bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P6-03-15: MCL-1 confers oncogenic role in breast cancer through modulating drug resistance and cancer stemness by targeting MRP1
Authors: Zhang Yuzhu , Huang Junyan , Bie Fengjie , Ren Liping , Chen Qianjun
Published: March 2020

Background: Breast cancer is the most common malignant tumor and the leading killer in women. Chemotherapy is one of the most important treatments for breast cancer. However, development of chemotherapy resistance is the main reason for 20-30% of breast cancer patients getting metastasis and leading to death. MCL-1, the anti-apoptotic protein, is not clarified in conforing chemotherapy resistance of Breast cancer. This work is mainly to prove that MCL-1 is the role of chemotherapy resistance and stemness of Breast cancer.Methods: We used large gene panels to detect pathological sections of tumors in drug-resistant and sensitive patients. We validated protein profiling by IHC in a larger cohort of samples. We performed the function of MCL-1 by knockdown and overexpression in vitro and in vivo. Luciferase assay and CHIP assay were used to prove the regulatory network between MCL-1 and MRP1.Result: Here, we find that MCL-1 is highly expressed in drug-resistant breast cancer tissues than sensitive. Functional studies reveal that MCL-1 plays important role in drug resistant by regulating apoptosis in breast cancer cells. We identity that knockdown of MCL-1 enhances sensitivity and reduces stem cell of breast cancer in vitro and in vivo, while overexpression has the opposite effect. Furthermore, by down and up regulation MCL-1, we show that MCL-1 regulates the expression of MRP1 (ABCC1) in breast cancer cells. Finally, we demonstrate that MCL-1 regulates ABCC1 expression through binding to its specific promoter region and promoting its transcription levels.Conclusion: Our work highlight the role of MCL-1 in chemoresistance and stemness, suggesting it could be used as a new clinical marker for breast cancer with drug resistance.Keyword:MCL-1, Breast cancer, chemoresistance, stemness, MRP1. Funding: Guangdong Natural Science Foundation No. 2017A030313719;Foundation Project of Guangzhou University of Traditional Chinese Medicine, No. XKP2019002.

Citation Format: Yuzhu Zhang, Junyan Huang, Fengjie Bie, Liping Ren, Qianjun Chen. MCL-1 confers oncogenic role in breast cancer through modulating drug resistance and cancer stemness by targeting MRP1 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-15.
Abstract P6-04-08: Mismatch repair defects induce metastasis of ER+ breast cancer
Authors: Khanal Sujita , Jimenez Athena , Haricharan Svasti
Published: March 2020

Estrogen receptor (ER) positive breast cancer is a leading cause of cancer-related death among women globally. Metastasis and endocrine treatment resistance are the two principal causes of death from ER+ breast cancer. There are few available targeted therapeutics for metastatic, endocrine treatment resistant disease other than CDK4/6 inhibitors. However, CDK4/6 inhibitors only work in a subset of patients and markers that can identify these patients have not yet been discovered. Considering cost and toxicity associated with chronic use of these inhibitors, it is critical to identify (a) biomarkers of response (b) combinatorial approaches to enhance efficacy. To achieve these goals, we need to understand the biology underlying endocrine treatment resistance and CDK4/6 inhibitor response. We recently identified loss of the MutL complex of mismatch repair (MLH1 and PMS2), as a cause of endocrine treatment resistance in 5-10% of women with primary (non-metastasized) ER+ breast cancer. We also demonstrated that primary ER+ breast cancer cells defective in these genes lacked ATM/Chk2 activation and were, therefore, sensitized to CDK4/6 inhibitors.

Here, we present data demonstrating that MutL loss induces metastasis of ER+ breast cancer cells, which can be prevented/treated using ATM/Chk2 activators in combination with CDK4/6 inhibitors. We observed increased migration and invasion in three independent cell line models of MutL loss when treated with endocrine therapies in vitro, and increased lung colonization in vivo. We observe a similar phenotype in a PDX model of MutL defective ER+ disease. We also demonstrate significant inhibition of metastatic phenotypes upon administration of a combination of CDK4/6 inhibitors and ATM/Chk2 activators.

Alternative targeted therapies that are effective against metastatic ER+ breast cancer remain elusive, and lethality associated with this diagnosis remains high. Current standard care comprises of endocrine treatment administered with CDK4/6 inhibitors. Even when effective, this combination is costly and associated with side effects as it requires chronic administration to maintain stable disease. The results of this study suggest that (a) MutL loss can be a predictor of increased risk for metastatic disease (b) MutL defective ER+ breast cancer has increased sensitivity to CDK4/6 inhibitors (c) combinatorial use of ATM/Chk2 activators with CDK4/6 inhibitors could significantly benefit ER+ breast cancer patients with defective MutL. These potential outcomes could greatly improve quality of life and decrease cancer-related death in thousands of women every year.

