CAR T Cells Beyond Cancer: Hope for Immunomodulatory Therapy of Infectious Diseases

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: Nov. 21, 2019

Infectious diseases are still a significant cause of morbidity and mortality worldwide. Despite the progress in drug development, occurrence microbial resistance is concern. Alternative therapeutic strategies required for non-responding or relapsing patients. Chimeric antigen receptor (CAR) T cells has revolutionized cancer immunotherapy, providing potential option patients who unresponsive to standard treatments. Recently two CAR cell therapies, Yescarta® (Kite Pharma/ Gilead) Kymriah® (Novartis) were approved by FDA treatments certain types non-Hodgkin lymphoma B-cell precursor acute lymphoblastic leukemia, respectively. The success adoptive therapy inspired researchers develop CARs treatment infectious diseases. Here, we review main achievements targeting viral infections, including Human Immunodeficiency Virus, Hepatitis C B Cytomegalovirus, opportunistic fungal infections such as invasive aspergillosis.

Language: Английский

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Innovations, challenges, and minimal information for standardization of humanized mice

EMBO Molecular Medicine, Journal Year: 2020, Volume and Issue: 12(7)

Published: June 24, 2020

Review24 June 2020Open Access Innovations, challenges, and minimal information for standardization of humanized mice Renata Stripecke Corresponding Author [email protected] orcid.org/0000-0001-7756-8460 Regenerative Immune Therapies Applied, Hannover Medical School, Hannover, Germany German Center Infection Research (DZIF), Region, Search more papers by this author Christian Münz orcid.org/0000-0001-6419-1940 Viral Immunobiology, Institute Experimental Immunology, University Zurich, Switzerland Jan Jacob Schuringa orcid.org/0000-0001-8452-8555 Department Hematology, Groningen, The Netherlands Karl-Dimiter Bissig Pediatrics, Duke Center, Durham, NC, USA Brian Soper Jackson Laboratory, Bar Harbor, ME, Terrence Meeham Kymab Biotechnology, Cambridge, UK Li-Chin Yao Sacramento, CA, James P Di Santo Institut Pasteur, INSERM U1223, Paris, France Michael Brehm Massachusetts Worcester, MA, Estefania Rodriguez Virology Dept., Bernhard Nocht Tropical Medicine, Hamburg, Anja Kathrin Wege Gynecology Obstetrics, Cancer Regensburg, Dominique Bonnet Francis Crick Institute, London, Silvia Guionaud Nonclinical Consulting, Canterbury, Kristina E Howard U.S. Food & Drug Administration, Silver Spring, MD, Scott Kitchen California, Los Angeles, Florian Klein Cologne, Kourosh Saeb-Parsy Johannes Sam Roche Innovation Amar Deep Sharma Andreas Trumpp orcid.org/0000-0002-6212-3466 Division Stem Cells Cancer, (DKFZ), Heidelberg, Heidelberg Cell Technology Medicine (HI-STEM gGmbH), Livio Trusolino Oncology, Torino Turin, Italy Candiolo FPO IRCCS, Candiolo, Carol Bult Leonard Shultz Information *,1,2,‡, Münz3,‡, Schuringa4,‡, Bissig5,‡, Soper6,‡, Meeham7,‡, Yao8, Santo9, Brehm10, Rodriguez11, Wege12, Bonnet13, Guionaud14, Howard15, Kitchen16, Klein17, Saeb-Parsy18, Sam19, Sharma1, Trumpp20,21, Trusolino22,23, Bult6 Shultz6,‡ 1Regenerative 2German 3Viral 4Department 5Department 6The 7Kymab 8The 9Institut 10University 11Virology 12Department 13The 14Guionaud 15U.S. 16University 17University 18University 19Roche 20Division 21Heidelberg 22Department 23Candiolo ‡These authors contributed equally to work *Corresponding author. Tel: +49 (511) 532-6999; Fax: 532-6975; E-mail: EMBO Mol Med (2020)12:e8662https://doi.org/10.15252/emmm.201708662 See the Glossary abbreviations used in article. PDFDownload PDF article text main figures. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures Info Abstract Mice xenotransplanted with human cells and/or expressing gene products (also known as "humanized mice") recapitulate evolutionary specialization diversity genotypic phenotypic traits. These models can provide a relevant vivo context understanding human-specific physiology pathologies. Humanized have advanced toward mainstream preclinical are now at forefront biomedical research. Here, we considered innovations challenges regarding reconstitution immunity tissues, modeling infections cancer, use testing drugs or regenerative therapy products. As number publications exploring different facets mouse has steadily increased past years, it is becoming evident that standardized reporting needed field. Therefore, an international community-driven resource called "Minimal Standardization Mice" (MISHUM) been created purpose enhancing rigor reproducibility studies Within MISHUM, propose comprehensive guidelines critical generated using mice. ADCC antibody-dependent cellular cytotoxicity, immune defense mechanism whereby effector such NK lyses target bound specific antibodies AML acute myeloid leukemia ART anti-retroviral BDBV Bundibugyo ebolavirus BiTE bispecific T-cell engagers registered trademark class recombinant monoclonal which bind CD3 receptor