Wu, Yangfeng Ge, Feifei Zhang, Danyi Wen, Dajun Yang, Yifan Zhai
Journal: Cancer Research (2020)

Abstract Osimertinib (AZD9291) is the first-line treatment for EGFR-mutated NSCLC; however, the majority of patients inevitably develop resistance due to de novo genomic abnormalities, such as C797S mutation, EGFR exon 20 insertion, MET amplification and other unknown mechanisms. Hence, effective therapies to overcome acquired resistance are urgently needed. Inhibition of BCL-2/BCL-xL has been reported to enhance apoptosis in EGFR-TKI resistant cells with low sensitivity to EGFR inhibition. In this study, we evaluated whether the combination of a dual BCL-2/BCL-xL inhibitor APG-1252 and chemotherapeutics could overcome osimertinib resistance in preclinical xenograft models. First, EGFR C797S mutation was introduced to human NCI-H1975 NSCLC cells to construct an NCI-H1975-C797S resistant cell line using CRISPR technology. NCI-H1975-C797S derived-xenografts were treated with APG-1252, cisplatin/docetaxel or their combinations. Combination therapy with APG-1252 and cisplatin or docetaxel exhibited synergistic antitumor activity. APG-1252 plus docetaxel combination achieved 100% tumor partial regression (PR). Similar results were demonstrated in a patient-derived xenograft (PDX) tumor model derived from an osimertinib-resistant NSCLC patient harboring 19del-T790M-C797S mutations. Furthermore, the combinations also exhibited enhanced antitumor activity in an osimertinib-resistant PDX model that the resistant mechanism remained unknown. In summary, our results suggest that the combination treatment with APG-1252 and chemotherapeutics can overcome acquired resistance to osimertinib and the combination deserves further clinical evaluations. Citation Format: Ran Tao, Guangfeng Wang, Douglas D. Fang, Guoqin Zhai, Yuanbao Li, Jing Lv, Miaoyi Wu, Yangfeng Ge, Feifei Zhang, Danyi Wen, Dajun Yang, Yifan Zhai. Combination of BCL-2/BCL-xL dual inhibitor APG-1252 and chemotherapeutics overcomes resistance to osimertinib in EGFR mutant NSCLC in preclinical models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6223.
Abstract 2152: Characterisation of co-expression of CD39 with other IO-relevant markers on major T/NK cell TIL subsets
Authors: Jim Hair, Nadia Luheshi, Simon J. Dovedi, Robert W. Wilkinson
Journal: Cancer Research (2020)

Abstract CD39 has recently been identified as critically differentiating tumour-reactive from bystander tumour-infiltrating leukocyte (TIL) CD8+ T cells. CD39 is an ectonucleotidase that degrades immunostimulatory ATP to ADP and AMP. CD73 then further metabolises AMP to generate immunosuppressive adenosine in the tumor microenvironment. To facilitate our understanding of CD39 as a therapeutic target we established a detailed receptor co-expression profile for CD39 with other immuno-oncology (IO)-relevant targets on TIL T/NK cells. TIL samples from three diseases (NSCLC, Renal cancer [RC] and Melanoma) were profiled, via the creation and use of a single large flow cytometry panel, combined with computational analysis. Unbiased clustering identified the expected major T and NK cell populations, however one of the most striking findings was that CD39 was highly differentially expressed across the different cell subsets. Almost all TREG cells were CD39 positive, whereas CD8+ T cells and NK cells were highly variable in their degree of expression of CD39. CD4+CD8+ T cells predominantly did not express cell surface CD39 and only very few CD4+ TCONV cells expressed CD39. The co-expression profile for TREG, TCONV and NK cells is presented, but we have also defined a detailed phenotype of the critical tumour-specific CD39+CD8+ T cell population. Our analyses show that CD39+CD8+ T cells express more markers associated with antigen-experienced T cells versus CD39-CD8+ T cells; a significantly greater proportion of CD39+CD8+ T cells expressed TIM3, CTLA-4, PD-1, TIGIT, CD137 and GITR versus CD39-CD8+ T cells. Significantly fewer CD39+CD8+ T cells than CD39-CD8+ T cells expressed CD28, a receptor known to be downregulated on antigen-experienced cytotoxic CD8+ T cells. These data reveal the detailed co-expression patterns of key IO-relevant receptors across TIL T and NK cell subsets and are consistent with recent reports identifying CD39 as a key marker differentiating the critical tumor-specific, antigen-experienced tumor infiltrating CD8+ T cells. Citation Format: Jim Hair, Nadia Luheshi, Simon J. Dovedi, Robert W. Wilkinson. Characterisation of co-expression of CD39 with other IO-relevant markers on major T/NK cell TIL subsets [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2152.
Abstract 4974: Q702, selective Axl/Mer/CSF1R triple kinase inhibitor enhance the activity of immune checkpoint inhibitor by alteration of immunosuppressive tumor microenvironment
Authors: Yeong-In Yang, Hwankyu Kang, Dongsik Park, Yeejin Jeon, Jeongjun Kim, Baejung Choi, Jaeseung Kim, Kiyean Nam
Journal: Cancer Research (2020)