Citation Format: Sujita Khanal, Athena Jimenez, Svasti Haricharan. Mismatch repair defects induce metastasis of ER+ breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-04-08.
Abstract P6-05-08: Progesterone receptor membrane component 1 controls cellular proliferation and plays a key role in the molecular circuitry of both ER positive and triple negative breast cancers
Authors: Pedroza Diego A , Bencomo Alejandra , Galvez Adriana , Subramani Ramadevi , Rajamanickam Venkatesh , Lakshmanaswamy Rajkumar
Published: March 2020

Introduction: Increased expression of progesterone receptor membrane component 1 (PGRMC1), has been linked to breast cancer cell proliferation and tumor growth via epidermal growth factor receptor (EGFR) dependent interaction. As estrogen receptor positive breast cancers receive endocrine therapy and triple negative breast cancers (TNBC) rely on chemotherapeutic agents and or small molecule inhibitors. PGRMC1 could be a potential therapeutic target for both estrogen receptor positive and TNBCs, however its mechanism of action remains elusive. We, aim to understand the signaling mechanism behind PGRMC1 and its potential as viable target for the treatment of breast cancers. Materials and Methods: A panel of non-malignant and malignant breast cell lines were cultured and screened for PGRMC1 expression. PGRMC1 overexpressing breast cancer cell lines were treated with AG-205 (PGRMC1 inhibitor) and PGRMC1 targeting siRNAs. MTS, qRT-PCR, Western blot, immunofluorescence, flow cytometry assays and phospho explorer antibody array analysis were performed. Results: Increased PGRMC1 mRNA and protein levels were observed in estrogen receptor positive ZR-75-1 and TNBC MDA-MB-468 cells, these results were validated and compared to online RNA-seq based gene expression analysis of breast cell lines and breast tumor data sets. Data from online databases also demonstrated PGRMC1 overexpression in multiple breast cancer subtypes (Luminal, Basal B and Basal A). Immunohistochemistry demonstrated strong staining for PGRMC1 in human breast cancer tissue compared to normal tissue. Both AG-205 treatment and PGRMC1 silencing decreased cell proliferation, induced cell cycle arrest at the G0/G1 phase, promoted apoptosis and reduced the capability of the cells to migrate and invade. Phospho-specific antibody array data demonstrated overall downregulation of the EGFR/PI3K/AKT signaling mechanisms following AG-205 and PGRMC1 silencing. Alteration in the expression of key markers of cell proliferation, apoptosis and cell cycle revealed that PGRMC1 inhibition decreases breast cancer proliferation. Conclusion: Our data demonstrate that PGRMC1 plays a prominent role in regulating breast cancer growth and progression by altering the EGFR/PI3K/AKT signaling mechanisms.

Citation Format: Diego A Pedroza, Alejandra Bencomo, Adriana Galvez, Ramadevi Subramani, Venkatesh Rajamanickam, Rajkumar Lakshmanaswamy. Progesterone receptor membrane component 1 controls cellular proliferation and plays a key role in the molecular circuitry of both ER positive and triple negative breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-05-08.
Abstract P6-05-13: Crosstalk of post-translational modifications upon ERalpha activation
Authors: Chang Kai-Hsiung , Wen Hui-Chin , Tsai Sin-Yin
Published: March 2020

Breast cancer risk correlates highly with sustained estrogen receptor (ER) activities. Estrogen antagonists (e.g. anti-estrogens) and estrogen synthesis blockers (e.g. aromatase inhibitors) are frontline treatment to hinder disease progression in patients with breast cancer because most malignant breast tumors exhibit ERalpha positive expression signature. ERalpha harbors several post-translational modifications such as phosphorylation, acetylation, methylation, ubiquitination, sumoylation, palmitoylation, and others. Dysregulation of such PTMs on ERalpha enables abnormal tumor cell proliferation and promote malignancy. Although individual PTM on ERalpha is extensively deciphered, it remains relatively unclear how PTMs interact with each other to coordinate and execute 1) the recruitment of co-activators and RNA polymerase machinery to chromatin and 2) promoter clearance after transcription activation. Here, we report a novel PTM crosstalk between transcription-coupled phosphorylation and an ubiquitination-like modification on ERalpha. We also reveal its potential roles in regulating ER transcriptional activation and its future application in managing ER positive breast cancer.

Citation Format: Kai-Hsiung Chang, Hui-Chin Wen, Sin-Yin Tsai. Crosstalk of post-translational modifications upon ERalpha activation [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-05-13.
Abstract P6-10-13: Associated ductal carcinoma in situ in primary operated TNBC is associated with a longer time to distant event
Authors: Ardui Jan , Wildiers Hans , Floris Giuseppe , Izci Hava , Punie Kevin , Geukens Tatjana , Van Nieuwenhuysen Els , Han Sileny , Berteloot Patrick , Laenen Annouschka , Janssens Hilde , Smeets Ann , Weltens Caroline , Vergote Ignace , Neven Patrick
Published: March 2020

Purpose We studied presence of accompanying ductal adenoma in situ (accom-DCIS) in a consecutive series of primary operated TNBC for distant time-to-event outcome. Methods A retrospective cohort study (diagnosis 1/1/2000 - 31/12/2017) of prospectively registered primary operated TNBC patients in UZ Leuven. Only TNBC of no special type were included. We compared patient (age, BMI, symptomatic/screening-detected) and tumor related factors (Nottingham Prognostic Index (NPI), Lymphovascular Involvement (LVI)) for accom-DCIS and analyzed the effect of accom-DCIS on distant time to event outcome using the Cox proportional hazards model. Multivariate models were used to correct for possible confounders. Results We included 524 patients. Median follow-up was 102 months. Mean age of patient was 57.3 [26-90] years and 361 had accom-DCIS (68,9 %); demographics, clinical-pathological characteristics and postoperative chemo- and radiotherapy were similar in patients with and without accom-DCIS; only LVI was significantly more likely to be present in accom-DCIS cases (p=<0.001). There were no differences in distant relapse rate (16.6% in accom-DCIS group vs 12.9% in no DCIS group [HR = 1.350, 95% CI (0.817;2.248) p=0.239]. Time to distant event was later if accom-DCIS was present: Mean time to distant event was 2.72yrs in the accom-DCIS group and 1.61yrs in the group with absent DCIS. In accom-DCIS 20/63 (31.8%) distant relapses occurred after 3 years while only 1/21 distant relapse (4.8%) occurred after 3 years in the non-DCIS group [HR =6.667, 95% CI (0.952-46.705) p=0,029]. Conclusion In our series of TNBCs, patients with and without accom-DCIS had similar distant relapse rates. Significantly more distant relapse occurred after 3 years in patients with accom-DCIS compared to patients without accom-DCIS.

