bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A181: Origin of tumor-elicited cytotoxic innate-like T-cell responses
Authors: Chou Chun , Dadi Saida , Nixon Briana G. , Li Ming 
Published: February 2019

Abstract
In most murine cancer models and human patients, cell-mediated cytotoxicity is critical for the destruction of tumor cells. Conventional CD8+ T-cells, which possess cytotoxic capacity, are thus the targets of most cancer immunotherapies. However, tumors that are poorly antigenic, immunosuppressive, or have low T-cell infiltration are often resistant to CD8+ T-cell-centric modalities. Thus, exploring the roles of other cytotoxic immune cell types will complement and synergistically enhance the potency of current treatments. Recently, our lab identified a population of tumor-infiltrating innate-like T-cells (ILTCs), which constitutively express high levels of cytotoxic molecules, are closely juxtaposed to tumor cells, and readily induce cytolysis of transformed target cells. Although armed with a polyclonal T-cell receptor (TCR) repertoire similar to conventional T-cells, ILTCs are phenotypically unconventional and innate-like by the concomitant expression of activating and inhibitory receptors typically found on natural killer (NK) cells but not on conventional T-cells. The specificity of ILTC TCR is unknown, and the extent to which TCR engagement maintains ILTCs and activates their effector functions in the context of tumor also remains ill-defined. While ILTCs and conventional T-cells share a thymic origin, genome-wide analyses revealed a distinct epigenetic landscape in ILTCs compared to conventional T-cells, suggesting that ILTCs constitute a disparate lineage and that alternative selection processes drive their fate choice during thymic development. Here, we showed that commitment to ILTC fate is instructed by distinct TCR specificity. Utilizing TCR retrogenic models and adoptive cell transfer approach, we identified the thymic and circulating ILTC-lineage-committed progenitor. These precursors are continuously generated by adult hematopoiesis and replenish the ILTC pool as the tumor develops. By acutely ablating TCRs, we demonstrated that tumor-resident ILTCs continuously require TCR for their maintenance. Together, our results delineate the ontogeny of ILTCs. Their unique TCR specificity, homing pattern, and innate-like features make ILTC a powerful candidate for bioengineering and adoptive cellular therapy.
Citation Format: Chun Chou, Saida Dadi, Briana G. Nixon, Ming Li. Origin of tumor-elicited cytotoxic innate-like T-cell responses [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A181.
Abstract A185: Effective expansion of poly-functional tumor-reactive TILs from NSCLC correlates with an immune-engaged T-cell profile in tumor tissues
Authors: Groot Rosa De , Loenen Marleen M. van , Guislain Aurélie , Amsen Derk , Haanen John B.A.G. , Monkhorst Kim , Hartemink Koen J. , Wolkers Monika C. 
Published: February 2019

Abstract
Non-small cell lung cancer (NSCLC) is the second most frequently occurring type of cancer. Because of the high mortality rates with the current treatment regimens, novel therapeutic approaches are warranted. The high mutational rate of the tumors, and the high level of T-cell infiltrates should render NSCLC patients eligible for autologous T-cell therapy. Here we show that tumor-infiltrating lymphocytes (TILs) from treatment naive, stage I-IIIa NSCLC tumors can be effectively expanded and reprogrammed. With an optimized detection essay for tumor-reactive T-cells, we observed that 13/17 tested TIL products (76.5%) from primary NSCLC tumor tissues contained cytokine-producing CD4+ and/or CD8+ T-cells in response to primary tumor digest. Tumor responses ranged from 0.5%-30%, and correlated well with activation markers on CD4+ and CD8+ T-cells. Importantly, 29.4% of the TIL products contained poly-functional T-cells that produced TNF-alfa and/or IL-2 in addition to IFN-gamma, and poly-functional T-cells correlated with high levels of tumor reactivity. Furthermore, high percentages of CD103+CD69+CD8+ T-cells, PD-1+CD4+ T-cells and FoxP3+CD25+CD4+ T-cells in the tumors were good predictors for the generation of highly tumor-reactive TIL products. In conclusion, we show that most NSCLCs contain tumor-specific T-cells that can be efficiently expanded and become highly poly-functional, depending on the initial T-cell profile of TILs. Our findings show the feasibility of culturing tumor-reactive TILs from NSCLC and provide keys to individualize adoptive T-cell therapy. Therefore, autologous T-cell therapy should be reconsidered as treatment for NSCLC patients.
Citation Format: Rosa De Groot, Marleen M. van Loenen, Aurélie Guislain, Derk Amsen, John B.A.G. Haanen, Kim Monkhorst, Koen J. Hartemink, Monika C. Wolkers. Effective expansion of poly-functional tumor-reactive TILs from NSCLC correlates with an immune-engaged T-cell profile in tumor tissues [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A185.
Abstract A192: Non-IL-2 blocking anti-CD25-targeting antibodies: depletion of regulatory T-cells driving optimal effector response for rejection of established tumors
Authors: Goubier Anne , Solomon Isabelle , Vargas Frederick Arce , Zervas Dimitrios , Qing Chen , Salimu Josephine , Brown Mark , Merchiers Pascal , Peggs Karl S. , Quezada Sergio A. 
Published: February 2019

