tbuckley/cabot-search huggingface dataset:
Venetoclax Increases Intratumoral Effector T Cells and Antitumor Efficacy in Combination with Immune Checkpoint Blockade
Authors: Frederick J. Kohlhapp, Dipica Haribhai, Rebecca Mathew, Ryan Duggan, Paul A. Ellis, Rui Wang, Elisabeth A. Lasater, Yan Shi, Nimita Dave, Jacob J. Riehm, Valerie A. Robinson, An D. Do, Yijin Li, Christine J. Orr, Deepak Sampath, Aparna Raval, Mark Merchant, Anahita Bhathena, Ahmed Hamed Salem, Keith M. Hamel, Joel D. Leverson, Cherrie Donawho, William N. Pappano, Tamar Uziel
Journal: Cancer Discovery (2020)

Abstract The antiapoptotic protein BCL2 plays critical roles in regulating lymphocyte development and immune responses, and has also been implicated in tumorigenesis and tumor survival. However, it is unknown whether BCL2 is critical for antitumor immune responses. We evaluated whether venetoclax, a selective small-molecule inhibitor of BCL2, would influence the antitumor activity of immune checkpoint inhibitors (ICI). We demonstrate in mouse syngeneic tumor models that venetoclax can augment the antitumor efficacy of ICIs accompanied by the increase of PD-1+ T effector memory cells. Venetoclax did not impair human T-cell function in response to antigen stimuli in vitro and did not antagonize T-cell activation induced by anti–PD-1. Furthermore, we demonstrate that the antiapoptotic family member BCL-XL provides a survival advantage in effector T cells following inhibition of BCL2. Taken together, these data provide evidence that venetoclax should be further explored in combination with ICIs for cancer therapy. Significance: The antiapoptotic oncoprotein BCL2 plays critical roles in tumorigenesis, tumor survival, lymphocyte development, and immune system regulation. Here we demonstrate that venetoclax, the first FDA/European Medicines Agency–approved BCL2 inhibitor, unexpectedly can be combined preclinically with immune checkpoint inhibitors to enhance anticancer immunotherapy, warranting clinical evaluation of these combinations. This article is highlighted in the In This Issue feature, p. 1
Abstract 1049: Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) in combination with PD-1 monoclonal antibody and/or antiangiogenic treatment in patients with metastatic solid tumors
Authors: Jia Wei, Qin Liu, Hanqing Qian, Jie Shao, Lijing Zhu, Lifeng Wang, Lixia Yu, Huizi Sha, Baorui Liu
Journal: Cancer Research (2020)

Abstract Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Nanotechnology has been reported to enhance immune responses of vaccines. Moreover, immunizing patients against such neoantigens, in combination with checkpoint inhibitor (CPI) and/or antiangiogenic drugs may elicit greater anti-tumor responses. Methods: Patient-specific mutation-containing neoantigens were selected on the basis of tumour-specific mutations whole-exome sequencing (WES) and RNA sequencing. Cancer testis antigens were obtained according to immunohistochemical staining and HLA-binding affinity prediction. Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) is an amphiphiles nanovaccine loaded with personalized vaccine encoding multiple neoantigens designed to induce neoantigen specific T cells responses. Patients will receive PVAC in combination with PD-1 monoclonal antibody and/or antiangiogenic drugs. Primary end points include safety and tolerability. Results: 9 microsatellite stability (MSS) patients, which had relapsed from standard treatments, are enrolled in this study. 4 patients (1 gastric cancer, 1 liver cancer, 1 cervical carcinoma, 1 soft tissue sarcoma) received PVAC in combination with PD-1 mAb, and another 5 patients (2 gastric cancer, 1 colon cancer, 1 NSCLC, 1 renal carcinoma) received PVAC in combination with PD-1 mAb and antiangiogenic therapy. No DLTs were reported. Five patients developed grade 1 subcutaneous indurations in the injection sites,which collected with nanovaccine. One patient had grade 2 rash caused by antiangiogenic drug. No drug related SAEs have been observed. There are 1 CR, 4 PR, 3 SD and 1 PD. Neoantigen specific T cell responses have been detected by IFN-γ Elispot from PBMCs. Conclusions: PVAC is safe and well tolerated. Clinical responses have been observed in combination with PD-1 mAb and antiangiogenic drugs and neoantigen-specific T cell response have been observed after vaccination. Clinical trial information: ChiCTR1900022986. Citation Format: Jia Wei, Qin Liu, Hanqing Qian, Jie Shao, Lijing Zhu, Lifeng Wang, Lixia Yu, Huizi Sha, Baorui Liu. Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) in combination with PD-1 monoclonal antibody and/or antiangiogenic treatment in patients with metastatic solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1049.
Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia
Authors: Denis Y Logunov, Inna V Dolzhikova, Olga V Zubkova, Amir I Tukhvatulin, Dmitry V Shcheblyakov, Alina S Dzharullaeva, Daria M Grousova, Alina S Erokhova, Anna V Kovyrshina, Andrei G Botikov, Fatima M Izhaeva, Olga Popova, Tatiana A Ozharovskaya, Ilias B Esmagambetov, Irina A Favorskaya, Denis I Zrelkin, Daria V Voronina, Dmitry N Shcherbinin, Alexander S Semikhin, Yana V Simakova, Elizaveta A Tokarskaya, Nadezhda L Lubenets, Daria A Egorova, Maksim M Shmarov, Natalia A Nikitenko, Lola F Morozova, Elena A Smolyarchuk, Evgeny V Kryukov, Vladimir F Babira, Sergei V Borisevich, Boris S Naroditsky, Alexander L Gintsburg
Journal: The Lancet (2020)
Abstract 3394: Brisk walking and hepatocellular carcinoma risk in US men and women
Authors: Xiao Luo, Wanshui Yang, Yanan Ma, Tracey Simon, Jeffrey Meyerhardt, Jeffrey Meyerhardt, Jeffrey Meyerhardt, Andrew Chan, Edward Giovannucci, Xuehong Zhang
Journal: Cancer Research (2020)