Citation Format: Jan Ardui, Hans Wildiers, Giuseppe Floris, Hava Izci, Kevin Punie, Tatjana Geukens, Els Van Nieuwenhuysen, Sileny Han, Patrick Berteloot, Annouschka Laenen, Hilde Janssens, Ann Smeets, Caroline Weltens, Ignace Vergote, Patrick Neven. Associated ductal carcinoma in situ in primary operated TNBC is associated with a longer time to distant event [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-13.
Abstract P6-16-08: Evaluation of cytochrome P450 4A11 overexpression in breast cancer cells in vitro and in vivo
Authors: Ali Sehar , Borin Thaiz , Arbab Ali
Published: March 2020

Metastatic breast cancer (BC) is a highly invasive form of cancer that contributes greatly to patient mortality. Due to the complex mechanisms underlying cancer growth and metastasis, novel therapeutic targets must be found to increase patient survival. One such target is the cytochrome P450 4 (CYP4) metabolic pathway leading to the production of 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE is a lipid signaling molecule that promotes both tumor cell proliferation and neovascularization in tumors by inducing the proliferation and migration of endothelial cells, therefore promoting BC tumor survival. N-hydroxy-N’-(4-butyl-2 methyl phenyl) formamidine (HET0016) is a selective inhibitor of 20-HETE synthesis, thus impairing tumor growth and neovascularization. This study aims to investigate changes in BC (MDAMB231 and MCF7) cell lines overexpressing CYP4A11, a human CYP4 enzyme, with and without HET0016 treatment. To accomplish this, cells that overexpressed CYP4A11 were produced using lentivirus infection and confirmed via western blot. Tumor cell aggressiveness was assessed in vitro using migration and proliferation assays. Tumor growth with and without CYP4A11 overexpression was also measured in vivo using athymic nude mice. The results demonstrated that cells overexpressing CYP4A11 showed protein levels 4 times higher than the non-modified cells. MDAMB231 is a triple-negative BC (TNBC) that, when overexpressing CYP4A11, demonstrated increased proliferation capacity and significant increased tumor growth compared to non-modified cells. TNBC cells overexpressing CYP4A11 also showed increased motility. However, modified MCF7 cells did not show significant alterations when compared to non-modified MCF7 cells. Additionally, all cells treated with HET0016 showed decreased migration in the first 24 hours. In conclusion, these results demonstrate that the overexpression of CYP4A11 in TNBC cells increased tumor aggressiveness, proving this pathway to be an important target for therapeutic inhibition.

Citation Format: Sehar Ali, Thaiz Borin, Ali Arbab. Evaluation of cytochrome P450 4A11 overexpression in breast cancer cells in vitro and in vivo [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-16-08.
Abstract TS1-3: Proteogenomics and Clinical Translation
Authors: Ellis MJ
Published: March 2020

Improvements in breast cancer treatment are being achieved at an increasing pace in all three clinical subsets of the disease, namely ER+ HER2- (luminal), HER2+ (HER2-driven) and ER- PgR- and HER2- (triple negative). While these disease groupings served as useful approximations of the immense diversity of breast cancer when only endocrine therapy, chemotherapy and trastuzumab were available, the inadequacy of this disease classification is readily evident when set against the sophistication of our growing therapeutic armamentarium. What is on the horizon to replace our simple immunohistochemistry-based subtyping approaches to avoid misdiagnosis and consequent mismanagement? In this lecture I will make the argument that the advent of efficient and accurate protein mass spectrometry provides the “missing link” in ‘omics analysis that integrates information derived from next generation DNA and RNA analysis to create a more secure diagnostic conclusion. The new field of “clinical proteogenomics” validates proposed disease drivers, dissects complex amplicons, monitors signaling perturbations in response to targeted treatments and determines the activity of the immune microenvironment. The advent of cloud computing promotes the efficient delivery of individualized proteogenomic therapeutic road maps as a near-term possibility.

Citation Format: MJ Ellis. Proteogenomics and Clinical Translation [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr TS1-3.
Abstract A13: Leveraging Zika virus and the immune system to treat glioblastoma
Authors: Jash Arijita , Govero Jennifer , Nair Sharmila , Diamond Michael S. , Chheda Milan G.
Published: March 2020

