bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 945: Advancing cancer immunotherapeutics: A focus on characterization of anti-CTLA-4 mAbs for better anti-tumor immunity and less toxicity
Authors: Du Xuexiang , Liu Mingyue , Zhang Yan , Tang Fei , Ai Chunxia , Zhang Peng , Zheng Pan , Liu Yang
Published: September 2020

Anti-CTLA-4 monoclonal antibodies confer a cancer immunotherapeutic effect (CITE) but cause severe immunotherapy-related adverse events (irAEs). How to uncouple the undesired irAEs from the beneficial CITE seen in cancer patients treated with anti-CTLA-4 and/or other checkpoints inhibitors has proven to be a daunting challenge, partially due to the lack of the understanding of the real MOA(mechanism of Action) of CITE and irAEs. Meanwhile, an animal model, which recapitulates clinical irAE and CITE, would be valuable for developing safer CTLA-4-targeting reagents. We not only discovered that the immunotherapy of current anti-CTLA-4 mAbs were dependent on Fc/Fc receptor mediated intra-tumor Treg depletion rather than the widely held mechanism of checkpoint blockade, which raised the reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy, we also establish one realistic irAEs model and find one mechanism of irAEs. In this model, the clinically used drug Ipilimumab (or TremeIgG1) induced severe irAEs especially when combined with an anti-PD-1 antibody; whereas another mAb L3D10 induced comparable CITE with very mild irAE under the same conditions. Humanization (HL12/HL32) of L3D10, which led to the loss of blocking activity, further increased safety without affecting the therapeutic effect. Furthermore, we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface, increasing the pH sensitivity of TremeIgG1 by introducing designed tyrosine-to-histidine mutations prevents antibody-triggered lysosomal CTLA-4 downregulation and dramatically attenuates irAE. Our data establish a new paradigm for cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies.

Citation Format: Xuexiang Du, Mingyue Liu, Yan Zhang, Fei Tang, Chunxia Ai, Peng Zhang, Pan Zheng, Yang Liu. Advancing cancer immunotherapeutics: A focus on characterization of anti-CTLA-4 mAbs for better anti-tumor immunity and less toxicity [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 945.
Abstract 965: Eribulin promotes a distinct immunogenic gene expression signature as compared with paclitaxel
Authors: Fermaintt Charles , Mooberry Susan , Risinger April L.
Published: September 2020

Microtubule targeted agents (MTAs) are a mainstay in the treatment of breast cancer and they are often used in combination with targeted agents, including immunotherapies. Although patients with triple-negative breast cancers (TNBCs) have historically had poorer clinical outcomes due in part to a lack of targeted therapeutic options, these cancers are often more immunogenic than other types of breast cancer. Recently, the combination of the PD-L1 inhibitor atezolizumab with the taxane nab-paclitaxel was found to prolong progression-free survival in patients with metastatic TNBC. Other combinations of MTAs and immune checkpoint inhibitors are actively being evaluated in clinical trials. There is a mechanistic rationale for this combination because paclitaxel is a direct TLR4 agonist that promotes activation of the innate immune system. To date, there has not been a comprehensive comparison of the immunomodulatory effects of different MTAs on immune cells or on or TNBC cells. We hypothesized that MTAs that differentially alter interphase microtubule structure and dynamics would have distinct effects on cell-intrinsic immunogenic pathways and that these effects could impact the efficacy of these drugs in combination with immunotherapies. The effects of 5 MTAs used for the treatment of TNBC, paclitaxel, docetaxel, ixabepilone, vinorelbine, and eribulin, on the expression of antitumor cytokines and other immunomodulatory genes in myeloid and TNBC cells was evaluated. Our results show that the TLR4-mediated induction of TNFα that occurs in response to paclitaxel was not observed with either eribulin or vinorelbine. Conversely, upregulation of type 1 interferons and interferon-stimulated genes (ISGs) was observed in monocytes and in bone-marrow derived macrophages within 6 h of treatment with eribulin or vinorelbine, but not with any of the microtubule stabilizers. Eribulin-mediated induction of type 1 interferons was also observed in a subset of eribulin-treated TNBC cells and was independent of its antimitotic effects. Importantly, type I interferon signaling has been shown to enhance the efficacy of immune checkpoint inhibitors, suggesting that microtubule destabilizers could have distinct advantages as compared to microtubule stabilizers in combination with these agents. Together, these results provide evidence that MTAs have different immune modulatory properties and suggest that the specific immune signatures initiated by different MTAs need to be considered for their optimal use with targeted agents, including checkpoint inhibitors. These studies were funded by Eisai.