tumor-specific antigen BLT bone marrow-liver-thymus BM marrow bNAbs broadly neutralizing capable types viral strains BRGF Balb/c Rag2−/− Il2rg−/− Flt3−/− BRGSA2DR2 BRGS HLA-A2 DR2 transgenes CAR chimeric CB cord blood CCR5 chemokine targeted R5 tropic HIV CD40L CD40 ligand CDX cell line-derived xenograft CRS cytokine release syndrome systemic inflammatory response be triggered infections, drugs, therapies DCs dendritic DRAG strain HLA-DR derived from NRG EBOV Zaire EBV Epstein–Barr virus ES embryonic stem FAH −/− knock-out fumarylacetoacetate hydrolase Flt3L Flt3 G-CSF granulocyte colony-stimulating factor GITR glucocorticoid-induced TNFR family-related protein GM-CSF granulocyte–macrophage gp glycoprotein GVHD graft-versus-host disease HAdV2 adenovirus 2 HBV hepatitis B HCMV cytomegalovirus HCT HSC transplantation routine clinical procedure performed hematopoietic patient (autologous) donor (allogeneic) combating malignancies correcting defects system HCV C Hematopoiesis differentiation lineages multipotent (HSCs) HIS immunodeficiency HLAs leukocyte antigens HSCs HSPCs hematopoietic/stem/progenitor HSVtk herpes simplex type 1 thymidine kinase huPBL peripheral lymphocyte IFN interferon IgG immunoglobulin G IgM M IL-2 interleukin Il2rg (IL-2) common gamma chain IL-3 3 IO Immuno-oncology iPS induced pluripotent LDL low-density lypoprotein Lin− lineage negative lymphomagenesis development lymphocytes T mAb M-CSF macrophage factors MDS myelodysplastic MERS Middle East respiratory syndrome-related coronavirus MHC major histocompatibility complex MISHUM MISTRG-6 (M-CSF), IL-3, IL-6, GM-CSF, thrombopoietin (TPO) MSCs mesenchymal stromal Myelo-ablated treated irradiation chemotherapy order decrease activity improve engraftment transplanted Myelodysplasia abnormal accumulation immature Myelofibrosis replacement scar tissue due proliferation NASH non-alcoholic steatohepatitis NIH National Institutes Health natural killer NOD Non-obese diabetic NOG NOD.Cg-PrkdcscidIl2rgtm1Sug/Jic NRGF NOD-Rag1−/− Flk2−/− NOD-Rag1tm1Mom Il2rgtm1Wjl/SzJ NSG NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ PBMCs mononuclear PD-1 programmed death PD-L1 PDX-MI PDX Model Minimal standard patient-derived PIRF POR−/−/Il2rg−/−/Rag2−/−/FAH−/− Rag1 recombination activating Rag2 RESTV Reston RSV Respiratory syncytial SC-beta cell-derived beta SCF scid CB17-Prkdcscid severely compromised immunodeficient SCID-hu SCID-humanized SHIV simian Sirpa signal regulatory alpha SUDV Sudan T1D diabetes TAFV Tai Forest TCB TCRs receptors Tim-3 mucin domain-containing TK-NOG transgenic (HSVtk) under albumin promoter (NOD.Cg-PrkdcscidIl2rgtm1SugTg(Alb-Tk)7-2/ShiJic) TPO Thrombopoietin Tregs TSLP thymic-stromal-cell-derived lymphopoietin uPA urokinase-type plasminogen activator expressed Studies engraftment, hematopoiesis, immunocompetent provided insights into regulation hematopoiesis immunity. However, do not always reflect responses humans because multiple species-specific differences. developing components (HIS) were created. tools test new vaccines without incurring risks patients. simplest method adoptive administration (PBMCs) (Fig 1A, Table 1). Since react forcefully against xenogeneic (MHC) I II so-called "huPBL" model faces hardship fulminant (GVHD) occurring 2–4 weeks after PBMC transfer. limited applicability follow antigenic responses, but immunosuppressive agents. Improvement described novel lacking II, resulting lower occurrences (Yaguchi et al, 2018; 2019). Figure 1. Development applications modelsSchematic representation materials (in blue), characteristics handling (black), analyses (red) models: (A) immunity; (B) metabolism; (C) infections; (D) malignancies; (E) immuno-oncology. Abbreviated items spelled out glossary. Download figure PowerPoint Checklist guideline Section 1: •. *Ethical approval informed consent *(Gestational) age Sex Ethnic origin Human (HLA-A, B, C, DR) Known latent (EBV, HCMV, HIV, HCV, LCMV, HBV) Exome sequence if available 2: tissues *Cell lines (mycoplasma tested other tests) primary cells/tissue through academic collections material transfer agreement/publicly commercial repositories *huPBL: Whole blood, *HSC: obtained fetal liver, mobilized adult donors, Hepatocytes (±non parenchymal cells) Primary tumors (isolation collection method) *Density fractionation (e.g., Ficoll) *Surface markers positive isolation (magnetic beads sorting) depletions *Single pooled *Fresh cryopreserved *Dose viable numbers * Dose weight *Genetic modifications reprogramming iPSC) *Ex expansion activation *Use scaffolds 3D culture *Organoids latently infected pathogens 3: recipient *Institutional *Strain/source/publicly agreement/stock *Human transgenes/knock-in *Knock-out genes *Sex *Age (weeks) reports Microbiota 4: *Anesthesia (local, general, dose) *Preconditioning (radiation dose/schedule pharmacologic myeloablation liver death) *Route injections (intravenous, intra-peritoneal, intra-femoral, intra-liver, intra-splenic) *Surgical implantation (under kidney capsule, intradermal, mammary fat pad) *Collection facial vein, cardiac puncture) *Administration cytokines (vendor, units per weight, route) vectors (type, dose, Non-invasive optical imaging methods (fluorescence, bioluminescence substrate, time, region interest) 5: *Relative chimerism (% huCD45+ 10, 15, 20 showing gating strategies) Absolute (absolute muCD45+ quantification *Kinetics huCD45+, huCD3+, huCD4+, huCD8+ huCD19+ chemokines detectable plasma terminal (ELISA, bead array appropriate control samples) immunoglobulins Kinetics huCD33+, huCD11c+, huCD11b+, huCD14+ 6, huNKp46+, hu56+, huCD16+ huCD19+, huCD27+, huIgM+, huIgG+, huIgA+, Terminal lymphatic (spleen, marrow, thymus, lymph nodes, mesenteric nodes total recovered tissue). organs (liver, lungs, brain, etc.…). Phenotypic characterization (naïve, central memory, effector, memory) Antigen-specific (ELISpot, intracellular staining IFN-γ TNF-α, tetramer analyses) produced dot-plot, binding flow cytometry) Analyses antibody functionality (neutralization) composition CyTOF Gene expression (microarrays, RNAseq) 6: regeneration Liver hepatoblast, hepatocytes (ES iPSC protocols), lung, gut, endocrine pancreas, Validation murine (ELISA secreted proteins) Functional validation: exogenous metabolism, titers hepatotropic viruses (HBV, etc.) postmortem immunostaining (human nuclei antibodies) Onset autoimmunity diabetes. 7: *Scientific informal nomenclature laboratory pathogen isolates *Availability agreement publicly Biosafety level containment: BSL-2, BSL-3, BSL-3**, BSL-4 *Gene modification reporter infection: intravenous, intranasal, intrarectal, intra-splenic *Determination titer dose challenge *Analyses infection dissemination PCR (primers, methods) histology (antibodies, pathogenesis (load survival, loss, enzymes, virus-induced tumor formation) (FACS, FISH, IF, PrimeFlow, single-cell sequencing) 8: oncology immuno-oncology *Donor (age, sex, HLA type) passaged Isolation selection *Tumor (HLA level, exome sequencing, mutations) *Cancer identity metastasis histopathological *Autologous allogeneic Characteristics growth (infiltration lymphocytes) modulation 9: *Chemical name *Vendor collaboration agreements *Dose, route, schedule Pharmacokinetics pharmacodynamics Antibody passive vaccination attenuated viruses, carrying targeting antibodies, virus-like particles, vaccine candidates drug metabolism liver: degree humanization upon testing, next-generation (PIRF other). Detection AST/ALT (liver damage), symptom (cytokine storm) 10: *Production scale, GMP-like GMP *Route, Readouts above 11: statistical correlative Commercially software t-test, ANOVA, etc.…) Specialized tests professional biostatisticians Heat-map Principal component Neural network Isogenic groups donors Asterisks indicate should required publications. A approach covered here detail (HCT) preconditioned (HSCs). Despite full mismatch between (HLA) on leads "fully" differentiate lineages, giving rise mature leukocytes, including several system. Robust lymphoid was pioneered back 1988 description (scid) engrafted autologous thymic (McCune 1988). This (SCID-hu) showed initially only transient presence (IgG) circulation. relevance background success later appreciated when observed non-obese (NOD)-scid had much higher capacity support engraftment. elucidated human-like (Sirpa) allele strain, popularly "don't eat me signal", bypassing phagocytosis macrophages (Takenaka 2007; 2012). Targeting (Il2rg) resulted absence (NK) well ablation lineages. In addition, (Rag1)−/− radioresistant host (Shultz 2007). Currently, there approximately 50 diverse biorepositories. Most these homozygous scid, Il2rg, Rag1, mutations express allele. NOD-scid IL2rg(−/−) (NSG), IL2rg−/− (NRG), NOD/Shi-scid (NOG) xenografting large variety cells, prospering (for recent reviews, see 2019; Allen It important thoughtful also about nature HSCs. Although differ greatly their biological characteristics, essentially engraft myelo-ablated irradiated reside (BM) niche. opened doors basic properties long-term durable repopulation sources HSCs, (CB) mostly used, they high frequencies Generally, range × 104–105 isolated administered enable efficient reconstitution. Several laboratories opted abundance explored generate larger cohorts (n = 30–40) compared 10–20). Some tried overcome limitation pooling systems HLA-matched, once develop, allograft reactions among complicate responses. Additionally, take consideration neonatal may intrinsically stage development. Further, consider ethical constraints difficulties procurement tissues. fact, US (NIH) currently supporting investigators seek develop rely (Allen surface allow identification, purification, analyses, define populations highest capacity. Xenotransplantation CD34+ most mice, corroborated evidence human-enriched (HSPCs) salvage optimally matched patients donors. Remarkably, defined CD93hi sub-fraction within (Lin−) CD34− CD38− present repopulating (Danet 2002). CD49f adhes