Glioblastoma (GBM) kills most adults within 2 years. One reason for inevitable recurrence is that GBM stem cells (GSCs) are resistant to existing therapies. Additionally, GBM is the hallmark example of an immunotherapy-resistant tumor. Since GSCs share properties with neural stem cells, we investigated whether the natural honing and lytic activity of Zika virus (ZIKV) could be harnessed to target and kill GSCs. We published the first use of ZIKV to kill GSCs: ZIKV kills GSCs in tumors removed from patients, with minimal impact on non-GSC tumor cells and importantly, normal human brain cells were not affected by ZIKV. In vivo, ZIKV more than doubled median survival in immunocompetent mice bearing orthotopic gliomas, and in 40-50% of cases, mice were cured. In new unpublished work, we assessed brains of mice treated with ZIKV and found that treatment induces a robust inflammatory response. Using MHC-I tetramers presenting ZIKV envelope (E) protein or luciferase peptides (expressed in the tumor cells), we found that CD8+ T cells in the region of the tumor respond to both ZIKV and tumor, and anti-tumor CD8+ T cells are increased after ZIKV infection compared to vehicle. Additionally, cured mice were protected against tumor rechallenge, suggesting ZIKV induces immunologic memory that can surveil against recurrence. Using blocking antibodies, we discovered that CD8+ T cells are required for the efficacy of ZIKV, and CD8+ T cells are required for long-term protection. Our findings suggest that ZIKV may be an effective therapy for GBM for two reasons: its direct targeting of treatment-resistant tumor cells in turn produces an antitumor inflammatory response. Such a response may now be further leveraged by immunotherapies.

Citation Format: Arijita Jash, Jennifer Govero, Sharmila Nair, Michael S. Diamond, Milan G. Chheda. Leveraging Zika virus and the immune system to treat glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A13.
Abstract A2: Identify biomarkers associated with immunotoxicities using single-cell RNAseq
Authors: Chen Jiamin , Pflieger Lance , Sathe Anuja , Grimes Sue , Brems Michael , Pattison Tabitha , Christensen Bryce , Rhodes Terence , Ji Hanlee
Published: March 2020

Recent advancements in immunotherapy are revolutionizing the landscape of clinical immuno-oncology and have significantly increased patient survival in a range of cancers. Notably, immune checkpoint blockade therapies have induced durable responses and provided tremendous clinical benefits to previously untreatable patients. However, unleashing immune system against cancer also disrupts the immunologic homeostasis and induces inflammatory responses, resulting in immune-related adverse events. The precise mechanisms underlying immune-related adverse events remain unknown. Furthermore, it is unclear why immune checkpoint blockade therapies only induce inflammatory side effects in some patients but not others. In this study, we identify biomarkers associated with adverse events in cancer immunotherapy. Leveraging high-throughput single-cell RNA sequencing (scRNAseq), we systematically characterize the functional impacts of immune checkpoint blockade on the patient immune system at single-cell resolution. The peripheral blood mononuclear cells (PBMCs) from six cancer patients with melanoma or non-small cell lung cancer (NSCLC) before (T0) and after (T1, T2) receiving immune checkpoint blockade therapies, i.e., anti-PD-1 and anti-CTLA4, were collected and sequenced thus far. The longitudinal study of PBMCs provides an opportunity to elucidate the dynamics of immune responses. In total, we sequenced more than 70,000 cells from 18 PBMC libraries. Notably, when PBMCs from T1 and T2 were compared to T0, we observed sustained immune activation in a variety of cell populations after checkpoint blockade. Furthermore, we found distinct pathway activations associated with specific checkpoint blockade. Currently, we are performing comprehensive analysis to identify specific immune subpopulations and cytokines associated with immune-related adverse events, e.g., colitis and pneumonitis. Ultimately, our study will identify clinically actionable biomarkers for response prediction and side effects alleviation in patients receiving immunotherapy in the era of precision medicine.

Citation Format: Jiamin Chen, Lance Pflieger, Anuja Sathe, Sue Grimes, Michael Brems, Tabitha Pattison, Bryce Christensen, Terence Rhodes, Hanlee Ji. Identify biomarkers associated with immunotoxicities using single-cell RNAseq [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A2.
Abstract A56: Releasing the brake on T-cell activation through inhibition of HPK1
Authors: Grimster Neil , Drew Lisa , Fawell Stephen , Mele Deanna A , Bommakanti Gayathri , Shen Minhui , Xu Kevin , Song Kun , Ziegler Rob , Kettle Jason , Mfuh Adelphe , Sheilds Jason
Published: March 2020

Introduction: Loss of immune surveillance is required for cancer cell growth and metastasis; tumors co-opt suppressive mechanisms to evade detection by the immune system. The immune system is equipped with multiple feedback mechanisms to limit inflammation to prevent autoimmunity; tumors activate these pathways to escape immunity. HPK1 (hematopoietic progenitor kinase 1) is a negative regulator of T-cell activation; the kinase activity limits T-cell signaling and tumoricidal cytokine production. Recent literature has shown that inactivation of the kinase function of HPK1 prevents tumor progression in murine tumor models (1).

Experimental Procedures: We used lentiviral delivered shRNAs and CRISPR/Cas9 technology to delete HPK1 in Jurkat cells and primary human T cells, respectively. Jurkat T cells (wt/KO) were activated with anti-CD3 antibody and cell lysates were assessed by Western blot to examine signaling events downstream of the T-cell receptor (TCR). Primary human T cells or CRISPR/Cas9 KO T cells were activated in vitro using anti-CD3/anti-CD28 antibodies in the presence or absence of prostaglandin E2 (PGE2). Cytokines were quantified by ELISA.

Results: We present novel findings demonstrating that the role of HPK1 is conserved in human Jurkat cells as well as in primary human T cells. Loss of HPK1 enhanced T-cell receptor signaling in Jurkat cells. In CRISPR/Cas9 KO HPK1 primary human T cells, TCR activation resulted in enhanced cytokine secretion and proliferation concomitant to a decrease in pSLP76, the target molecule phosphorylated by HPK1. In addition, HPK1 KO cells were rescued from PGE2-mediated suppression. A screening and assessment of HPK-1 inhibitor compounds that enhance T-cell function is ongoing.