Citation Format: Charles Fermaintt, Susan Mooberry, April L. Risinger. Eribulin promotes a distinct immunogenic gene expression signature as compared with paclitaxel [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 965.
Abstract 97: Analysis of Pten-null mouse astrocytes revealed overlapping transcribed genes with human glioblastoma transcriptome
Authors: Liu Tian , Or Penelope Mei-Yu , Wong Chi-Wai , Cheung Stanley Kwok-Kuen , Wang Yubing , Wang Yiwei , Chan Andrew M.
Published: September 2020

Glioblastoma is an aggressive form of brain cancer with universally poor prognosis. Even with optimal therapy, the cancer recurs frequently. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene whose mutations are often found in multiple human cancers. PTEN encodes a lipid phosphatase and serves as a negative regulator of the phosphoinositide 3-kinase (PI3K) pathway. Cumulative evidence suggests that PTEN mutations play significant roles in tumorigenesis of glioblastoma as 60% of glioblastoma patients acquired mutations in this gene. Based on our preliminary data, transcriptomic profiling of primary astrocytes derived from Pten knockout mice revealed an overlapping enrichment of mitotic regulators and cell cycle related pathways with human GBM. 4 genes (RCC1, RCC2, NEK2, and CHK2) were validated to be significantly upregulated in PTEN KO astrocytes by qRT-PCR. Regulator of chromatin condensation 2 (RCC2) has been reported to be guanine-nucleotide exchange factor (GEF) for Rac1 and RalA GTPase and act as a regulator of cell cycle progression. Accumulating evidence revealed a pro-tumorigenic role of RCC2 in multiple cancers such as tumor growth and tumor metastasis. Via siRNA inhibition of RCC2, we demonstrated that knocking down of RCC2 in glioblastoma cell lines suppresses cell growth and RCC2 is essential for both G1-S and G2-M progression. Additionally, RCC2 knocking down and a PI3K inhibitor LY294002 inhibit glioblastoma cell viability in a synergistic manner. In summary, PTEN deficiency leads to the upregulation of RCC2, which may promote tumorigenesis of glioblastoma by dysregulating cell cycle progression.To further explore the RCC2 roles, we will find the potential downstream target of RCC2 in dysregulating cell cycle and its potential therapeutic effect in vivo. Funding: General Research Fund Grant #14113519 from The Research Grants Council of Hong Kong

Citation Format: Tian Liu, Penelope Mei-Yu Or, Chi-Wai Wong, Stanley Kwok-Kuen Cheung, Yubing Wang, Yiwei Wang, Andrew M. Chan. Analysis of Pten-null mouse astrocytes revealed overlapping transcribed genes with human glioblastoma transcriptome [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 97.
Abstract 973: Telomere stress potentiates host STING-dependent anti-tumor immunity
Authors: Zhang Anli , Mender Ilgen , Ren Zhenhua , Han Chuanhui , Deng Yafang , Siteni Silvia , Li Huiyu , Shay Jerry W. , Fu Yang-Xin
Published: September 2020

Telomerase is an attractive target for anti-tumor therapy as it is almost universally expressed in cancer cells but not in normal cells. Here we show that treatment with a telomerase-mediated telomere-targeting drug, 6-thio-2'-deoxyguanosine (6-thio-dG), leads to tumor regression in innate and adaptive immune-dependent manners in syngeneic and humanized mouse colon cancer models. 6-thio-dG treatment causes telomere-associated DNA damages that are sensed by dendritic cells (DCs) and activates the host cytosolic DNA sensing STING/IFN-I pathway, resulting in enhanced cross-priming capacity of DCs and tumor-specific CD8 T-cell activation. Moreover, 6-thio-dG overcomes resistances to checkpoint blockade in advanced mouse cancer models. Together, our results unveil how 6-thio-dG induced telomere stress increases innate sensing and adaptive anti-tumor immunity and provide a strong rationale for sequentially combining telomerase directed telomere-targeted therapy with immunotherapy.

Citation Format: Anli Zhang, Ilgen Mender, Zhenhua Ren, Chuanhui Han, Yafang Deng, Silvia Siteni, Huiyu Li, Jerry W. Shay, Yang-Xin Fu. Telomere stress potentiates host STING-dependent anti-tumor immunity [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 973.
Abstract 976: The systematic identification of novel immune checkpoint averting the metastasis of ovarian cancer: The role of IL20/IL24-IL20RA axis
Authors: Li Jia , Xuan Qin , SHI JIE , Wang Longlong , Shi Yi , Xiang Rong
Published: September 2020

Ovarian cancer has high mortality among all gynecological malignancies due to the lack of clear symptoms at early stage and the metastasis of cancer cells when diagnosed with advanced stage. The disseminated ovarian cancer cells have to overcome the immune surveillance in abdominal environment, which are rich in many types of immune cells, to survive and proliferate. However, the key genes and mechanisms preventing the metastasis of ovarian cancer cells into abdominal sites keep largely unexplored. Here, through an in vivo, genome-scale CRISPR/Cas9 knockout screening, we identified IL-20/IL24-IL20RA as a key checkpoint preventing the abdominal metastasis of ovarian cancer cells. In ovarian cancer patients, the level of IL20RA is dramatically decreased in metastatic cancer cells when compared with that in primary sites. Overexpression of IL20RA in highly metastatic ovarian cancer cells greatly suppressed the abdominal metastasis of ovarian cancer and the formation of ascites. In contrast, silencing IL20RA could increase the metastasis of ovarian cancer cells. We further examined IL20RA mediated crosstalk between the disseminated cancer cells and the immuno-microenvironment in mouse in vivo ovarian cancer models and in vitro co-culture experiments. Silencing IL20RA in ovarian cancer cells resulted in a dramatic decrease of M1 subtype of macrophages and increase of the M2 subtype of macrophages without affecting the population of T and B lymphocytes in ascites. Further mechanistic studies revealed that the ovarian cancer cells, when invaded into the abdominal sites, greatly induced the mesothelial cells in peritoneum to produce IL20RA ligands, i.e., IL-20 and IL-24, which in turn activated the IL20RA downstream signaling in ovarian cancer cells to trigger the production and maturation of IL-18. IL-18, when secreted into the microenvironment, was able to promote the polarization of macrophages into M1-subtype to clear the cancer cells. Thus, we identified a novel immune checkpoint IL-20/IL24-IL20RA that was always downregulated in metastatic ovarian cancer cells to prevent the formation of an anti-tumor immune microenvironment, which could be utilized to develop new strategies for the immunotherapy of ovarian cancers.