Abstract Central to the Immune Checkpoint Inhibitors (ICI) mechanism is the activation and infiltration of the cytotoxic CD8+ T cells following tumor-antigen recognition. However, the effector functions of the CD8+ T cells can be highly compromised by immunosuppressive tumor microenvironment (TME). There is the growing appreciation of the potential contributions of innate immune modulation to antitumor immunity which suggests the need for the novel strategies to elicit a more efficient/robust immune response against malignant cells. Axl/Mer/CSF1R play vital roles in the immunosuppressive TME by increasing regulatory T cell, M2 macrophage, myeloid-derived suppression cell (MDSC) and suppressing antigen presentation. Previously, we have reported a novel selective Axl/Mer/CSF1R kinase inhibitor, Q702 and demonstrated tumor regression by alteration of the immunosuppressive TME. We present the anti-tumor efficacy and immune mechanism of Q702 in combination with anti-PD-1 in the various syngeneic models. The combination of Q702 and anti-PD-1 demonstrated tumor regression through enhanced tumor infiltration of effector immune cells, altered cytokine expression promoting promoted tumor specific antigen presentation and unregulated PD-L1 expression on tumor cells. Additionally, the Q702 alone induced tumor regression in the anti-PD-1 non-responding syngeneic models. These results suggest that the innate immune modulation in the TME by Q702 in combination with an ICI can be through synergistic mechanisms of action. In addition, the data suggests that Q702 could potentially broaden the patient population that benefits from ICI-based immunotherapy. Q702 is progressing through IND-enabling studies to support initiation of a Phase 1 oncology clinical study in early 2020. Citation Format: Yeong-In Yang, Hwankyu Kang, Dongsik Park, Yeejin Jeon, Jeongjun Kim, Baejung Choi, Jaeseung Kim, Kiyean Nam. Q702, selective Axl/Mer/CSF1R triple kinase inhibitor enhance the activity of immune checkpoint inhibitor by alteration of immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4974.
Abstract 2675: Single-CellRNA-Seq reveals the transcriptional landscape of the immune microenvironment in chemical induced liver cancer
Authors: Jian He
Journal: Cancer Research (2020)