Conclusions: In summary, HPK1 function is conserved in human T cells and inhibitors of HPK1 could enhance antitumor immunity through increased T-cell function, overcoming suppressive signals in the tumor microenvironment and broadening the response to check point inhibitors for cancer immunotherapy.

Reference

1. Hernandez S, Qing J et al. The kinase activity of hematopoietic progenitor kinase 1 is essential for the regulation of T cell function. Cell Rep 2018;25:80-94.

Citation Format: Neil Grimster, Lisa Drew, Stephen Fawell, Deanna A Mele, Gayathri Bommakanti, Minhui Shen, Kevin Xu, Kun Song, Rob Ziegler, Jason Kettle, Adelphe Mfuh, Jason Sheilds. Releasing the brake on T-cell activation through inhibition of HPK1 [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A56.
Abstract A60: GM-CSF modulation restricts the secretion of main cytokines associated with CAR T-cell induced cytokine release syndrome
Authors: Sachdeva Mohit , Aranda-Orgilles Beatriz , Duchateau Philippe , Poirot Laurent , Valton Julien
Published: March 2020

Emerging CAR T-cell therapies have shown high remission rates in patients with hematologic malignancies. Despite the success of these novel immunotherapies, multiple adverse effects are associated with CAR T-cell infusions. Cytokine release syndrome (CRS) is one of the most common CAR T cell-associated toxicities and results from the rapid elevation of inflammatory cytokines, which can be life threatening. CRS is commonly managed in the clinic with anti-IL-6R antibodies and glucocorticoids. While efficacious, these treatments address CRS only after it has initiated; therefore, alternative therapeutic strategies preventing CRS onset remain an urgent need. Using cytokine profiling arrays, we identified that secreted granulocyte macrophage colony stimulating factor (GM-CSF) contributes to CRS, since elevated GM-CSF levels promote macrophage-dependent secretion of key CRS biomarkers including MCP-1, IL-6, and IL-8. Modulation of GM-CSF levels either via genetic engineering of CAR T-cells using TALEN® technology or via neutralizing-antibodies resulted in a marked reduction of macrophage-dependent release of CRS-associated cytokines, while preserving antitumor activity. Our work proposes a novel therapeutic strategy to improve the overall safety of CAR T-cell therapies in cancer patients by using GM-CSF knockout CAR T cells.

Citation Format: Mohit Sachdeva, Beatriz Aranda-Orgilles, Philippe Duchateau, Laurent Poirot, Julien Valton. GM-CSF modulation restricts the secretion of main cytokines associated with CAR T-cell induced cytokine release syndrome [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A60.
Abstract A70: Bridging nonclinical studies to clinical design using quantitative systems pharmacology model of T cell-engaging bispecifics
Authors: Lin Lin , Wille Lucia , Betts Alison , Hua Fei , Hagen David , Park Jennifer , Apgar Josh , Burke John
Published: March 2020

Purpose: T cell-engaging bispecific molecules (TCEs) are protein therapeutics that can bind to both T cells, via CD3 interactions, and target cells through target specific/overexpressed molecules. The TCEs bring cytolytic T cells to kill tumor cells through the formation of the trimolecular complex (CD3:TCE:Target). While it offers a potentially very potent approach to treat cancer, it also has a complex relationship between binding potency, exposure, and efficacy. These complex relationships bring challenges to drug discovery and development such as identifying optimal Kds for the drug candidate, predicting efficacious dose, and selecting dosing regimen in clinical study.

Methods: A quantitative systems pharmacology model was developed for solitomab, a bispecific T-cell engager binding to CD3 and EpCAM. The model includes solitomab binding to both CD3 and EpCAM in both tumor and normal tissue, different E:T ratios for tumor and normal tissue, turnover of CD3 and EpCAM proteins, as well as pharmacokinetics (PK) and tissue distribution of the drug. Literature data such as binding Kds, in vitro cell killing, and PK were used to inform model development.

Results: Using the calibrated QSP model, we demonstrated that the trimolecular complex per T cells required for in vitro T-cell killing are ~200 molecules, which is similar to the number predicted at the maximal tolerated dose observed in the clinical study despite many differences between in vivo and in vitro conditions such as E:T ratios. The therapeutic index (TI) for solitomab was predicted to be close to 1 based on the trimolecular complex per T cells in tumor and in normal tissue. This result is consistent with clinical observation. Using the developed model, we explored the effects of varying binding Kds to EpCAM and CD3, varying half-life of the drug, and varying target expression levels on TI.

Conclusion: Current work demonstrated the possibility of using a QSP model integrating in vitro data, human PK, and target biology to predict efficacious dose and TI for treating cancer. The model also demonstrated the complex relationship between Kds, target expression level, drug half-life, and TI for TCEs. This model can be used to guide future drug candidate selection and clinical study design.

