Publications by authors named "S Guedan"

25 Publications

Identification of cell surface targets for CAR-T cell therapies and antibody-drug conjugates in breast cancer.

ESMO Open 2021 Apr 7;6(3):100102. Epub 2021 Apr 7.

Department of Hematology, Hospital Clinic, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. Electronic address:

Background: Two promising therapeutic strategies in oncology are chimeric antigen receptor-T cell (CAR-T) therapies and antibody-drug conjugates (ADCs). To be effective and safe, these immunotherapies require surface antigens to be sufficiently expressed in tumors and less or not expressed in normal tissues. To identify new targets for ADCs and CAR-T specifically targeting breast cancer (BC) molecular and pathology-based subtypes, we propose a novel in silico strategy based on multiple publicly available datasets and provide a comprehensive explanation of the workflow for a further implementation.

Methods: We carried out differential gene expression analyses on The Cancer Genome Atlas BC RNA-sequencing data to identify BC subtype-specific upregulated genes. To fully explain the proposed target-discovering methodology, as proof of concept, we selected the 200 most upregulated genes for each subtype and undertook a comprehensive analysis of their protein expression in BC and normal tissues through several publicly available databases to identify the potentially safest and viable targets.

Results: We identified 36 potentially suitable and subtype-specific tumor surface antigens (TSAs), including fibroblast growth factor receptor-4 (FGFR4), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), GDNF family receptor alpha 1 (GFRA1), integrin beta-6 (ITGB6) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We also identified 63 potential TSA pairs that might be appropriate for co-targeting strategies. Finally, we validated subtype specificity in a cohort of our patients, multiple BC cell lines and the METABRIC database.

Conclusions: Overall, our in silico analysis provides a framework to identify novel and specific TSAs for the development of new CAR-T and antibody-based therapies in BC.
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http://dx.doi.org/10.1016/j.esmoop.2021.100102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038941PMC
April 2021

CAR-T Cells Hit the Tumor Microenvironment: Strategies to Overcome Tumor Escape.

Front Immunol 2020 17;11:1109. Epub 2020 Jun 17.

Department of Hematology and Oncology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain.

Chimeric antigen receptor (CAR) T cell therapies have demonstrated remarkable efficacy for the treatment of hematological malignancies. However, in patients with solid tumors, objective responses to CAR-T cell therapy remain sporadic and transient. A major obstacle for CAR-T cells is the intrinsic ability of tumors to evade immune responses. Advanced solid tumors are largely composed of desmoplastic stroma and immunosuppressive modulators, and characterized by aberrant cell proliferation and vascularization, resulting in hypoxia and altered nutrient availability. To mount a curative response after infusion, CAR-T cells must infiltrate the tumor, recognize their cognate antigen and perform their effector function in this hostile tumor microenvironment, to then differentiate and persist as memory T cells that confer long-term protection. Fortunately, recent advances in synthetic biology provide a wide set of tools to genetically modify CAR-T cells to overcome some of these obstacles. In this review, we provide a comprehensive overview of the key tumor intrinsic mechanisms that prevent an effective CAR-T cell antitumor response and we discuss the most promising strategies to prevent tumor escape to CAR-T cell therapy.
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http://dx.doi.org/10.3389/fimmu.2020.01109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311654PMC
April 2021

Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability.

J Clin Invest 2020 06;130(6):3087-3097

Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Chimeric antigen receptor-T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response.
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http://dx.doi.org/10.1172/JCI133215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260017PMC
June 2020

Analysis of Antitumor Effects of CAR-T Cells in Mice with Solid Tumors.

Methods Mol Biol 2020 ;2086:251-271

Department of Hematology and Oncology, Hospital Clinic, Institut d'Investigacions BiomÒdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Animal models provide an essential tool to study the efficacy of CAR-T cell treatments. Most of the current works test human CAR-T cells in immunodeficient animals, typically NOD Scid Gamma (NSG) mice transplanted with human tumors. Despite the limitations of this model, including the difficulty to study the interaction between CAR-T cells and the human innate system and to assess the toxicity of this therapy, NSG are extensively used for adoptive T cell transfer studies. In this chapter, we will describe the protocols to test CAR-T cells in NSG animals with solid tumors. We first describe the implantation of human xenograft tumors in NSG animals, followed by CAR-T cell administration and assessment of antitumor responses. We will also review the protocols to analyze T cell persistence in the blood of treated animals. Finally, we will focus on the analysis of the tumors at the end point of the experiment, including the percentage, phenotype, and function of tumor infiltrating T cells, and loss of antigen expression.
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http://dx.doi.org/10.1007/978-1-0716-0146-4_19DOI Listing
December 2020

Analysis of CAR-Mediated Tonic Signaling.

Methods Mol Biol 2020 ;2086:223-236

Department of Hematology and Oncology, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

CARs are synthetic receptors designed to drive antigen-specific activation upon binding of the scFv to its cognate antigen. However, CARs can also elicit different levels of ligand-independent constitutive signaling, also known as tonic signaling. Chronic T cell activation is observed in certain combinations of scFv, hinge, and costimulatory domains and may be increased due to high levels of CAR expression. Tonic signaling can be identified during primary T cell expansion due to differences in the phenotype and growth of CAR-T cells compared to control T cells. CARs displaying tonic signaling are associated with accelerated T cell differentiation and exhaustion and impaired antitumor effects. Selecting CARs which configuration does not induce tonic signaling is important to enhance antigen-specific T cell responses. In this chapter, we describe in detail different protocols to identify tonic signaling driven by CARs during primary T cell ex vivo expansion.
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http://dx.doi.org/10.1007/978-1-0716-0146-4_17DOI Listing
December 2020