bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1614: The effect of tumor mutation burden on immune checkpoint inhibitors in non-small cell lung cancer
Authors: Zhao Jie , Dong Yiting , Bai Hua , Duan Jianchun , Wang Guoqiang , Xu Jiachen , Wang Zhijie , Wang Jie 
Published: July 2021

Abstract
Backgroud: Tumor mutation burden (TMB) remains a promising but ambiguous biomarker for the efficacy of immune checkpoint inhibitors (ICIs)-based regimens. We conducted multifaceted systematic review and meta-analysis, and public cohort validation, to provide pooled evidence of the prediction value of TMB for ICIs in advanced non-small cell lung cancer (NSCLC).
Methods: Mirror-based meta-analysis balancing the confounding factors was applied in Part1, and Bayesian network meta-analysis was conducted in Part2. PubMed, Embase, and Cochrane Central were searched and abstracts from conference were reviewed. All randomized controlled trials (RCTs) that investigated the predictive value of TMB in advanced NSCLC patients receiving ICIs were included. Baseline characteristics, hazard ratios (HRs) with 95% confidence intervals (95% CIs) for progression-free survival (PFS) and overall survival (OS) stratified by TMB status were extracted. Furthermore, public cohorts of advanced NSCLC treated with ICIs with genomic sequencing were analyzed in Part 3.
Results: 10 RCTs covering 4443 patients and 5 public cohorts with 573 patients as validation were included. 9 RCTs were included in
Part1a. TMB-high subgroup exhibited significantly superior PFS than TMB-low subgroup (HR 0.56, 95% CI 0.47-0.67) in NSCLC treated with ICIs compared with chemotherapy, and such superiority was consistent in the preplanned subgroup analysis based on the line of therapy, regimen modality, test method of TMB and PD-L1 expression. 7 RCTs were included in Part1b. No significant difference of PFS or OS was observed between anti-PD-L1 and anti-PD-1 according to TMB status. 7 RCTs were included in Part2. Among all first-line regimens in TMB-high group, platinum-based doublet chemotherapy combined with anti-PD-1 was most likely to rank first for PFS (probability of ranking best 48.29%, surface under the cumulative ranking curve 0.83), anti-PD-L1 plus anti-cytotoxic T-lymphocyte A antigen-4 (CTLA-4) provided the most favorable OS (63.89%, 0.86), and platinum-based chemotherapy ranked worst for PFS (0.03%, 0.11) and OS (0.02%, 0.09). In Part3, TMB was validated to be an independent predictor, which could further distinguish beneficiaries of ICIs in those with PD-L1 expression less than 50%.
Conclusions: TMB could be used to identify beneficiaries of ICIs contained therapies and played a crucial role in determining the optimal first-line treatment among various available strategy for advanced NSCLC patients.
Citation Format: Jie Zhao, Yiting Dong, Hua Bai, Jianchun Duan, Guoqiang Wang, Jiachen Xu, Zhijie Wang, Jie Wang. The effect of tumor mutation burden on immune checkpoint inhibitors in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1614.
Abstract 1620: Efficacy and safety of ICIs in lung cancer patients with interstitial pneumonia
Authors: Fu Yan , Gong Fuyu 
Published: July 2021

Abstract
Background: ICIs has demonstrated efficacy against metastatic lung cancer. However, immune-related adverse events can occur, among which pneumonitis is relatively common. Lung cancer patients with interstitial pneumonia (IP) have a higher risk of pneumonitis associated with anticancer therapy. We hypothesized that the benefit of ICIs may outweigh the risks of pneumonitis in patients with lung cancer who have IP. We performed a pilot trial to evaluate the safety of ICIs in lung cancer patients with IP.
Methods: Previously treated, inoperable NSCLC patients with IP were enrolled. Patients received anti-PD-1/L1 as monotherapy or in combination with other agents, respectively.
Results: A total of 21 lung cancer patients were selected, including 15 (71.4%) male and 6 (28.6%) female with a median age of 62. None experienced drug related nonhematologic grade 3/4 or hematologic grade 4 adverse events in the 12 weeks following the initiation of ICIs treatment. Furthermore, none of the patients had pneumonitis of any grade. At the time of analysis, all patients were alive, and 11 had experienced a partial response.
Conclusion: ICIs therapy may be feasible in lung cancer patients with IP.
Citation Format: Yan Fu, Fuyu Gong. Efficacy and safety of ICIs in lung cancer patients with interstitial pneumonia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1620.
Abstract 1626: PMC309, a highly selective anti-VISTA antibody enhances T cell activation through blocking the interaction of T cells and myeloid derived suppressor cells (MDSC)
Authors: Park Cheon Ho , Byun Sang Soon , An Jin Yong , Ha Sun Hyung , Han Hye Rim , Kang Nu Ri , Park Beom Yong , Lee Eun Ah , Park Hyun Sun , Yoo Jin-San , Lee Weon Sup 
Published: July 2021