Citation Format: Jia Li, Qin Xuan, JIE SHI, Longlong Wang, Yi Shi, Rong Xiang. The systematic identification of novel immune checkpoint averting the metastasis of ovarian cancer: The role of IL20/IL24-IL20RA axis [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 976.
Abstract 985: SOCS3 deficiency blocked autophagy-dependent myeloid differentiation of early-stage myeloid-derived suppressor cells via the miR-155/C/EBPβ/Wnt axis
Authors: Zhang Wenwen , Jiang Mengmeng , Zhang Rui , Liu Pengpeng , Ye Yingnan , Ren Xiubao , Yu Wenwen , Yu Jinpu
Published: September 2020

Early-stage myeloid-derived suppressor cells (eMDSCs) are a newly defined subset of myeloid-derived suppressor cells (MDSCs) that accumulate densely in tumors and potently promote tumor growth and metastasis by suppressing antitumor immune responses in vitro and in vivo. We previously identified a subset of eMDSCs in human breast cancer with a characteristic phenotype of Lin-HLA-DR-CD33+. We also found that SOCS3 deficiency and sustained activation of the JAK/STAT signaling pathway are critical molecular events coordinating the differentiation of eMDSCs, although the distinct molecular regulation has not been fully elucidated. Herein, we genetically constructed conditional SOCS3 knockout mice with SOCS3 deficiency specifically in the myeloid linage (SOCS3MyeKO). We delineated that the number of eMDSCs in SOCS3MyeKO mice (eMDSCsSOCS3KO) with the murine GMP phenotype increased significantly, and these cells suffered from a differentiation block in the myeloid lineage. To explore which pathways participated in dysfunctional eMDSC differentiation, we performed whole-genome RNA sequencing and miRNA microarray on CD11b+Gr-1+ cells, eMDSCsfl/fl and eMDSCsSOCS3KO to screen the potential regulatory ceRNA network in eMDSCsSOCS3KO. CD11b+Gr-1+ cells isolated from SOCS3fl/fl mouse spleens were used as mature myeloid cell controls. The transcriptome results and corresponding intervention experiment revealed that the differentiation block in eMDSCsSOCS3KO was caused by SOCS3 deficiency-mediated limited autophagy activation in an AMPK-independent manner. The results of miRNA microarray and RNA sequencing demonstrated that miR-155 overexpression and Wnt/β-catenin pathway activation were involved in the SOCS3 knockout-mediated myeloid differentiation block and autophagy repression. Further experiments revealed that miR-155 was induced by activation of the STAT3/NK-κB pathway upon SOCS3 deficiency, which consequently activated the Wnt/β-catenin pathway via targeting C/EBPβ. Furthermore, applying a specific miR-155 antagonist or the autophagy agonist rapamycin efficiently suppressed tumor growth and eMDSC infiltration in vivo. Overall, these findings indicated that SOCS3 deficiency blocked autophagy-dependent myeloid differentiation of e-MDSCs via the miR-155/C/EBPβ/Wnt axis, and thus targeted therapy against this pathway could be a potential therapeutic target in breast cancer.

Citation Format: Wenwen Zhang, Mengmeng Jiang, Rui Zhang, Pengpeng Liu, Yingnan Ye, Xiubao Ren, Wenwen Yu, Jinpu Yu. SOCS3 deficiency blocked autophagy-dependent myeloid differentiation of early-stage myeloid-derived suppressor cells via the miR-155/C/EBPβ/Wnt axis [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 985.
Abstract 994: Tumor NLRP3 drives melanoma progression and immunosuppression by IL-1b-mediated host pro-tumor effects
Authors: Marchetti Carlo , Tengesdal Isak , Dinarello Charles , Fujita Mayumi
Published: September 2020

Introduction: Melanoma NLRP3 inflammasome activation is involved in tumor progression and melanoma-induced immunosuppression via IL-1β-mediated effect.