Abstract Emerging evidence indicates a potential beneficial effect of vigorous physical activity on hepatocellular carcinoma (HCC) by improving energy balance, immune response, and insulin sensitivity. However, the association between moderate physical activity, such as brisk walking, and the risk of HCC remains largely unknown. Two prospective cohorts of 77,535 women from the Nurses' Health Study and 44,779 men from the Health Professionals Follow-up Study were included. Weekly time spent on brisk walking and other physical activity were updated biennially. The Cox proportional hazard regression model was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95%CIs). After an average 23.1-year follow-up, a total of 138 incident HCC cases were identified. In the multivariable-adjusted model, engaging in brisk walking was significantly associated with a lower risk of HCC (over 1 hour/week vs. non-brisk walking; HR: 0.44, 95%CI: 0.27-0.70; Ptrend&amp;lt;0.001). Further adjustment for body mass index (BMI) and type 2 diabetes (T2D) yielded similar results (HR: 0.51; 95%CI: 0.31-0.83; Ptrend=0.006). The association between brisk walking and HCC risk was generally consistent across all subgroups, including age, BMI, T2D, smoking status, aspirin use, and alcohol consumption (all P&amp;gt;0.05 for interaction). In conclusion, brisk walking was associated with a significantly lower risk of developing HCC among US men and women. If confirmed, brisk walking might serve as a feasible way for some individuals for HCC primary prevention. Citation Format: Xiao Luo, Wanshui Yang, Yanan Ma, Tracey Simon, Jeffrey Meyerhardt, Jeffrey Meyerhardt, Jeffrey Meyerhardt, Andrew Chan, Edward Giovannucci, Xuehong Zhang. Brisk walking and hepatocellular carcinoma risk in US men and women [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 3394.
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: Nikola Mikic, Anders R. Korshøj
Journal: Cancer Research (2020)

Abstract 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 1175: Race informs survival disparities in head and neck cancer clinical trials
Authors: Jeffrey C. Liu, Brian Egleston, Elizabeth Blackman, Camille Ragin
Journal: Cancer Research (2020)