Citation Format: Lin Lin, Lucia Wille, Alison Betts, Fei Hua, David Hagen, Jennifer Park, Josh Apgar, John Burke. Bridging nonclinical studies to clinical design using quantitative systems pharmacology model of T cell-engaging bispecifics [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A70.
Abstract A83: Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade
Authors: Miller Brian C. , Sen Debattama R. , Abosy Rose Al , Bi Kevin , Virkud Yamini , LaFleur Martin W. , Yates Kathleen B. , Lako Ana , Felt Kristen , Naik Girish S. , Manos Michael , Gjini Evisa , Ishizuka Jeffrey J. , Hodi F. Stephen , Rodig Scott J. , Sharpe Arlene H. , Haining W. Nicholas
Published: March 2020

T-cell dysfunction in the tumor microenvironment (TME) is a hallmark of many cancers. Reinvigoration of T-cell function by PD-1 checkpoint blockade can result in striking clinical responses, but is only effective in a minority of patients. The mechanisms by which anti-PD-1 therapy acts on exhausted T cells are not fully understood. Here we show that anti-PD-1 therapy acts on a specific subpopulation of CD8+ tumor-infiltrating lymphocytes (TILs) in melanoma mouse models, which can also be found in patients with melanoma. Exhausted CD8+ TILs contain a subpopulation of “progenitor exhausted” T cells with critical functional attributes that are not shared by the majority “terminally exhausted” TILs: they retain more polyfunctionality, persist following transfer into tumor-bearing mice, and differentiate to repopulate terminally exhausted TILs in the TME. As a result, progenitor exhausted CD8+ TILs are better able to control tumor growth than terminally exhausted cells. Progenitor exhausted, but not terminally exhausted, CD8+ TILs can respond to anti-PD-1 therapy. Melanoma patients with a higher percentage of progenitor exhausted cells have a longer duration of response to checkpoint blockade therapy. Therefore, approaches to expand progenitor exhausted CD8+ T cells in the tumor microenvironment may be an important component of improving checkpoint blockade response.

Citation Format: Brian C. Miller, Debattama R. Sen, Rose Al Abosy, Kevin Bi, Yamini Virkud, Martin W. LaFleur, Kathleen B. Yates, Ana Lako, Kristen Felt, Girish S. Naik, Michael Manos, Evisa Gjini, Jeffrey J. Ishizuka, F. Stephen Hodi, Scott J. Rodig, Arlene H. Sharpe, W. Nicholas Haining. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A83.
Abstract PR13: Adjuvant TLR-3 administration enhances proinflammatory immune responses and is associated with extended survival in glioblastoma patients treated with dendritic cell vaccination
Authors: Antonios Joseph P. , Everson Richard G. , Mochizuki Aaron , Khattab Sara , Soto Horacio , Romiyo Prashant , Sun Matthew Z. , Moughon Diana , Billingslea-Yoon Emma , Odesa Sylvia , Li Gang , Kawaguchi Eric , Salazar Alex , Yong William , Schlossman Jason , Ellingson Benjamin , Wang Anthony C. , Cloughesy Timothy , Prins Robert M. , Liau Linda M.
Published: March 2020

Malignant glioma, associated with a poor prognosis, is the most common primary malignant brain tumor in adults. We and others have documented immune responses following dendritic cell (DC) vaccination as an active immunotherapeutic treatment for these patients. In this phase II clinical trial, we randomized malignant glioma patients to receive autologous tumor lysate pulsed DC vaccination with and without adjuvant Toll-like receptor (TLR) agonists. TLRs are present on dendritic cells and serve to modulate immune responses. Twenty-three patients with WHO grade III or IV glioma were treated with three intradermal injections of autologous tumor lysate-pulsed DC on days 0, 14, and 28 followed by an adjuvant placebo, TLR-7 agonist (resiquimod), or TLR-3 agonist (Poly ICLC). Mass cytometry (CyTOF) was used to analyze immune cell populations of patient peripheral blood mononuclear cells (PBMC) before and following treatment. DC-vaccinated patients who received adjuvant Poly ICLC treatment had a significantly improved median survival of 54 months over placebo (11 months) and adjuvant resiquimod (17 months) groups (P<0.01). CyTOF and single-cell RNA sequencing (scRNseq) gene expression analysis of systemic PBMCs from patients demonstrated increased immune cell activation and expression of proinflammatory genes. Notably, the expansion of a heterogenous myeloid cell population was noted to correlate with increased survival, corroborating preclinical evidence that these cells modulate adaptive immunity in the tumor microenvironment. Overall, these findings suggest that adjuvant Poly ICLC treatment improves outcomes with autologous lysate-pulsed DC vaccine treatment via modulation of proinflammatory pathways.

This abstract is also being presented as Poster B27.

Citation Format: Joseph P. Antonios, Richard G. Everson, Aaron Mochizuki, Sara Khattab, Horacio Soto, Prashant Romiyo, Matthew Z. Sun, Diana Moughon, Emma Billingslea-Yoon, Sylvia Odesa, Gang Li, Eric Kawaguchi, Alex Salazar, William Yong, Jason Schlossman, Benjamin Ellingson, Anthony C. Wang, Timothy Cloughesy, Robert M. Prins, Linda M. Liau. Adjuvant TLR-3 administration enhances proinflammatory immune responses and is associated with extended survival in glioblastoma patients treated with dendritic cell vaccination [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR13.
Application of Histone Deacetylase Inhibitors in Renal Interstitial Fibrosis
Authors: Nie Ling , Liu Yong , Zhang Bo , Zhao Jinghong
Published: March 2020