Abstract: Melanoma-associated inflammation participates in the generation of a tumor permissive environment, which promotes tumor progression and metastasis. The pro-inflammatory cytokine IL-1β mediates several inflammatory diseases and the modulation of the immune system. In the context of malignancy, IL-1β is a validated target in mouse models of cancer, including melanoma, where the cytokine contributes to immunosuppression, angiogenesis, metastasis, and regulation of myeloid derived suppressor cells. In this study, we demonstrate that the NLRP3 inflammasome drives the maturation of the pro-inflammatory cytokine IL-1β in melanoma cells. Accordingly, analysis of melanoma biopsies (N=461) showed increased NLRP3 expression in the lesions which correlates with the IL-1β levels. In melanoma-bearing mice, NLRP3 inhibition with a clinically evaluated NLRP3 inflammasome inhibitor OLT1177 (dapansutrile), showed to decrease melanoma progression and tumor-induced inflammation reducing the circulating levels of IL-6, G-CSF, and VEGF compared to vehicle tumor-bearing mice. Analysis of myeloid-derived suppressor cell (MDSC) populations revealed that NLRP3 inflammasome inhibition was sufficient to prevent MDSCs expansion (both PMN-MDSCs and M-MDSCs), restoring the population to the non-tumor-bearing level. The effect observed on MDSCs in tumor-bearing mice following NLRP3 inhibition resulted in increased NK cells activation in primary tumors (Figure). These data establish a new correlation between IL-1β, NLRP3, melanoma-induced immunosuppression and tumor progression. Considering that NLRP3 inhibition resulted in decreased tumor-induced immune evasion as well as an increased tumoricidal immune response, we evaluated the effect of the addition of NLRP3 inhibition to checkpoint inhibition. Tumor bearing mice treated with OLT1177 and anti-PD-1 showed reduced tumor progression compared to the single-agent treatments. In conclusion, NLRP3 inflammasome inhibition was successful in preventing IL-1β processing in melanoma cells and tumor progression. These findings suggest that NLRP3 may represent a potential therapeutic target for melanoma.

Citation Format: Carlo Marchetti, Isak Tengesdal, Charles Dinarello, Mayumi Fujita. Tumor NLRP3 drives melanoma progression and immunosuppression by IL-1b-mediated host pro-tumor effects [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 994.
Abstract CT022: A first-of-its-kind prospective study of a multi-cancer blood test to screen and manage 10,000 women with no history of cancer
Authors: Papadopoulos Nickolas
Published: September 2020

One of the most compelling approaches to reduce cancer-specific morbidity and mortality is earlier detection. Minimally-invasive screening tests, such as liquid biopsies, hold much promise in this regard. However, prospective clinical studies of these new methods are required to ensure that the anticipated benefits outweigh the potential risks. We describe an interim analysis of a study that enrolled 10,006 women 65 to 75 years of age who had no prior history of cancer, in a population with a high degree of compliance with standard-of-care screening. Enrollment occurred between September 2017 and May 2019. The study evaluated the prospective implementation of a multi-cancer, multi-analyte screening blood test (DETECT-A blood test) incorporating DNA and protein markers. Participants with positive DETECT-A blood test results were followed by an imaging test (generally PET-CT) to localize the putative cancer. The DETECT-A blood test combined with standard-of-care screening doubled the number of cancers detected by screening. The DETECT-A blood test effectively identified subjects with multiple types of cancer, with a positive predictive value higher than existing non-invasive screening tests for individual cancers. The DETECT-A blood test identified ten different cancer types, including seven types for which there is currently no screening test available. No serious adverse events were observed in any participants enrolled in the study. 65% of the cancers detected by the blood test were classified as local or regional disease. Somatic mutations in TP53, BRAF, KRAS, or PIK3CA were the most common alterations identified in plasma; in all cases where tumor tissue was available, the mutations detected in plasma were confirmed to be present in the primary tumor. These results are the first to demonstrate that a minimally-invasive multi-cancer blood test can be safely incorporated into routine clinical care. Moreover, this is the first study to show that it can be used to guide patient management in real-time, leading to surgery with intent to cure in asymptomatic individuals.

Citation Format: Nickolas Papadopoulos. A first-of-its-kind prospective study of a multi-cancer blood test to screen and manage 10,000 women with no history of 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 CT022.
Abstract CT184: Optimizing Tumor Treating Fields therapy for recurrent glioblastoma with targeted and individualized skull remodeling surgery. A multi-center randomized phase 2 trial
Authors: Mikic Nikola , Korshøj Anders R.
Published: September 2020

Background: We will initiate (March 2020) a randomized, comparative, multi-center, investigator-initiated, interventional, phase 2 trial (NCT04223999) testing the efficacy of a potentially new treatment modality for recurrent glioblastoma (GBM). The new treatment modality combines individualized targeted skull remodeling surgery (SR-surgery) with Tumor Treating Fields (TTFields) and best practice medical oncological therapy. The aim of SR-surgery is to enhance the electric field in the tumor region, by removing bone with burrholes. Preclinical research indicate that this modality provides a marked and focal enhancement (~100%) of TTFields. We concluded (April 2019) a phase 1 safety/feasibility trial indicating improved overall survival without additional toxicity from the intervention. The following randomized, comparative phase 2 trial aims to validate superior efficacy of the intervention.

Method: The trial is designed as a comparative, 1:1 randomized, minimax two-stage phase 2 with an expected 70 patients to a maximum sample size of 84 patients. After 12-months follow-up of the first 52 patients an interim futility analysis will be performed. The two trial arms will consist of either a) TTFields, best practice oncological treatment (control arm) or b) SR-surgery, TTFields and best practice oncology (interventional arm).Major eligibility criteria include age ≥ 18 years, supratentorial GBM, Karnofsky performance score (KPS) ≥ 70, focal tumor, and lack of uncontrollable epilepsy or significant co-morbidity. Study design aims to detect a 20% increase in the overall survival rate 12 months (OS12) assuming OS12 = 40% in the control group and OS12= 60% in the intervention group. Secondary endpoints include hazard rate ratio of overall survival and progression-free survival, objective response rate, quality of life, KPS, steroid dose, and toxicity. Patient follow-up is until death or 36 months (trial duration). Expected average for follow-up is 18 months. Every 3. month there will be an assessment of toxicity, response and QoL. Endpoint data will be collected at the end of the trial, occurrence of suspected unexpected serious adverse reactions (SUSARs) or unacceptable serious adverse events (SAEs), withdrawal of consent, or loss-to-follow-up.