Abstract Background: Survival disparities between blacks and whites in head and neck cancer are well documented, with access to care and socioeconomic status (SES) as major contributors. However, the impact of race alone on survival is much less clear. Previous attempts to evaluate the role of race have been limited by access to care/SES as major confounders. We set out to directly assess the role of race in head and neck cancer by evaluating treatment outcomes of subjects enrolled in clinical trials. In this population, access to care and socioeconomic confounders are minimized because all patients receive identical treatments. Methods: Clinical trial data from the Radiation Therapy Oncology group (now NRG) studies were obtained by request. Seven RTOG Studies (RTOG 0129, 0234, 9003, 9111, 9501, 9512, 9703) were included for study. Studies were included if they were phase II or III trials that employed survival as an endpoint, e.g. progression free survival (PFS), disease free survival (DFS), overall survival (OS). Studies that were small (&amp;lt;200 patients) or did not use survival as an endpoint (e.g. side effect trial) were excluded. For each black patient enrolled in a clinical trial, a white patient matched in the same arm of that trial was used as a control. The study null-hypothesis was that there would be no race derived impact on survival and thus the chance of survival favoring either whites or blacks in each matched pair would be 50%. Results: Across the seven trials, 468 blacks were identified and matched with 468 white study arm specific controls. Whites had better outcomes than blacks in 60% of matched pairs (p&amp;lt;0.001). Blacks were consistently more likely to have worse outcomes. When outcomes were collapsed by PFS/DFS, the failure rate was significantly higher in blacks (HR=1.46, p&amp;lt;0.001)). Failure was largely due to locoregional failure, and blacks were at higher risk (sHR =1.43, p=0.002). The development of distant metastasis within the paired cohorts was not significantly different (sHR=1.15, p=0.38), suggesting that locoregional failure was the major driver of failure. Conclusions: In this analysis of head and neck cancer patients in clinical trials, blacks consistently had worse outcomes in comparison to study arm specific white controls. This suggests that race alone confers a worse survival independent of socioeconomic and access to care factors. Further study is needed to confirm these findings, and to explore other causes underlying this disparity. Citation Format: Jeffrey C. Liu, Brian Egleston, Elizabeth Blackman, Camille Ragin. Race informs survival disparities in head and neck cancer clinical trials [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 1175.
Abstract 2979: The effect of interferon gamma on melanoma progression under MAPK inhibitor therapy
Authors: Kevin Chen, Rachel McMillan, Mona Chatrizeh, Willy Hugo
Journal: Cancer Research (2020)

Abstract About half of metastatic cutaneous melanoma harbor a mutation in the BRAF protein, causing constitutive activation of the MAPK pathway. Currently, patients with such mutation are treated with MAPK pathway inhibitors (MAPKi) targeting the mutant BRAF and its downstream MEK proteins. However, within a span of 6-12 months, these patients will relapse, and their tumors will acquire resistance to this treatment. In this project, we aim to understand the role of IFN gamma (IFNg) to help us determine if the resistance phenotype differs between cells exposed with MAPKi alone versus cells treated with MAPKi and IFNg. Previous literature has reported on the development of a dedifferentiated resistance phenotype which was characterized by a downregulation of MITF and an upregulation of AXL proteins. However, the patient-derived transcriptomic data comparing paired tumors pre- and post-MAPKi therapy did not show such changes in MITF or AXL levels. We posit that the discrepancy may be because most of the earlier studies on MAPKi resistance were done in vitro or immune-suppressed in vivo models. Melanoma biopsies from patients responding to MAPKi treatment showed a substantial increase in the tumor-infiltrating T cell and other immune cells. One of the most dominant immune factors produced by the T cells is the interferon gamma (IFNg). Intriguingly, our data show that IFNg, in the presence of MAPKi, can suppress the dedifferentiation switch that is induced by MAPKi-alone. Specifically, through serial western blots, we discovered that MAPKi and IFNg reduced the previously reported AXL upregulation and MITF downregulation in four different mutant BRAF melanoma lines. RNA sequencing from the same time points revealed that melanoma treated with MAPKi and IFNg upregulate IFN-stimulated genes that are typically expressed by immune cells; this leads us to believe that some novel transcriptomic programs have been activated by the combination of MAPKi and IFNg. By solely examining one immune factor, IFNg, we discovered one potential explanation for the discrepancy in the prevalence of MAPKi-induced dedifferentiation phenotype in the patient-derived melanoma samples. We are in the midst of performing drug screening experiments on MAPKi and IFNg-resistant melanoma lines in order to discover novel therapeutic vulnerabilities that were not observed with MAPKi-alone. Finally, by taking into account the secreted factors in the tumor microenvironment, our study can provide a more accurate depiction of MAPKi resistance evolution in mutant BRAF melanoma patients. Citation Format: Kevin Chen, Rachel McMillan, Mona Chatrizeh, Willy Hugo. The effect of interferon gamma on melanoma progression under MAPK inhibitor therapy [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 2979.
Abstract 4688: Interaction of LEDGF/p75 with oncogenic transcription factors in docetaxel resistant prostate cancer cells
Authors: Greisha L. Ortiz Hernandez, Evelyn S. Sanchez-Hernández, Carlos A. Casiano
Journal: Cancer Research (2020)