Background: Renal interstitial fibrosis is characterized by the accumulation of extracellular matrix proteins, which is a common feature of chronic kidney diseases. Summary: Increasing evidence has shown the aberrant expression of histone deacetylases (HDACs) in the development and progression of renal fibrosis, suggesting the possibility of utilizing HDAC inhibitor (HDACi) as therapeutics for renal fibrosis. Recent studies have successfully demonstrated the antifibrotic effects of HDACis in various animal models, which are associated with multiple signaling pathways including TGF-β signaling, EGRF signaling, signal transducer and activator of transcription 3 pathway, and JNK/Notch2 signaling. This review will focus on the utilization of HDACi as antifibrotic agents and its relative molecular mechanisms. Key Messages: HDACis have shown promising results in antifibrotic therapy, and it is rational to anticipate that HDACis will improve clinical outcomes of renal fibrosis in the future.
The Clinical and Molecular Characteristics of Sex-Determining Region Y-Box 2 and its Prognostic Value in Breast Cancer: A Systematic Meta-Analysis
Authors: Zhao Gang , Wang Xiaozhen , Qu Limei , Zhu Zhu , Hong Jinghui , Hou Haiqin , Li Zuonong , Wang Jun , Lv Zheng
Published: March 2020

Objective: Transcription factor SOX2 (sex-determining region Y-box 2) has a crucial role in the maintenance of the stem cell state. However, current evidence regarding the role of SOX2 in breast cancer is conflicting. We conducted this meta-analysis to clarify the association of SOX2 expression with clinical and molecular features and its prognostic effect on breast cancer. Methods: All relevant articles were searched using electronic databases. The pooled odds ratios (ORs) or hazard ratios (HRs: multivariate Cox survival analysis) with their 95% confidence intervals (CIs) were calculated. Results: A final total of 18 studies containing 3,080 patients with breast cancer were included. SOX2 protein expression was not related to age, menopausal status, lymph node metastasis, lymphovascular invasion, molecular estrogen receptor status, progesterone receptor status, triple-negative status, and the overall survival in breast cancer, but was closely associated with advanced tumor grade (grade 3 vs. grade 1–2: OR = 2.74, 95% CI = 1.85–4.06, p < 0.001), clinical stage (stage 3–4 vs. stage 0–2: OR = 2.46, 95% CI = 1.37–4.40, p = 0.002), pT stage (T stage 2–4 vs. T stage 1: OR = 1.52, 95% CI = 1.07–2.17, p = 0.019), molecular human epidermal growth factor receptor 2 (HER2) status (positive vs. negative: OR = 1.61, 95% CI = 1.21–2.14, p = 0.001), epidermal growth factor receptor (EGFR) status (positive vs. negative: OR = 2.21, 95% CI = 1.13–4.33, p = 0.021), and worse disease-free survival (DFS) (HR = 2.66, 95% CI = 1.20–5.91, p = 0.016) of breast cancer. Conclusions: SOX2 expression is correlated with breast cancer progression, HER2 status, and EGFR status, and may be an independent prognostic marker for predicting poor DFS.
Complete Remission of Relapsed Hodgkin’s Lymphoma following Brentuximab Vedotin and Gemcitabine Combination Therapy with Severe Hypotension as Possible Treatment-Related Adverse Event: A Case Report
Authors: Purwanto Ibnu , Utomo Bambang P. , Ghozali Ahmad
Published: March 2020

A 40-year-old Asian female with heavily treated relapsed Hodgkin’s lymphoma showed complete remission (CR) after receiving 8 cycles of brentuximab vedotin (BV) in combination with gemcitabine as 4th line treatment. The patient remained in CR at the 18-month post-treatment follow-up. She developed severe hypotension (50/36 mm Hg) with upper and lower limb petechiae and edema after the addition of gemcitabine on the 6th cycle of BV. This adverse event resolved after 3 days of treatment with vasopressor and high-dose corticosteroid. The addition of dexamethasone for the subsequent 2 cycles successfully prevented this adverse event from recurring.
Main Patterns of Fetal Cardiac Remodeling
Authors: Crispi Fàtima , Sepúlveda-Martínez Álvaro , Crovetto Francesca , Gómez Olga , Bijnens Bart , Gratacós Eduard
Published: March 2020

The heart is a central organ in the fetal adaptation to an adverse environment. Fetal cardiac changes may persist postnatally and increase the risk of cardiovascular disease in adulthood. Knowledge about fetal cardiac structural as well as functional remodeling has radically improved over the last few years. As it occurs in postnatal life, the fetal heart remodels – changing its structure and shape – to adapt to an insult. Several conditions have been reported to be associated with fetal cardiac remodeling including intrauterine growth restriction, diabetes, exposure to antiretroviral drugs, conception by assisted reproductive technologies, pulmonary stenosis, and other congenital heart diseases. Here we summarized the main observable patterns of cardiac remodeling, i.e., globular shape, hypertrophy without dilation, and hypertrophy with cardiomegaly. We discuss the potential pathophysiology behind different types of remodeling. Defining precisely the distinct patterns of fetal cardiac remodeling is critical for advancing in the understanding of fetal cardiovascular programming and its consequences on adult health, and potentially for the design of preventive strategies that might have an impact on long-term cardiovascular health.
Prevalence of Mild Cognitive Impairment in Rural Thai Older People, Associated Risk Factors and their Cognitive Characteristics
Authors: Griffiths Jiranan , Thaikruea Lakkana , Wongpakaran Nahathai , Munkhetvit Peeraya
Published: March 2020