Abstract The immune cell types as well as their numbers and activities in the tumor microenvironment (TME) may contribute to tumor progression, metastasis, prognosis and clinical response to cancer immunotherapies. Hepatocellular Carcinoma (HCC) is a type of highly heterogeneous solid tumor, causing high morbidity and mortality in the world, especially in China, however, the immune microenvironment of HCC has not been well-defined so far. In the present work, we first employed single-cell RNA sequencing on diethylnitrosamine (DEN)-induced mouse HCC model to depict the changing landscape of the immune cell composition, lineages and functional activities in TME during tumorigenesis, showing the distinct immune features in precancerous and cancerous lesions. The data indicated that the tumor-associated immune changes appeared early in pathological progression and the specific subsets of T and B cells were preferentially enriched in TME of HCC. We identified the signature genes for these specific cell subsets, and then mapped them onto the HCC RNA-seq dataset of human The Cancer Genome Atlas (TCGA) database. We found a cluster of naïve B cells characterized by high expression of CD38 was associated with better prognosis of human HCC. In addition, the inter-cellular interaction map was established based on the receptor-ligand bonding at single cell resolution. Taken together, this study will be helpful to the comprehensive understanding of dynamic immune microenvironment and cellular networks, especial naïve B cells, during HCC pathogenesis, which could provide a novel insight into the therapeutics for the HCC. Citation Format: Jian He. Single-CellRNA-Seq reveals the transcriptional landscape of the immune microenvironment in chemical induced liver cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2675.
Natural History of Functional Tricuspid Regurgitation Quantified by Cardiovascular Magnetic Resonance
Authors: Yang Zhan, Dany Debs, Mohammad A. Khan, Duc T. Nguyen, Edward A. Graviss, Shaden Khalaf, Stephen H. Little, Michael J. Reardon, Sherif Nagueh, Miguel A. Quiñones, Neal Kleiman, William A. Zoghbi, Dipan J. Shah
Journal: Journal of the American College of Cardiology (2020)
Abstract 738: Utility of Assessing HER2 RNA expression for precision medicine
Authors: Yifei Shen, Christian Cruz Pico, Vakul Mohanty, Amber Johnson, Jia Zeng, Kenna Mills Shaw, Ken Chen, Funda Meric-Bernstam
Journal: Cancer Research (2020)

Abstract Genomic analysis of tumors is rapidly becoming routine clinical practice. Most of the next generation sequencing (NGS)-based oncology assay focused on DNA alteration data for single nucleotide variants (SNVs), insertions and deletions (indels) and copy number variants (CNVs) of genes which have targeted drug. Although RNA sequencing technology is increasingly being explored, its clinical utility still needs to be clarified. As there is a growing number of HER2-targeted therapies, in this study, we dissected the association between HER2 amplification, RNA overexpression, HER2 protein expression by immunohistochemistry (IHC) and reverse phase proteomic arrays (RPPA) in 618 breast tumors in the TCGA. We conducted unsupervised clustering analysis based on HER2 RNA-seq gene expression and RPPA protein data to identify HER2 overexpression samples. As expected there was a strong correlation with ERBB2 copy number with HER2 RNA expression (R2 = 0.56, P &amp;lt;0.001), and HER2 protein expression by IHC (R2 = 0.25, P &amp;lt; 0.001). RNA expression also correlated with HER2 IHC (R2 = 0.40, P &amp;lt; 0.001) and HER2 protein expression by RPPA (R2 = 0.68, P &amp;lt; 0.001). We performed unsupervised clustering analysis based on RPPA protein data and gene expression data of the HER2 gene, all the breast cancer samples were classified as two distinct clusters. Among the two subgroups, one subgroup had significantly higher expression and protein level of HER2 gene. The clustering results of most breast tumors were consistent with the IHC score and copy number data. The gene expression cutoff value to distinguish the HER2 overexpression subgroup from the other was about 204 FPKM. In addition, we identified two HER2 overexpression tumors which were classified as HER2 negative based on IHC. Studies are planned to test transcriptomic based actionability in patient derived models. Our results suggest that RNA-seq gene expression data may identify patients with HER2 overexpression that may be classified as HER2 negative based on IHC. Further studies are needed to determine the role of HER2 RNA overexpression as a predictive marker and to determine HER2 RNA expression across tumor types. Citation Format: Yifei Shen, Christian Cruz Pico, Vakul Mohanty, Amber Johnson, Jia Zeng, Kenna Mills Shaw, Ken Chen, Funda Meric-Bernstam. Utility of Assessing HER2 RNA expression for precision medicine [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 738.
Abstract 5837: Exploring integrated stress response pathway to target MYC-amplified medulloblastoma
Authors: Sofya Langman, Poul H. Sorensen
Journal: Cancer Research (2020)