Language: Английский

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Attacking Latent HIV with convertibleCAR-T Cells, a Highly Adaptable Killing Platform

Cell, Journal Year: 2019, Volume and Issue: 179(4), P. 880 - 894.e10

Published: Oct. 1, 2019

Language: Английский

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Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo

Nature Medicine, Journal Year: 2020, Volume and Issue: 26(11), P. 1776 - 1787

Published: Aug. 31, 2020

Language: Английский

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Applying a clinical lens to animal models of CAR-T cell therapies

Molecular Therapy — Methods & Clinical Development, Journal Year: 2022, Volume and Issue: 27, P. 17 - 31

Published: Aug. 30, 2022

Chimeric antigen receptor (CAR)-T cells have emerged as a promising treatment modality for various hematologic and solid malignancies over the past decade. Animal models remain cornerstone of pre-clinical evaluation human CAR-T cell products are generally required by regulatory agencies prior to clinical translation. However, pharmacokinetics pharmacodynamics adoptively transferred T dependent on recipient factors, posing challenges accurately predicting engineered behavior in non-human animal models. For example, murine xenograft did not forecast now well-established cytokine-driven systemic toxicities seen humans, highlighting limitations that do perfectly recapitulate complex immune systems. Understanding concordance well discrepancies between existing data experiences, along with established advantages each model, will facilitate investigators' ability appropriately select design optimal future products. We summarize current state this field, disadvantages approach depending questions being asked.

Language: Английский

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Stem cell-derived CAR T cells show greater persistence, trafficking, and viral control compared to ex vivo transduced CAR T cells

Molecular Therapy, Journal Year: 2024, Volume and Issue: 32(4), P. 1000 - 1015

Published: Feb. 27, 2024

Adoptive cell therapy (ACT) using T cells expressing chimeric antigen receptors (CARs) is an area of intense investigation in the treatment malignancies and chronic viral infections. One limitations ACT-based CAR lack vivo persistence maintenance optimal function. Therefore, alternative strategies that increase function CAR-expressing are needed. In our studies humanized bone marrow/liver/thymus (BLT) mouse model nonhuman primate (NHP) HIV infection, we evaluated two CAR-based gene approaches. ACT approach, used cytokine enhancement preconditioning to generate greater anti-HIV