Abstract
TME (tumor microenvironment) consists of blood & lymphatic vessels, stromal cells, and immune cells such as lymphocytes, macrophages, and antigen-presenting cells (APC). Cellular interactions among various immune cell types within TME regulate tumor growth, metastasis, and resistance to cancer therapy. V-domain Ig suppressor of T cell activation (VISTA) is a negative checkpoint regulator highly expressed on tumor-infiltrating myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAMs) and VISTA blockade could enhance antitumor immunity in TME. PMC-309 binding to VISTA expressing cells is highly selective and the selectivity is maintained even in the low pH conditions that mimic TME. Binding of PMC-309 on MDSC cells enhances the secretion of IFN-γ, TNF-α, and IL-2 in Mixed Lymphocyte Reaction (MLR) settings. In in vivo study, PMC-309 suppressed tumor growth, which was further attenuated with an anti-PD1 antibody. The anti-tumor activity was associated with enhanced T cell activation, increased secretion of pro-inflammatory cytokines, and increased penetration of tumor-infiltrating leukocytes (TIL) into TME. Patients who became resistant to anti-CTLA-4 and anti-PD(L)1 antibody showed increased expression of VISTA, suggesting that anti-VISTA therapeutics can help to treat the patients who do not respond well to other immuno-oncology drugs. We are developing PMC-309 as a next generation immuno-oncology (IO) agent, which can convert immunologically cold into hot tumors as a mono- or combo- therapy with other IO agent.
Citation Format: Cheon Ho Park, Sang Soon Byun, Jin Yong An, Sun Hyung Ha, Hye Rim Han, Nu Ri Kang, Beom Yong Park, Eun Ah Lee, Hyun Sun Park, Jin-San Yoo, Weon Sup Lee. PMC309, a highly selective anti-VISTA antibody enhances T cell activation through blocking the interaction of T cells and myeloid derived suppressor cells (MDSC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1626.
Abstract 1627: Preclinical characterization of a novel CTLA-4-targeted ETB for direct Treg depletion
Authors: Khanna Swati , Howard Caleigh , Rabia Lilia A. , Aldana Alvaro , Zhao Jay , Chang Betty , Ramos Hilario J. , Iberg Aimee 
Published: July 2021