Abstract Medulloblastoma (MB) accounts for 20% of diagnosed brain tumors in children. The Group 3 (G3) MB subtype is found to be especially malignant. Current G3 MB treatment regimens provide for 50% 5-year survival rates and are associated with severe side effects, including hearing loss and neurocognitive deficits. G3 MB is characterized by MYC overexpression, which drives elevated protein translation in tumor cells. High expression levels of PERK correlate with poor survival outcome in G3 MB, and knockdown of PERK combined with hypoxic stress induces apoptosis in MB cells. PERK is an eIF2α kinase that responds to ER stress and is one of the key mediators of unfolded protein response. When ER stress is detected, PERK phosphorylates eIF2α to shut down global translation and to initiate integrated stress response. However, there are 3 other eIF2α kinases that work alongside PERK to help cells respond to various stresses. ISRIB is in an integrated stress response inhibitor that blocks P-eIF2α attenuation by eIF2B, thus maintaining high translation levels under stress. Combining ISRIB with stress such as hypoxia induces apoptosis in MB cells. In addition, combination of ISRIB and hypoxia is correlated with increased levels of oxidative stress. Apart from restoring global translation levels, ISRIB can prevent stress granules (SGs) from being formed. High expression of SG proteins such as G3BP1 and YB1 also correlates with poor survival outcome in G3 MB patients. When SG formation is inhibited by knocking down expression of G3BP1 and G3BP2, MB cells undergo higher levels of apoptosis under vincristine induced stress. We show that preventing G3 MB cells from undergoing integrated stress response and inhibiting formation of stress granules induces higher levels of cancer cell death. Overall, combining ISRIB with conventional chemotherapy may enhance the effects of the latter, which is increasingly relevant for patients suffering from G3 MB. Citation Format: Sofya Langman, Poul H. Sorensen. Exploring integrated stress response pathway to target MYC-amplified medulloblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5837.
Abstract CT183: CD5+ B-cell count is a favorable prognostic factor associated with progression-free survival in glioblastoma patients receiving chemoradiation and pembrolizumab
Authors: Cheryl J. Claunch, Claire Diaz, Riley A. Roth-Carter, Lauren Popp, Rochelle Fu, Amy E. Huddleston, Dana L. Moussalli, Julie Peterson, Kutluay Uluc, Laszlo Szidonya, Guang Fan, Ferdinando Pucci, Ramon F. Barajas, Leslie L. Muldoon, Edward A. Neuwelt, Prakash Ambady
Journal: Cancer Research (2020)

Abstract The exploratory endpoint for our prospective single-arm study (NCT 03347617) evaluated longitudinal changes in immune cell sub-populations (B-cells, T-cells, NK cells, monocytes, and myeloid cells) in 25 newly diagnosed glioblastoma patients who received standard of care chemoradiation with concurrent pembrolizumab after maximal safe resection. Patient demographics included the following: 15 males, 10 females, age range 25-72 years old, mean age 52 years old, 8 MGMT unmethylated, 17 MGMT methylated, 7 IDH1 mutant, and 18 IDH1 wild-type. Flow cytometry was performed on blood collected at predetermined timepoints (pre-treatment, post-radiation, suspected progression, and confirmed progression) and immune cell sub-populations were evaluated as covariates in survival analysis using Cox proportional hazards regression in R. CD5+ CD19+ B-cell count was significantly associated with progression-free survival at pre-treatment (hazard ratio (HR)= 0.76; likelihood ratio test (LRT) p=0.029) and post-radiation (HR = 0.16; LRT p=0.004) timepoints. No association with progression-free survival was found in 25 other immune cell sub-populations evaluated. The study will continue to monitor for progression. Results of imaging, tissue histology, overall survival analysis and functional studies in animal models are pending. Investigations of the immunological mechanisms underlying the potential anti-tumor activity of CD5+ B-cells are ongoing and include detection and characterization of anti-tumor antibodies, T cell-dependence of the response, and whether it is triggered by pembrolizumab. Modulating CD5+ B-cells, or the antibodies they produce, may have therapeutic implications in improving checkpoint inhibition in glioblastoma. Citation Format: Cheryl J. Claunch, Claire Diaz, Riley A. Roth-Carter, Lauren Popp, Rochelle Fu, Amy E. Huddleston, Dana L. Moussalli, Julie Peterson, Kutluay Uluc, Laszlo Szidonya, Guang Fan, Ferdinando Pucci, Ramon F. Barajas, Leslie L. Muldoon, Edward A. Neuwelt, Prakash Ambady. CD5+ B-cell count is a favorable prognostic factor associated with progression-free survival in glioblastoma patients receiving chemoradiation and pembrolizumab [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT183.