Language: Английский

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RNA Viruses as Tools in Gene Therapy and Vaccine Development

Genes, Journal Year: 2019, Volume and Issue: 10(3), P. 189 - 189

Published: March 1, 2019

RNA viruses have been subjected to substantial engineering efforts support gene therapy applications and vaccine development. Typically, retroviruses, lentiviruses, alphaviruses, flaviviruses rhabdoviruses, measles viruses, Newcastle disease picornaviruses employed as expression vectors for treatment of various diseases including different types cancers, hemophilia, infectious diseases. Moreover, vaccination with viral has evaluated immunogenicity against agents protection challenges pathogenic organisms. Several preclinical studies in animal models confirmed both immune responses lethal challenges. Similarly, administration animals implanted tumor xenografts resulted regression prolonged survival, some cases complete clearance. Based on results, clinical trials conducted establish the safety virus delivery. stem cell-based lentiviral provided life-long production factor VIII potentially generating a cure hemophilia A. cancer patients generated anti-tumor activity, even progression-free survival.

Language: Английский

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Chimeric antigen receptor T-cell approaches to HIV cure

Current Opinion in HIV and AIDS, Journal Year: 2018, Volume and Issue: 13(5), P. 446 - 453

Published: June 7, 2018

Purpose of review Combination antiretroviral therapy (ART) has enabled tremendous progress in suppressing HIV replication infected patients. However, ART alone cannot eradicate and its latent, persisting reservoirs. Novel approaches are needed to the virus or achieve functional cure absence ART. Recent findings Adoptive T-cell therapies were initially tested HIV-infected individuals with limited efficiency. Benefiting from new improved methodologies, an increasing array CAR been successfully developed cancer immunotherapy field, demonstrating promising avenues that could be applied HIV. Numerous studies have characterized various HIV-specific constructs, types cytolytic effector cells, CAR-expressing cells' trafficking reservoir compartments, warranting further in-vivo efforts. Notably, ability cells persist function low-antigen environments vivo, is, ART-suppressed patients, remains unclear. Summary Despite results preclinical studies, only a handful clinical trials initiated worldwide. Several obstacles remain prior successful application In this review, we survey current state address paths towards realizing goal efficacious product.

Language: Английский

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Advances in Developing CAR T-Cell Therapy for HIV Cure

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: March 10, 2020

Acquired immune deficiency syndrome (AIDS), which is caused by HIV infection, an epidemic disease that has killed millions of people in the last several decades. Although combination antiretroviral therapy (cART) enabled tremendous progress suppressing replication, it fails to eliminate latently infected cells, and individuals remain positive for life. Lifelong required maintain control virus may result significant problems, including long-term toxicity, high cost, stigma. Therefore, novel therapeutic strategies are urgently needed viral reservoir host cure. In this review, we compare potential regarding cure focus on how might utilize chimeric antigen receptor-modified T cells (CAR T) as a infection.

Language: Английский

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CAR-T Cells Targeting Epstein-Barr Virus gp350 Validated in a Humanized Mouse Model of EBV Infection and Lymphoproliferative Disease

Molecular Therapy — Oncolytics, Journal Year: 2020, Volume and Issue: 18, P. 504 - 524

Published: Aug. 8, 2020

Epstein-Barr virus (EBV) is a latent and oncogenic human herpesvirus. Lytic viral protein expression plays an important role in EBV-associated malignancies. The EBV envelope glycoprotein 350 (gp350) expressed abundantly during lytic reactivation sporadically on the surface of latently infected cells. Here we tested T cells expressing gp350-specific chimeric antigen receptors (CARs) containing scFvs derived from two novel gp350-binding, highly neutralizing monoclonal antibodies. were fused to CD28/CD3ζ signaling domains retroviral vector. produced gp350CAR-T specifically recognized killed gp350+ 293T vitro. best-performing 7A1-gp350CAR-T cytotoxic against EBV+ B95-8 cell line, showing selectivity Fully humanized Nod.Rag.Gamma mice transplanted with cord blood CD34+ EBV/M81/fLuc strain monitored dynamically for spread. Infected recapitulated EBV-induced lymphoproliferation, tumor development, systemic inflammation. We adoptive transfer autologous CD8+gp350CAR-T administered protectively or therapeutically. After therapy, 75% controlled reduced spread showed lower frequencies EBER+ B malignant lack In summary, proof-of-concept preclinical efficacy impending lymphoproliferation lymphomagenesis.

Language: Английский

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