Abstract
The accumulation of regulatory T-cells (Tregs) in the tumor hampers effector antitumor activity and correlates with a poor prognosis in several human cancers. Increasing the effector T-cell (Teff) to regulatory T-cell (Treg) ratio is known to result in improved control of established tumors. Studies demonstrating high levels of CD25 expression on Tregs and only low levels on Teff in human tumors have underscored its relevance as a target for Treg depletion. This supported the development of anti-CD25 depleting monoclonal antibodies (mAbs) as a promising monotherapy as well as combination partner in cancer immunotherapies. To date, anti-CD25 antibodies for clinical use have been designed to block IL-2 binding and signaling through the IL-2 receptor complex and also depletes CD25 positive cells. Since IL-2 is a critical cytokine involved in T-cell activation and proliferation, we hypothesized that a depleting antibody targeting CD25 but unable to block IL-2 signaling would promote a more potent anti-tumor response by preferentially depleting Tregs while still allowing IL-2 to stimulate effector T-cells expressing low levels of CD25 on their surface. We therefore compared the functional activity of anti-mouse CD25 depleting mAbs with and without IL-2 blocking activity. After having confirmed their differential impact on IL-2 signaling in vitro and in vivo, we evaluated the therapeutic activity of these mAbs in various syngeneic tumor models. While both the IL-2 blocking and non-IL-2 blocking mAbs showed equivalent Treg-depleting activity, the antibody sparing IL-2 signaling (αCD25NIB) promoted stronger antitumor effect than the IL-2 blocking mAb, with complete tumor regression observed in 70-100% of the mice after a single administration of the antibody. We demonstrated that the αCD25NIB would be an ideal partner for combination against several tumor types including “immune cold” tumors and αPD-L1 resistant tumors. Our data demonstrate that targeting CD25 with ADCC enabled antibodies preserving IL-2 signaling is a novel and powerful strategy for rejection of established tumors via depletion of Treg cells and enhanced, cell intrinsic, IL-2-driven effector T-cell activation.
Citation Format: Anne Goubier, Isabelle Solomon, Frederick Arce Vargas, Dimitrios Zervas, Chen Qing, Josephine Salimu, Mark Brown, Pascal Merchiers, Karl S. Peggs, Sergio A. Quezada. Non-IL-2 blocking anti-CD25-targeting antibodies: depletion of regulatory T-cells driving optimal effector response for rejection of established tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A192.
Abstract A199: TNFR2-targeted elimination of Tregs and tumor-residing T-cells in a murine colon cancer model
Authors: LaMontagne Russell 
Published: February 2019