Citation Format: Nikola Mikic, Anders R. Korshøj. Optimizing Tumor Treating Fields therapy for recurrent glioblastoma with targeted and individualized skull remodeling surgery. A multi-center randomized phase 2 trial [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 CT184.
Abstract CT262: Multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab, and pertuzumab in HR-positive, HER2-positive metastatic breast cancer
Authors: Cascetta Krystal Pauline , Poulikakos Poulikos , Shapiro Charles , Fasano Julie , Bhardwaj Aarti , Irie Hanna , Goel Anupama , Klein Paula , Ru Meng , Tiersten Amy
Published: September 2020

Background: Overexpression or amplification of HER2 occurs in approximately 15-20% of patients and roughly half of these tumors are hormone receptor (HR) positive. The use of aromatase inhibitors in the metastatic setting is well established while significant improvement in overall survival has been established with the use of trastuzumab or pertuzumab in HER2-overexpressing tumors. This study will examine the combination of endocrine therapy, palbociclib, and dual HER2 therapy with pertuzumab and trastuzumab in women with metastatic HR+, HER2+ breast cancer. Trial Design: Multicenter, phase I/II trial of Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HR+, Her2+ metastatic breast cancer. Eligibility Criteria: Newly diagnosed stage IV HR+, HER2+ breast cancer patients. Specific Aims: Phase I: To determine the maximum dose tolerated of palbociclib. Phase II: To determine the clinical benefit rate (CBR) of treatment with anastrozole, palbociclib, trastuzumab, and pertuzumab in HR+, HER2+ metastatic breast cancer patients. Exploratory: Examine potential biomarkers of response to palbociclib including expression of cyclin D1, cyclin E1 and E2, CDK 2, CDK 4, CDK 6, retinoblastoma, phosphorylated retinoblastoma, and p16. RNA sequencing will be used to assess for other predictors of response in an unbiased manner to assess for correlation with inhibition of Ki-67 and phosphorylated retinoblastoma expression as well as evaluate for potential mechanisms of resistance. Methods: This study will evaluate the maximum tolerated dose (MTD) of the Anastrozole, Palbociclib, Trastuzumab and Pertuzumab. Once the MTD is reached, we will assess the clinical benefit rate using a Simon's II stage design among a maximum 30 patients. Accrual: Maximum of 36 subjects. Current Enrollment: Enrollment to phase I ended in October 2018 with one dose escalation to palbociclib 125mg, at which level one DLT was observed. Thus, the MTD was determined at palbociclib 125 mg and subsequent phase II patients will be treated at this dose level. Enrollment to phase II began in February 2019. 39% of planned patients have been enrolled as of January 2020. Clinical trial registry number: NCT03304080.

Citation Format: Krystal Pauline Cascetta, Poulikos Poulikakos, Charles Shapiro, Julie Fasano, Aarti Bhardwaj, Hanna Irie, Anupama Goel, Paula Klein, Meng Ru, Amy Tiersten. Multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab, and pertuzumab in HR-positive, HER2-positive metastatic breast 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 CT262.
Abstract CT401: The experience of treating patients with cancer during the COVID-19 pandemic in China
Authors: Zhang Li , Zhu F , Xie L , Wang C , Wang J , Chen R , Jia P , Guan H Q. , Peng L , Peng P , Zhang P , Chu Q , Shen Q , Wang Y , Xu S Y. , Zhao J P. , Zhou M , Chen Y
Published: September 2020

Background: Cancer patients are regarded as highly vulnerable group in the current SARS-CoV-2/COVID-19 pandemic. Up to date, the clinical characteristics of cancer patients with COVID-19 are largely unknown.

Patients and methods: In this retrospective cohort study, we collected and analyzed data of the cancer patients with y confirmed COVID-19 infection from three designated hospitals in Wuhan, China from Jan 13, 2020, to Feb 26, 2020. Univariate and multivariate analyses were performed to assess the risk factors associated with severe events defined as a condition that admission to an intensive care unit, the use of mechanical ventilation, or death. We also followed 124 cancer patients with immune checkpoint inhibitors (ICI) and their families for their infection rate and clinical outcome.

Results: Twenty-eight COVID-19 infected cancer patients were included with median age of 65.0 years (IQR:56.0-70.0) and male gender of 60.7% (17/28). Amount of these 28 patients, 7 (25%) had lung cancer, and 8 (28.6%) were considered to be infected via hospital-associated transmission. Fifteen (53.6%) patients had severe events with the mortality rate of 28.6%. The last anti-tumor treatment within 14 days from the diagnoses of COVID significant increased risk of developing severe events (HR=4.079, 95%CI 1.086-15.322, P=0.037). The common chest CT findings were ground-glass opacity (21, 75.0%) and patchy consolidation (13, 46.3%). The patchy consolidation on CT had a higher risk for developing severe events (HR=5.438, 95%CI 1.498-19.748, P=0.010). There was only one patient (1/124, 0.8%) who have been on ICI treatment for his metastatic HCC confirmed with COVID infection, and with mild clinic presentation and a short hospital course.