Abstract
Regulatory T cell (Treg) depletion enhances the anti-tumor efficacy of CTLA-4 targeted mAbs in preclinical models, and is a mechanism supported by retrospective clinical data analysis. In response to these findings, many next-generation CTLA-4 targeting therapeutics have been designed to increase Fc-mediated Treg depletion in the tumor microenvironment. CTLA-4-targeted engineered toxin bodies (ETBs) are designed to deplete Tregs in the tumor microenvironment (TME) directly and in a manner independent of Fc-mediated effector functions, offering a unique approach to CTLA-4 targeted therapy. ETBs, or engineered toxin bodies, are large molecule proteins consisting of an antibody fragment genetically fused to a proprietary de-immunized (DI) form of the Shiga-like toxin A subunit (SLTA). Once engaged to the specific cell surface target of interest, in this case CTLA-4, ETBs internalize, route to the cytosol, and permanently inactivate ribosomes through an irreversible enzymatic process. This results in cell death via apoptotic mechanisms.Here we describe the preclinical characterization of a lead candidate CTLA-4-targeted ETB. CTLA-4-ETB-A directly binds and specifically kills CTLA-4 positive cells in vitro and induces apoptosis of ex-vivo expanded Tregs. CTLA-4-ETB-A is designed to bind CTLA-4 in a manner unique from classic blocking antibodies and is not expected to have sustained blocking ability in vivo due to the relatively short half-life of an ETB compared to a neutralizing mAb. We predict this will allow for focused Treg depletion in the TME based on target expression levels, while sparing autoreactive T cell activation in the periphery. Utilizing human CTLA-4 knock in mouse syngeneic tumor models, we show that CTLA-4-ETB-A can reduce the % Tregs and increase the CD8/Treg ratio in the TME. Preclinical assessment of safety and pharmacodynamic signals are underway in cynomolgus studies.
Citation Format: Swati Khanna, Caleigh Howard, Lilia A. Rabia, Alvaro Aldana, Jay Zhao, Betty Chang, Hilario J. Ramos, Aimee Iberg. Preclinical characterization of a novel CTLA-4-targeted ETB for direct Treg depletion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1627.
Abstract 1646: Development of small-molecule HPK1 inhibitors to unleash tumor-specific T cell responses
Authors: Katibah George , Ohol Yamini , Bucher Cyril , Adusumilli Lavanya , Kaveri Deepika , Robles Omar , Sun Michael , Cho Cynthia , Milestone Heather , Ames Rachel , Jacobson Scott , Nebalasca Dan , Gomez- Guagua Justy , Sanchez Jerick , Grandcolas Molly , Wong Steve , Brovarney Martin , Ramana Chandru , Zaw Thant , Nguyen Lan , Tivitmahaisoon Parcharee , Ng Andrew , Ma Anqi , Gomez Blanca , Ko Michelle , Leger Paul , Jackson Jeffrey , Shibuya Grant , Shakhmin Anton , Bradford Delia , Xu Mengshu , Zibinsky Mikhail , Poon Daniel , Wustrow David , Kassner Paul , Brockstedt Dirk 
Published: July 2021

Abstract
Hematopoietic progenitor kinase 1 (HPK1) is an intracellular protein kinase that negatively regulates T cell signaling and proliferation. Upon T cell receptor (TCR) activation, active HPK1 phosphorylates the adaptor protein SLP76 in the TCR complex, recruiting the negative regulator 14-3-3 and targeting components of the TCR signaling complex for degradation. HPK1 thus limits the TCR signaling important for mounting an effective immune response against tumor cells. We are employing structure-guided drug design to develop potent small-molecule inhibitors of HPK1. Our compounds potently inhibit HPK1 in biochemical assays, reduce levels of phosphorylated SLP76 and concomitantly increase IL-2 production by Jurkat T cells. Importantly, our HPK1 inhibitors enhance cytokine production by human and mouse primary T cells above that observed with TCR activation alone. Treatment of mice with orally available HPK1 inhibitors results in increased activation of antigen-specific CD8+ T cells in vivo and decreased tumor growth as single agent and in combination with clinically relevant checkpoint inhibitor antibodies. Our work confirms the importance of HPK1 for T cell function and supports HPK1 as a promising next generation immuno-oncology target.
Citation Format: George Katibah, Yamini Ohol, Cyril Bucher, Lavanya Adusumilli, Deepika Kaveri, Omar Robles, Michael Sun, Cynthia Cho, Heather Milestone, Rachel Ames, Scott Jacobson, Dan Nebalasca, Justy Gomez- Guagua, Jerick Sanchez, Molly Grandcolas, Steve Wong, Martin Brovarney, Chandru Ramana, Thant Zaw, Lan Nguyen, Parcharee Tivitmahaisoon, Andrew Ng, Anqi Ma, Blanca Gomez, Michelle Ko, Paul Leger, Jeffrey Jackson, Grant Shibuya, Anton Shakhmin, Delia Bradford, Mengshu Xu, Mikhail Zibinsky, Daniel Poon, David Wustrow, Paul Kassner, Dirk Brockstedt. Development of small-molecule HPK1 inhibitors to unleash tumor-specific T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1646.
Abstract 1647: CAPTIV-8: A prospective trial of atezolizumab using a multivariate model incorporating whole genome and transcriptome analysis
Authors: Titmuss Emma , Pender Alexandra , Pleasance Erin , Brown Scott , Grisdale Cameron J. , Topham James , Shen Yaoqing , Bonakdar Melika , Taylor Gregory A. , Williamson Laura , Mungall Karen , Chuah Eric , Mungall Andrew J. , Moore Richard A. , Lavoie Jean-Michel , Yip Stephen , Lim Howard , Renouf Daniel J. , Sun Sophie , Jones Steven J. , Holt Robert , Marra Marco A. , Laskin Janessa 
Published: July 2021