Introduction: Mild cognitive impairment (MCI) is a transitional stage between normal cognition and dementia. A review showed that 10–15% of those with MCI annually progressed to Alzheimer’s disease. Objective: This study aimed to investigate the prevalence and risk factors associated with MCI as well as the characteristics of cognitive deficits among older people in rural Thailand. Methods: A cross-sectional study in 482 people who were 60 years old and over was conducted in northern Thailand. The assessments were administered by trained occupational therapists using demographic and health characteristics, Mental Status Examination Thai 10, Activities of Daily Living – Thai Assessment Scale, 15-item Geriatric Depression Scale and the Montreal Cognitive Assessment-Basic (MoCA-B, Thai version). Results: The mean age of MCI was 68.3 ± 6.82 years, and most had an education ≤4 years. The prevalence of MCI in older people was 71.4% (344 out of 482), and it increased with age. Low education and diabetes mellitus (DM) were the significant risk factors associated with cognitive decline. Older people with MCI were more likely to have an education ≤4 years (RR 1.74, 95% CI 1.21–2.51) and DM (RR 1.19, 95% CI 1.04–1.36) than those who did not. The 3 most common cognitive impairments according to MoCA-B were executive function (86%), alternating attention (33.1%) and delayed recall (31.1%). Conclusion: The prevalence of MCI in older Thai people in a rural area is high compared with that in other countries. The explanation might be due to low education and underlying disease associated with MCI. A suitable program that can reduce the prospects of MCI in rural Thailand is needed.
Impact of Silicone Stent Placement in Symptomatic Airway Obstruction due to Non-Small Cell Lung Cancer – A French Multicenter Randomized Controlled Study: The SPOC Trial
Authors: Dutau Hervé , Di Palma Fabrice , Thibout Yoann , Febvre Michel , Cellerin Laurent , Naudin Frédérique , Hermant Christophe , Vallerand Hervé , Lachkar Samy , Fournier Clément , Laroumagne Sophie , Quiot Jean-Jacques , Vergnon Jean-Michel ,   SPOC Investigators
Published: March 2020

Background: Therapeutic bronchoscopy (TB) is an accepted strategy for the symptomatic management of central airway malignant obstruction. Stent insertion is recommended in case of extrinsic compression, but its value in preventing airway re-obstruction after endobronchial treatment without extrinsic compression is unknown. Objective: Silicone stent Placement in symptomatic airway Obstruction due to non-small cell lung Cancer (SPOC) is the first randomized controlled trial investigating the potential benefit of silicone stent insertion after successful TB in symptomatic malignant airway obstruction without extrinsic compression. Method: We planned an inclusion of 170 patients in each group (stent or no stent) over a period of 3 years with 1-year follow-up. The 1-year survival rate without symptomatic local recurrence was the main endpoint. Recurrence rate, survival, quality of life, and stent tolerance were secondary endpoints. During 1-year follow-up, clinical events were monitored by flexible bronchoscopies and were evaluated by an independent expert committee. Results: Seventy-eight patients (mean age 65 years) were randomized into 2 arms: stents (n = 40) or no stents (n = 38) after IB. Consequently, our main endpoint could not be statistically answered. Improvement of dyspnea symptoms is noticeable in each group but lasts longer in the stent group. Stents do not change the survival curve but reduce unattended bronchoscopies. In the no stent group, 19 new TB were performed with 16 stents inserted contrasting with 10 rigid bronchoscopies and 3 stents placed in the stent group. In a subgroup analysis according to the oncologic management protocol following TB (first-line treatment and other lines or palliation), the beneficial effect of stenting on obstruction recurrence was highly significant (p < 0.002), but was not observed in the naïve group, free from first-line chemotherapy. Conclusion: Silicone stent placement maintains the benefit of TB after 1 year on dyspnea score, obstruction’s recurrence, and the need for new TB. Stenting does not affect the quality of life and is suggested for patients after failure of first-line chemotherapy. It is not suggested in patients without previous oncologic treatment.
The Multicomponent, Multitarget Therapy SUC in Cats with Chronic Kidney Disease: A Multicenter, Prospective, Observational, Nonrandomized Cohort Study
Authors: Brandenburg Uta , Braun Gabriele , Klein Peter , Reinhart Erich
Published: March 2020

Background: We compared the natural multicomponent, multitarget therapy SUC (Solidago compositum ad us. vet., Ubichinon compositum and Coenzyme compositum, Heel GmbH, Baden-Baden, Germany) to the well-known angiotensin-converting enzyme inhibitor benazepril in a prospective, observational, nonrandomized, two-arm cohort study of cats with chronic kidney disease (CKD). The objective was to assess the tolerability and the effectiveness of SUC in cats with CKD. Material and Methods: One hundred thirty-six cats were screened for CKD, and 70 cats were eligible for the study. Thirty-three cats were assigned to the SUC treatment, and 35 cats received benazepril. All cats were diagnosed with CKD. The follow-up period was 168 days. Response was assessed as an improved or stable serum creatinine from baseline to the end of the study. Additionally, a clinical summary score, as measure of quality of life, was evaluated. Results: Serum creatinine remained close to baseline in both study groups with slightly improved values in the SUC group. The clinical summary score improved significantly in the SUC group on days 3, 7, 28, 56 and 112, but not on day 168. Conclusions: Within the limitations of the study, the results carry implications for the usefulness of SUC as an interesting new treatment option for feline CKD. The results indicate that SUC might be more effective if given at least twice weekly.
First Case of Intracranial Mycotic Aneurysm Caused by Prevotella intermedia Associated with Chronic Sinusitis in a Korean Adult
Authors: Park Hea Ree , Chang Jeonghyun , Kim Sollip , Um Tae Hyun , Cho Chong Rae
Published: March 2020

Intracranial infection caused by anaerobic bacteria is rare, and it is difficult to identify absolute anaerobes in the clinical laboratory, especially when the bacterial load is low. Here, we report the first case of intracranial mycotic aneurysm caused by Prevotella intermedia associated with chronic sinusitis and successful identification of the bacteria by 16S rRNA sequencing from bacterial growth in broth only.