Conclusions: Cancer patients showed aggressive presentation and poor outcomes with the COVID-19 infection. It is recommended that vigorous screening for COVID-19 infection should be performed for cancer patients with anti-tumor. From our limited data, there is no evidence to suggest difference in cancer patients on ICI treatment.

Citation Format: Li Zhang, F Zhu, L Xie, C Wang, J Wang, R Chen, P Jia, H Q. Guan, L Peng, P Peng, P Zhang, Q Chu, Q Shen, Y Wang, S Y. Xu, J P. Zhao, M Zhou, Y Chen. The experience of treating patients with cancer during the COVID-19 pandemic in China [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 CT401.
Abstract CT404: Adapting oncologic practice to COVID19 outbreak: From outpatient triage to risk assessment for specific treatment in Madrid, Spain
Authors: Gomez-Martin Carlos
Published: September 2020

Since December 2019, when the first cases of pneumonia associated with a new coronavirus were reported in Wuhan (China), we have witnessed the rapid and massive spread of this disease; affecting more than 2 million people worldwide in mid-April. Cancer patients, especially those undergoing active chemotherapy, are especially vulnerable due to treatment-induced immunosuppression and their frequent comorbidities. Despite an increasing number of papers describing the characteristics of the disease and its possible treatments, oncology patients barely represent a minority in the series reported so far, and their peculiar characteristics are not detailed in these publications.

On March 6, 2020, when officially in Spain there were only 117 cases and 2 deceased from COVID19, a patient admitted for another reason was diagnosed with Sars-CoV-2 related infection In the following 48 hours, a full set of new procedures were put in place that modified all the clinical care of our oncology patients.

Regarding Day Hospital and Outpatient clinics on-site active screening by trained staff for all patients and companions were implemented. Also we limited the number of outpatient visits to minimum indispensable. All chemo Treatments were reconsidered based on objectives, life expectancy, and type of therapy and clinical status of every patient.

For all patients admitted routine blood test and Chest Xr or CT of the lungs performed previously to been transferred to Ward. Specifics and separate wards for suspected, confirmed and negative coronavirus patients were prepared as well as dedicated staff (including Oncologist, Infectious Diseases Consultants and Internist) to attend COVID19 + patients 24/7

Since March 9th, more than 280 cancer patients have been actively screened for Sars-coV-2 infection, and 90 patients have been admitted to be specifically treated for this disease.

Data on clinical characteristics and outcomes for the first 63 patients will be presented, with special mention to tumor burden, grade of immunosuppression, type of treatment and comorbidities. Preliminary data on Tocilizumab treatment on this setting will also be shared as well as some significant relationships between clinical and analytical parameters and risk of severe pulmonary and vascular events in this population.

Citation Format: Carlos Gomez-Martin. Adapting oncologic practice to COVID19 outbreak: From outpatient triage to risk assessment for specific treatment in Madrid, Spain [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 CT404.
Abstract LB-005: Senescence reprogramming in primary tumors initiates prostate cancer metastases
Authors: Guccini Ilaria , Revandkar Ajinkya , D'Ambrosio Mariantonietta , Colucci Manuel , Pasquini Emiliano , Mosole Simone , Troiani Martina , Alimonti Andrea
Published: September 2020

Recent studies have raised fundamental questions about the possibility that senescence induced either by oncogene activation or chemotherapy, while initially restricting tumorigenesis, may promote cancer metastases at a late stage. This coexisting dichotomy remains unclear due to the lack of evidence on the mechanism by which senescent tumor cells initiate metastases, a fatal and therapeutically challenging hallmark of cancer. Here, we put forward the hypothesis that the genetic make-up of the tumors accounts for the distinct outcomes of senescence in cancer. Using different genetically engineered mouse models we demonstrate that inactivation of Timp1 is capable to switch senescence driven by the loss of PTEN and chemotherapy from a tumor-suppressive into a tumor-promoting response that drives metastases. Of note, depletion of senescent tumor cells by the senolytic compound ABT263 or p53 genetic inactivation significantly impeded metastases formation in Ptenpc-/-; Timp1-/- mice, indicating the involvement of senescence in the metastatic process. Moreover, enhancement of senescence by Docetaxel therapy decreased the proliferation of prostate tumors in Ptenpc-/- mice, whereas it accelerated metastases formation in Ptenpc-/-; Timp1-/- mice. Mechanistically, TIMP1-loss in PTEN-deficient cells reprogrammed the senescent-secretome significantly changing the levels of GDF15, FGF and IGFBP thereby promoting cellular invasion, migration and the up-regulation of a metastases-associated gene signature. In prostate cancer patients, we found that TIMP1 is commonly lost in combination with PTEN in advanced and metastatic prostate tumors and that TIMP1 inactivation is associated with TIMP1 promoter methylation. Altogether, these findings highlight the crucial role of TIMP1 as the gatekeeper that limits the pro-metastatic function of senescent tumor cells, implying that senescence inducing therapies should be administered with caution in patients affected by cancers with TIMP1 inactivation.