Abstract
Introduction: Tumor necrosis factor receptor 2 (TNFR2, or TNFRSF1B) is a lymphoid marker of the most potent regulatory T-cell (Treg) subtype and a commonly expressed oncogene in human tumors. TNFR2 Tregs are also enriched in the tumor microenvironment. TNFR2 antagonistic antibodies have been developed to inhibit NFkB-driven growth through the TNFR2 receptor, showing both Treg and tumor inhibition with specificity for the tumor microenvironment (Sci Signaling 2017). A mouse surrogate, TY101, has been developed to assess efficacy in murine models of colon cancer. Methods: We designed monoclonal antibodies to target the TNFR2 oncogene and directly kill tumor cells in syngeneic murine models of colon cancer: CT26 and MC28. All studies were conducted by an independent third party (Champions Oncology). The primary endpoint was a reduction in tumor size. Results: In MC38 mice, the TNFR2 antagonist combined with anti-PD1 immunotherapy was more effective than placebo or immunotherapy alone in reducing mean tumor volume (P=0.004). In CT26 mice, the TNFR2 antagonist as a monotherapy was more effective compared to placebo or combination therapy with anti-PD1 (p&lt;0.0001). Conclusions: The results of this study in syngeneic mice suggest that novel anti-TNFR2 antibodies have potential to be used either alone or in combination with immunotherapy as a treatment for colon cancer and should be studied in future trials.
Citation Format: Russell LaMontagne. TNFR2-targeted elimination of Tregs and tumor-residing T-cells in a murine colon cancer model [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A199.
Abstract A206: Extracellular matrix anchoring of locally administered cytokines safely potentiates systemic cancer immunotherapy
Authors: Momin Noor 
Published: February 2019

Abstract
Cytokines coordinate essential mechanisms required for an antitumor response. As a result, they robustly synergize with other immunotherapies. Unfortunately, the clinical use and approval of cytokines is frequently plagued by dose-limiting toxicities. Improving the therapeutic index of cytokines can be achieved by better localizing their effects to the tumor and away from healthy tissue. Recent efforts have shown that local injections of immunomodulatory agents at or around a tumor lesion improve the efficacy and reduce the systemic exposure of these agents. However, even when administered directly into a tumor, cytokines exhibit rapid tumor clearance and limited intratumoral retention, thus doing little to address issues of toxicity and efficacy. Here we demonstrate that extracellular matrix (ECM) anchoring of intratumorally administered cytokines is a facile strategy to retain and confine these agents in the tumor. Although the ECM is an abundant component of both tumors and healthy tissue alike, intratumoral administration obviates the need to target a tumor-specific antigen. Instead, the abundance of matrix lends itself to being an effective and general target for localization across all solid tumors. ECM-anchoring of cytokines via fusion to a matrix-binding protein significantly improves their therapeutic index. Additionally, the combination of ECM-anchored cytokines with a systemic immunotherapy (e.g., a tumor-targeting antibody, checkpoint blockade, a cancer vaccine, or CAR-T-cell therapy) enhances overall survival in syngeneic tumor models compared to combination treatments using unanchored cytokines. Cytokines that are actively retained in the tumor can safely and significantly potentiate systemic immunotherapy. Given the abundant expression of ECM across different cancers, matrix-anchoring of cytokines embodies a tumor-agnostic strategy that can readily be combined with other immunotherapeutic modalities.
Citation Format: Noor Momin. Extracellular matrix anchoring of locally administered cytokines safely potentiates systemic cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A206.
Abstract A212: Expanded CD8+PD-1+ T-cell and TCR repertoire signatured clinical response of adoptive T-cell immunotherapy in advanced pancreatic cancers
Authors: Qiao Guoliang 
Published: February 2019