Abstract Prostate Cancer (PCa) progression leads to an advanced stage called metastatic castration PCa (mCRPC), for which currently there is no cure in spite of advances in treatment with new generation anti-androgen drugs and chemotherapy with taxanes such as docetaxel (DTX). Our group demonstrated previously that the stress oncoprotein Lens Epithelium Derived Growth Factor of 75 kD (LEDGF/p75) is upregulated in clinical prostate tumors and contributes to DTX-resistance in mCRPC cells. However, little is known about the molecular mechanisms by which LEDGF/p75 promotes taxane resistance. The C-terminus of LEDGF/p75 contains a domain called the Integrase Binding Domain (IBD), which in T cells is responsible for tethering the HIV-integrase complex to transcriptionally active chromatin. In non-PCa cells, the LEDGF/p75 IBD interacts with transcription complexes, such as Menin-MLL and the c-MYC binding protein JPO2, to promote cell survival. However, the relevance of these and others protein-protein interactions (PPIs) in the context of PCa chemoresistance has never been explored. This study was designed to test the hypothesis that interactions between LEDGF/p75, the c-MYC binding protein JPO2, Menin and MLL in DTX-resistant mCRPC cells contribute to chemoresistance. We demonstrated by immunoblotting a significant co-upregulation of JPO2, c-MYC, Menin, MLL, and LEDGF/p75 in the DTX-resistant PC3-DR and DU145-DR cell lines, compared to the parental, drug sensitive cells. We also observed nuclear co-localization of these proteins by immunofluorescence microscopy and confocal microscopy. Using an immunoprecipitation approach, we confirmed that endogenous JPO2, c-MYC, Menin, and MLL co-immunoprecipitate with LEDGF/p75 in the DTX-resistant PCa cell lines. We are extending these studies to other known interacting partners of LEDGF/p75 to determine if they are also upregulated in DTX-resistant PCa cells and interact with this protein in the chemoresistance context. In addition, we have initiated studies to evaluate the effects of pharmacologic and genetic inhibition of LEDGF/p75 and its interacting partners on sensitization of DR cells to DTX. We predict that targeting LEDGF/p75 PPIs will disrupt transcriptional activity contributing to DTX resistance. Our goals are to establish the contribution of these PPIs to LEDGF/p75-mediated transactivation of DTX resistance-associated genes, and target these interactions to overcome PCa chemoresistance. Citation Format: Greisha L. Ortiz Hernandez, Evelyn S. Sanchez-Hernández, Carlos A. Casiano. Interaction of LEDGF/p75 with oncogenic transcription factors in docetaxel resistant prostate cancer cells [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 4688.
Abstract 3450: Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors
Authors: Ting Tao, Hui Shi, Adam D. Durbin, Meng Wang, Antonio R. Perez-Atayde, Wendy B. London, Alejandro Gutierrez, Bernardo Lemos, A. Thomas Look
Journal: Cancer Research (2020)

Abstract Peripheral sympathetic nervous system tumors are the most common extra-cranial pediatric tumors in children and include neuroblastoma, ganglioneuroblastoma (intermixed and nodular) and ganglioneuroma. The etiology and molecular pathogenesis of ganglioneuromas remains largely unknown. Surgery is the only effective therapy for ganglioneuroma, which can be challenging due to the location of the tumor and involvement of surrounding structures. Thus, there is need for well tolerated presurgical therapies that could reduce the size and extent of ganglioneuroma, and therefore limit surgical morbidity. Here we found high levels of phosphorylated AKT expressed in 10 of 11 patients with ganglioneuroma, but only in 1 of 15 who had poorly differentiated neuroblastoma (p&amp;lt;0.0001, Fisher's exact test). Consistent with these results, zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. Histopathological analysis and whole-transcriptome sequencing revealed that zebrafish ganglioneuroma highly resembles human ganglioneuroma. Inhibition of the downstream AKT target, mTOR, using sirolimus in zebrafish with ganglioneuroma effectively reduced the tumor burden, providing preclinical evidence for efficacy with this well tolerated drug. Our results implicate activated AKT as a tumorigenic driver in ganglioneuroma. We propose a clinical trial of sirolimus as a means to shrink large ganglioneuromas prior to resection in order to reduce surgical morbidity. Citation Format: Ting Tao, Hui Shi, Adam D. Durbin, Meng Wang, Antonio R. Perez-Atayde, Wendy B. London, Alejandro Gutierrez, Bernardo Lemos, A. Thomas Look. Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors [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 3450.