Citation Format: Ilaria Guccini, Ajinkya Revandkar, Mariantonietta D'Ambrosio, Manuel Colucci, Emiliano Pasquini, Simone Mosole, Martina Troiani, Andrea Alimonti. Senescence reprogramming in primary tumors initiates prostate cancer metastases [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 LB-005.
Abstract LB-024: Development of a non-invasive clinically applicable real time cell tracking platform for evaluating cell-based cancer therapy using magnetic resonance imaging (MRI)
Authors: Akers Johnny C. , Wei Zhao , Jang Hyungseok , Chang Eric , Du Jiang , Thu Mya S.
Published: September 2020

While advancement in chimeric antigen receptors (CARs) has greatly improved the anti-tumor activity of immune cell-based therapies utilizing modified T lymphocytes (CAR-T) and natural killer cells (CAR-NK), there remains a critical unmet need for diagnostic technologies to help evaluate their biological performance effectively and efficiently after injecting into the body.The ability to better understand the biodistribution of injected cells and devise dosing strategies are key determinants to the success or failure of cell therapy. However, clinicians are limited by the available technology for real time in-vivo tracking of cell therapy products in clinical settings. Here we present a clinically applicable novel magnetic agent that can effectively label a variety of cell types used in cancer cell therapy development including T cells, NK cells, and neural stem cells (NSCs), and when combined with the 3D ultrashort echo time Cones (3D UTE-Cones) sequence, can enable quantitative assessment of cell therapy products using MRI. In this study, we optimized loading of our tracking agent into T cells, NK cells, and NSCs, evaluated the morphology and viability of the labeled cells, and confirmed internalization of the labeling agent by Prussian blue staining and TEM. The in vitro MRI properties of the labeled cells were quantitated by the 3D UTE-Cones sequence. Ex vivo MRI analysis was performed by injecting labeled cells into harvested mouse livers and brains to ascertain their MRI visibility in tissues using a clinical MRI scanner. We confirmed that our magnetic labeling agent efficiently labeled each cell line tested, and the morphology or viability of the labeled cells were unaffected. The MRI detectability of labeled cells were confirmed by in vitro MRI phantoms. Further, using quantitative susceptibility mapping (QSM), T1, and T2* mapping based on 3D UTE-Cones sequences, we found near perfect correlations between cell density and MRI properties. By applying the parameters established in the MRI phantoms, we were able to detect and quantity the number of labeled cells injected into mouse livers and brains ex vivo. In summary, we have developed a clinically applicable imaging-based platform that empowers cell therapy researchers to better understand the results of their biodistribution and dosing studies through real-time cell tracking and quantitative assessments using MRI.

Citation Format: Johnny C. Akers, Zhao Wei, Hyungseok Jang, Eric Chang, Jiang Du, Mya S. Thu. Development of a non-invasive clinically applicable real time cell tracking platform for evaluating cell-based cancer therapy using magnetic resonance imaging (MRI) [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 LB-024.
Abstract LB-031: The significant role of 14-3-3 sigma including signal transduction, cell cycle regulation, and malignant transformation in human gastric cancer
Authors: Jung Jiyoon , Lee Kyunghee , Koh sungae , Kim sangwoon
Published: September 2020

Background: 14-3-3 protein family have many diverse functions in cellular responses including cell cycle regulation, apoptosis and malignant transformation in a broad range of organisms. 14-3-3 sigma induces G2 arrest enabling the repair of damaged DNA. Especially 14-3-3 sigma is frequently lost in tumor cells and surrounding tissues, indicate that becomes lost at an early stage in invasive cancer. The purpose of this study is to identify the role of HGF upregulated 14-3-3 sigma associated with cancer cell proliferation and invasion in gastric cancer and to identify the role of 14-3-3 sigma level in vivo by analysis 14-3-3 serum level in gastric cancer patients who underwent gastrectomy.

Methods: In our study we used cell culture, Northern blotting, cDNA microarray analysis, western blotting, RT-PCR, Zymography, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 14-3-3 sigma knock-down with short hairpin RNA (shRNA), electrophoresis mobility-shift assay, chromatin immunoprecipitation assay, Standard two chamber invasion assay. And we conducted the 14-3-3 sigma ELISA (enzyme-linked immunosorbent assay) of 37 blood samples of patients, who underwent gastrectomy for gastric cancer.

Results: First, we confirmed that the expression level of 14-3-3 sigma was up-regulated by HGF(hepatocyte growth factor) in gastric cancer cell. To identify associated pathway of HGF-induced 14-3-3 sigma about MMP-1 (matrix metalloproteinase-1) expression, the cells were treated with MEK (Mitogen-activated protein kinase kinase) inhibitor(PD098059) and then analyzed by Western blotting. The HGF-mediated MMP-1 protein level was decreased with PD098059. The role for 14-3-3 sigma associated with MMP-1 was determined by knock down cell of 14-3-3 sigma. 14-3-3 sigma-sh RNA cells showed a decreased level of MMP-1, pERK and pp38. HGF-mediated cell proliferation and in vitro invasion was decreased in 14-3-3 sigma knock down cell. We also identified that 14-3-3 sigma serum level was statistically significant decreased after gastrectomy in gastric cancer patients with stage 2 or 3. (p value < 0.05)

Conclusions: Our results support the hypothesis that 14-3-3 sigma plays an important role in the cell proliferation in gastric cancer, and knock down this domain, it can be preventing to gastric cancer progression. And 14-3-3 sigma serum level is associated with status of treatment locally advanced gastric cancer.