Abstract
Dramatic and durable responses to immune checkpoint inhibitors (ICIs) have been observed across multiple tumor types, but identifying the patients most likely to respond to these drugs remains challenging, particularly in the context of metastatic and pre-treated disease. Recent clinically approved biomarkers for patient selection are tumor agnostic, but currently all approved markers are evaluated independently. Through the Personalized Onco Genomics (POG) program at BC Cancer, we aimed to study the impact of evaluating multiple biomarkers in a tumor agnostic cohort. We performed whole genome and transcriptome analysis (WGTA) on fresh tumor biopsies from a heterogeneous pan-cancer cohort of 82 patients with advanced metastatic disease subsequently treated with ICIs. Established biomarkers, including tumor mutation burden (TMB) and CD8+ T cell scores, were able to distinguish responders in our advanced and pre-treated cohort. Additionally, we discovered that combining multiple biomarkers provided the best stratification of patients, suggesting a multifaceted approach, such as WGTA, may be suitable for more accurate identification of patients that may benefit from ICIs. As such, we have initiated a Phase II clinical trial, CAPTIV-8 (NCT04273061), which is distinctive in its use of WGTA to evaluate multiple markers including TMB, CD8+ T cell scores, an M1-M2 macrophage score and viral integration to select patients most likely to respond to atezolizumab. Clinical and genomic data prospectively collected from two hundred patients will be evaluated to test the efficacy of combining these biomarkers and identify additional biomarkers of response which can be used to guide treatment with ICIs.
Citation Format: Emma Titmuss, Alexandra Pender, Erin Pleasance, Scott Brown, Cameron J. Grisdale, James Topham, Yaoqing Shen, Melika Bonakdar, Gregory A. Taylor, Laura Williamson, Karen Mungall, Eric Chuah, Andrew J. Mungall, Richard A. Moore, Jean-Michel Lavoie, Stephen Yip, Howard Lim, Daniel J. Renouf, Sophie Sun, Steven J. Jones, Robert Holt, Marco A. Marra, Janessa Laskin. CAPTIV-8: A prospective trial of atezolizumab using a multivariate model incorporating whole genome and transcriptome analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1647.
Abstract 1652: Co-targeting distinct hallmark capabilities for therapeutic benefit in pre-clinical GBM models
Authors: Chryplewicz Agnieszka , Hanahan Douglas 
Published: July 2021

Abstract
Glioblastoma (GBM) is the most common primary tumor arising in the central nervous system (CNS). The currently approved standard of care has transient clinical benefit as GBM tends to be exceedingly aggressive. Despite pronounced efforts to identify novel therapies, curative options for GBM do not exist and the survival rate of diagnosed patients is very low. Therefore, there is an urgent need for new treatment strategies, and one approach would be to co-target and thereby disrupt distinct hallmarks of cancer, aiming to elicit sustained therapeutic responses. We have assessed this concept by combining a tricyclic antidepressant -imipramine - with drugs targeting VEGF-A ligand or VEGF-Receptor in mice bearing de novo GBM. All monotherapies were ineffective. In notable contradistinction, we found that combinatorial regimens significantly increased survival benefit and regressed established tumors. Investigation of the basis for the therapeutic efficacy revealed that combining the VEGF pathway inhibitor with imipramine hyperactivated autophagy to the level of eliciting cancer cell-intrinsic autophagy-associated cell death, whilst modifying the tumor vasculature to be more normal-like. In addition, imipramine downregulated an M2-like phenotype of tumor-associated macrophages and reprogramed them to express chemokines attracting otherwise rare CD8 T cells, which were demonstrably contributing to the observed efficacy. As such, these hallmark co-targeting combinations served to reprogram the GBM microenvironment from immunosuppressive to pro-inflammatory, thereby sensitizing the tumors to immune checkpoint blockade, as evidenced by enhanced responses when an anti-PD-L1 therapy was included in the mix. The results to be presented will elaborate a provocative new therapeutic approach for glioblastoma that has prospect to motivate clinical evaluation in this daunting form of human cancer.
Citation Format: Agnieszka Chryplewicz, Douglas Hanahan. Co-targeting distinct hallmark capabilities for therapeutic benefit in pre-clinical GBM models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1652.
Abstract 1666: Tumor-specificity of tumor-infiltrating CD8+ t cells determines the potential of immune checkpoint inhibitors in breast cancer
Authors: Kim Jee Ye , Lee Yong Joon , Jeon Seung hyuck , Nam Heejin , Jung Jae Hyung , Kim Seung Il , Shin Eui-Cheol 
Published: July 2021