Abstract
Purpose: Advanced pancreatic cancer(APC) has remained challenging to treat effectively. This study aimed to explore the biologic antitumor activities of sorted CD8+PD-1+T-cells expanded from peripheral blood mononuclear cells (PBMCs) and analyze the prognostic values of fold expansion capacity of functional CD8+PD-1+T-cells and TCR repertoire after ex vivo expansion. Experimental Design: 25 selected APC patients who had been previously confirmed with improved clinical response based on chemotherapeutic S-1 plus adoptive T-cell immunotherapy were further stratified to identify the biologically molecular mechanism of expanded CD8+PD-1+T-cell and restored TCR repertoire on post-infused patients’ peripheral blood T lymphocytes phenotype and subsequent association with clinical responses. Results: The harvested PMBCs were expanded ex vivo under the cytokines’ stimulation. The induced CD3+, CD3+CD4+, CD3+CD8+T-cells components reached the peak value in 15 days. CD8+T-cells exhibited enhanced expression of PD-1, LAG-3, and TIM-3 after ex vivo expansion except for 4-1BB. Survival analysis showed that patients with ratio of post/pre CD8+PD-1+T-cells more than 2 had significantly favorable overall survival (OS) (median OS time 238 days versus 142 days, P=0.024) and progressive-free survival (PFS) (median PFS time 180 days vs 85 days, P=0.002). The sorted CD8+PD-1+T-cells were featured by enhanced antitumor activities with the appearance of increased release of IFN-γ secretion and up-regulation of 4-1BB after co-culture with autologous tumor cell line. TCR repertoire diversity simultaneously rose during the ex vivo expansion in which increased unique clones could result in peripheral blood immunologically phenotypic improvements represented by CD8+ enhancement and CD8+/CD28- decline. Moreover, TCR increased unique clones were associated with significantly favorable OS (median OS time 216 days versus 112 days, P=0.031) and PFS (median PFS time 166 days vs 79 days, P=0.043) and the alteration of CD8+PD-1+T-cells (r2=0.464, P=0.001). Conclusion: This study showed that CD8+PD-1+T-cells after ex vivo expansion in 15 days could be identified as the tumor-reactive cells. The present discoveries were filled with that expanded CD8+PD-1+T-cells and restored TCR repertoire were significantly associated with clinical responses in APC.
Citation Format: Guoliang Qiao. Expanded CD8+PD-1+ T-cell and TCR repertoire signatured clinical response of adoptive T-cell immunotherapy in advanced pancreatic cancers [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A212.
Abstract A214: An in vitro preclinical package to assess the safety and efficacy of ImmTAC™ molecules
Authors: Ribeiro Ana , Dobrzycki Tomasz , Harper Jane , Bossi Giovanna , Wright Debbie , Stacey Andrea , Bedke Nicole , Martinez-Hague Ruth , Blat Dan , Humbert Laure , Donellan Zoe , Paston Samantha , Weigand Luise , Canestraro Martina , Gordon-Smith Sophie Botta , Jakobsen Bent K. , Dukes Joseph 
Published: February 2019

Abstract
Immune Mobilising Monoclonal TCRs Against Cancer (ImmTAC) molecules are a new class of bi-specific biologic specifically designed to recognize and eradicate cancer cells. ImmTAC molecules are composed of an affinity-enhanced T-cell receptor (TCR) fused to an anti-CD3 effector function engineered to recognize peptides presented by human leukocyte antigen (HLA) and induce T-cell activation and T-cell mediated killing of tumor cells. TCR-based immunotherapeutic strategies offer distinct advantages over traditional antibody-based therapies, most notably providing access to up to nine-fold more cancer targets by targeting intracellularly processed peptides presented by HLA as opposed to cell surface proteins. Preclinical testing of ImmTAC molecules can prove particularly challenging as these molecules are exquisitely human-specific, requiring a human peptidome and intact human immune system; thus the use of conventional animal models is inappropriate. Given that these molecules harness the full force of the immune system, robust preclinical testing is essential to predict safety and efficacy and inform on clinical dosing for first-in-human studies. Here we present, to our knowledge, the first entirely in vitro preclinical package that comprises a range of cellular and molecular assays to assess the efficacy, safety and specificity of ImmTAC molecules. To exemplify our approach, we draw upon the preclinical testing of multiple ImmTAC molecules, including IMCgp100, the first ImmTAC molecule to reach the clinic. We propose that this preclinical package can be applied to the testing of other TCR-based therapies to deliver a more physiologically relevant model.
Citation Format: Ana Ribeiro, Tomasz Dobrzycki, Jane Harper, Giovanna Bossi, Debbie Wright, Andrea Stacey, Nicole Bedke, Ruth Martinez-Hague, Dan Blat, Laure Humbert, Zoe Donellan, Samantha Paston, Luise Weigand, Martina Canestraro, Sophie Botta Gordon-Smith, Bent K. Jakobsen, Joseph Dukes. An in vitro preclinical package to assess the safety and efficacy of ImmTAC™ molecules [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A214.
Abstract A217: TCR affinity determines the fate of T-cells in tumors
Authors: Shakiba Mojdeh 
Published: February 2019