Citation Format: Jiyoon Jung, Kyunghee Lee, sungae Koh, sangwoon Kim. The significant role of 14-3-3 sigma including signal transduction, cell cycle regulation, and malignant transformation in human gastric 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 LB-031.
Abstract LB-107: TET2/DNMT3A mutations and exceptional response to novel epigenetic agent in human malignancies
Authors: Yang Sherry X. , Rubinstein Larry , Nguyen Dat , Larenjeira Angelo B. , Kinders Robert , Difilippantonio Michael , Doroshow James H.
Published: September 2020

Background: Challenges remain on the selection of patients who potentially respond to a class of drugs that target the epigenetics for cancer treatment. This study aims to investigate TET2/DNMT3A mutations, their role on prognosis, and relation between the mutations and antitumor activity of a novel epigenetic agent in multiple human cancer cell lines and animal models. Methods: TET2/DNMT3A mutation data in human malignancies were obtained from cBioPortal. Eighteen cancer cell lines and multiple mouse models bearing representative human solid tumors were subjected to 4'-thio-2'-deoxycytidine (T-dCyd) or saline treatment. Gene mutations were examined by whole exome and/or Sanger sequencing in these cell lines. Pharmacodynamic modulation of specific gene expression was analyzed in xenograft tumor samples by immunohistochemistry. Results: TET2 and DNMT3A were frequently mutated in angioimmunoblastic/peripheral T-cell lymphomas, several types of leukemias and cutaneous squamous cell carcinoma, and mutated in lung, breast, skin, and kidney cancers. T-dCyd significantly reduced cell survival in lung NCI-H23, breast BT549, melanoma SKMEL5 and renal ACHN cancer cells that harbor deleterious TET2 and nonsynonymous DNMT3A mutations compared to 14 lines without such pattern of alterations (P = 0.006; 2-sided T-test). Anti-tumor effect was validated in vivo; T-dCyd significantly inhibited tumor growth in mice with TET2/DNMT3A mutation-positive tumors. Histological evaluation revealed a near eradication of tumor cells by T-dCyd in NCI-H23 xenografts. T-dCyd administrations led to a remarkable and persistent p21Waf1/Cip1 increase during treatment (P < 0.0001). In contrast, little activity was observed in xenograft models without this pattern of gene mutations. Conclusions: Cancer cells and animal models examined with TET2 and DNMT3A-mutant genotype are sensitive to T-dCyd treatment.

Citation Format: Sherry X. Yang, Larry Rubinstein, Dat Nguyen, Angelo B. Larenjeira, Robert Kinders, Michael Difilippantonio, James H. Doroshow. TET2/DNMT3A mutations and exceptional response to novel epigenetic agent in human malignancies [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 LB-107.
Abstract LB-145: Immunomodulatory activity of selective DRD2 antagonist ONC201, an imipridone, in metastatic endometrial cancer (mEC)
Authors: Tarapore Rohinton S. , Prabhu Varun V. , Mok Samuel C. , Yeung Chilam Au , Rodriguez Lorna , Girda Eugenia , Mantia-Smaldone Gina , Bae-Jump Victoria , Lu Guangrong , Oster Wolfgang , Allen Joshua E.
Published: September 2020

ONC201 is a small molecule DRD2 antagonist and ClpP agonist that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The enhanced immune modulatory nature of ONC201 was observed in a Phase I study that revealed increased infiltration of granzyme B+ and CD56+ cells, corroborating preclinical reports of NK cell intratumoral infiltration in response to ONC201. A broad induction of immune cytokines and effector molecules was observed in patients treated with ONC201, in particular among patients who experienced at least stable disease by RECIST for 12 or more weeks. Patients who had a > 50% induction in serum perforin, a cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and NK cells, upon ONC201 administration had better outcomes. Regressions in individual metastatic lesions were noted in a small number of EC patients. A multi-center Phase 2 study to explore the efficacy of weekly ONC201 in recurrent or metastatic Type II EC enrolled 5 patients with recurrent EC who underwent paired tumor biopsies before and 9 days after ONC201 initiation. Four of the 5 patients exhibited a 2-5-fold increase in CD4+ Thelper cells in their tumors and the majority of these patients also had CD4+FoxP3+ cells, indicating a significant population of Tregulatory cells (Treg). One patient exhibited an 80% increase in CD8+ T-cells in their tumor 8 days after initiating ONC201. Two of the patients had >2 fold induction of intratumoral granzyme B expression that was surprisingly not accompanied by NK cell infiltration, as assessed by CD56 staining. These results may be consistent with innate immune system activation by ONC201 that results in T-cell modulation. The multi-fold increase in Treg expression could be suppressing tumor cell death. As such, ONC201 dose intensification or combination with immunotherapy are being evaluated for ONC201 in the context of endometrial cancer.

Citation Format: Rohinton S. Tarapore, Varun V. Prabhu, Samuel C. Mok, Chilam Au Yeung, Lorna Rodriguez, Eugenia Girda, Gina Mantia-Smaldone, Victoria Bae-Jump, Guangrong Lu, Wolfgang Oster, Joshua E. Allen. Immunomodulatory activity of selective DRD2 antagonist ONC201, an imipridone, in metastatic endometrial cancer (mEC) [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 LB-145.