Abstract
Tissue-resident memory CD8+ T cells (TRMs), marked by expression of CD103, are considered to play a key role as anti-tumor immune response in breast cancer. However, prognostic value of TRMs and heterogeneity in CD103+ TRMs of breast cancer in terms of tumor-specificity needs further understanding to establish immuno-therapeutic implications. Here, we isolated tumor-infiltrating CD103+TRMs in breast cancer samples and matched peripheral blood mononuclear cells (PBMCs) which were prospectively collected from 127 patients who underwent surgical resection between July 2016 and May 2020 at Severance Hospital, Seoul, Republic of Korea. Multi-color flow cytometry analyses were performed.CD103+TRMs consist of both tumor-antigen specific CD8+ T cells and bystander CD8+ T cells, such as viral antigen-specific CD8+ T cells. Dissection of CD103+TRMs with CD39 expression reveals a clonally-distinct subpopulation exhibiting tumor-antigen specificity and reactivity with transcriptionally and phenotypically exhaustive features. CD39+CD103+ TRMs were enriched in HER2 enriched and triple-negative breast cancer(TNBC) subtypes, but not in Hormone receptor(HR) positive/HER2 not enriched subtypes, implying that the role of tumor-infiltrating CD8+ T cells in eliciting anti-tumor immune response differ among molecular subtypes. In line with early-exhaustive features of CD39+CD103+TRMs, inhibition of either PD-1 alone or both PD-1 and CTLA-4 reinvigorate the proliferation and the cytokine production of CD8+ TILs in HER2 and TNBC subtypes. Our findings indicate that different immuno-therapeutic strategies should be considered to different subtypes of breast cancer.
Citation Format: Jee Ye Kim, Yong Joon Lee, Seung hyuck Jeon, Heejin Nam, Jae Hyung Jung, Seung Il Kim, Eui-Cheol Shin. Tumor-specificity of tumor-infiltrating CD8+ t cells determines the potential of immune checkpoint inhibitors in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1666.
Abstract 167: Multiomics profiling of BAP1 loss in uveal melanoma
Authors: Baqai Usman , Purwin Timothy , Bechtel Nelisa , Chua Vivian , Han Anna , Aplin Andrew E. 
Published: July 2021

Abstract
BRCA1 Associated Protein 1 (BAP1) is a tumor suppressor gene with identified mutations in various cancers including uveal melanoma (UM), malignant mesothelioma, renal cell carcinoma, and cutaneous melanoma. The protein forms multicomplexes with various transcription factors and cell cycle regulators. It also functions as a deubiquitylating enzyme primarily located in the nucleus and acts on histone 2A, leading to altered gene transcription. Recently, it was shown to play a role in apoptotic signaling, homologous-directed repair, and ferroptosis regulation. Over 90% of metastatic UM cases report loss-of-function BAP1 mutations. There is a strong association between loss-of-function BAP1 mutations, metastasis, and poor disease prognosis, the mechanisms for which remain unclear. Understanding the role of BAP1 in metastasis may help uncover therapeutic approaches and improve overall survival outcomes for metastatic UM patients. Here we used a multi-omics approach to investigate changes in gene expression in UM with BAP1 loss. Bioinformatics analysis using multiple UM patient and cell line data sets revealed upregulation of key cell-cell adhesion genes, CDH1, CADM1, and SDC2 with loss of BAP1. These adhesion proteins may be involved with facilitating collective migration or enable metastatic seeding. Together, these data prompt further investigation into the specific roles of BAP1 during the metastatic cascade in UM, from primary dissemination in the eye to seeding in the liver.
Citation Format: Usman Baqai, Timothy Purwin, Nelisa Bechtel, Vivian Chua, Anna Han, Andrew E. Aplin. Multiomics profiling of BAP1 loss in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 167.