Abstract
T-cell-mediated immune responses are triggered by T-cell receptor (TCR) binding to peptide-major histocompatibility complex (pMHC). In acute infections, affinity of TCR:pMHC interaction is a critical determinant of T-cell expansion and effector function. However, little is known about how tumor (neo) antigen affinity impacts T-cell differentiation and dysfunction in tumors. To investigate the functional and molecular programs determined by affinity, we generated an in vivo tumor model expressing altered peptide ligands (APL) derived from a native tumor neoantigen recognized by antigen-specific CD8 T-cells with varying functional avidity. While affinity did not impact T-cell activation in tumor draining lymph nodes, it drove distinct functional and molecular pathways at the tumor site: key transcription factors and effector molecules were regulated by signal strength, preserving a cell-intrinsic functional program in T-cells with lower-affinity interactions, while certain hallmarks of T-cell dysfunction, including the expression of some inhibitory receptors, were affinity-independent. RNAseq and ATACseq analyses revealed distinct affinity-dependent transcriptional and epigenetic programs in low- vs. high-affinity T-cells that drive their functional differences. Together these results reveal that TCR:pMHC affinity plays a critical role in defining the epigenetic and transcriptional states and ultimately fate of tumor-specific T-cells.
Citation Format: Mojdeh Shakiba. TCR affinity determines the fate of T-cells in tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A217.
Abstract A223: CD36-mediated metabolic adaptation guides regulatory T-cells in tumors
Authors: Wang Haiping , Ho Ping-Chih 
Published: February 2019

Abstract
Regulatory T-cells (Tregs) play an indispensable role in maintaining peripheral tolerance and preventing autoimmune disease. In addition to modulating tissue homeostasis, the suppressive properties of Tregs can also be harnessed by cancers to evade immunosurveillance. Therefore, depleting Tregs has been shown to unleash antitumor immunity and interrupt formation of an immunosuppressive tumor microenvironment (TME). However, systemic loss of Tregs due to Treg depletion also leads to severe autoimmunity. Therefore, the identification of novel approaches that specifically target intratumoral Tregs is direly needed for unleashing antitumor immunity and cancer immunotherapy. Here we show that intratumoral Tregs increase lipid uptake and content and elevated expression of CD36, a fatty acid translocase, as compared to Tregs in circulation and other normal tissues, in several cancer types. By using the transgenic mice model, we found that Treg-specific ablation of CD36 reduces accumulation of intratumoral Treg and suppresses tumor growth. Importantly, Treg-specific CD36 deficiency does not lead to autoimmunity in aged mice and CD36-deficient Tregs remain their suppressive activity on restraining CD4 T-cell-induced inflammatory bowl disease. Mechanistically, CD36 expression supports survival of intratumoral Tregs by fine-tuning their mitochondrial fitness via PPAR signaling. Thus, high expression of CD36 in intratumoral Tregs orchestrates Treg metabolic adaptation in tumors by intervening metabolic regulations, and further promotes tumor growth by suppressing the antitumor immune responses. Ultimately, anti-PD-1 blockade treatment elicits therapeutic benefits in mice with Treg-specific ablation of CD36. Altogether, our study suggests that CD36 might be a potential target for specifically waning down intratumoral Tregs and provide proof-of-concept evidence that targeting CD36 in tumors could unleash antitumor immunity and synergize with checkpoint blockade treatment.
Citation Format: Haiping Wang, Ping-Chih Ho. CD36-mediated metabolic adaptation guides regulatory T-cells in tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A223.