Victor Tkachev

PTPN2 Deletion Enhances CAR-T Effector Function and CNS Trafficking in a Non-Human Primate Model

Francesca Alvarez Calderon, Ryan A. Fleming, Marlana Winschel, Lev Gorfinkel et autres

B-cell targeting CAR-T cells (CAR-T) therapies achieve high remission rates, yet durable responses occur in fewer than 40% of patients. Deletion of negative T-cell regulators such as PTPN2, a key inhibitor of TCR and cytokine signaling, represents a promising strategy to enhance …

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Concerted changes in the pediatric single-cell intestinal ecosystem before and after anti-TNF blockade

Hengqi Betty Zheng, Benjamin A. Doran, Kyle Kimler, Alison Yu et autres

Crohn’s disease is an inflammatory bowel disease (IBD) commonly treated through anti-TNF blockade. However, most patients still relapse and inevitably progress. Comprehensive single-cell RNA-sequencing (scRNA-seq) atlases have largely sampled patients with established treatment-refractory IBD, limiting our understanding of which cell types, subsets, …

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Precision editing of cyclophilin A generates cyclosporine- and voclosporin-resistant cellular therapies

Holly Wobma, Francesca Alvarez Calderon, Kayleigh Ingersoll Omdahl, Xianliang Rui et autres

Abstract Recipients of allogeneic transplants or patients with autoimmune disease require immune suppression, often with calcineurin inhibitors. There is an expanding repertoire of immune effector cell therapies, including CD19 CAR-T cells and viral-specific T cells, deployed in these patients; however, ongoing calcineurin …

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Author response: Concerted changes in the pediatric single-cell intestinal ecosystem before and after anti-TNF blockade

Hengqi Betty Zheng, Benjamin A. Doran, Kyle Kimler, Alison Yu et autres

Crohn’s disease is an inflammatory bowel disease (IBD) commonly treated through anti-TNF blockade. However, most patients still relapse and inevitably progress. Comprehensive single-cell RNA-sequencing (scRNA-seq) atlases have largely sampled patients with established treatment-refractory IBD, limiting our understanding of which cell types, subsets, …

Concerted changes in the pediatric single-cell intestinal ecosystem before and after anti-TNF blockade

Hengqi Betty Zheng, Benjamin A. Doran, Kyle Kimler, Alison Yu et autres

Crohn’s disease is an inflammatory bowel disease (IBD) commonly treated through anti-TNF blockade. However, most patients still relapse and inevitably progress. Comprehensive single-cell RNA-sequencing (scRNA-seq) atlases have largely sampled patients with established treatment-refractory IBD, limiting our understanding of which cell types, subsets, …

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Refined design of a CD117 antibody-drug conjugate safely and effectively conditions non-human primates for autologous transplant-based gene therapy

Lev Gorfinkel, Boya Liu, Yi Liu, Madhura Panditrao et autres

Abstract Introduction: Standard chemotherapy and irradiation-based conditioning for hematopoietic stem cell transplant (HCT) and autologous-transplant-based gene therapy (GT) is associated with significant toxicities. Because of this, there is a concerted effort to develop targeted conditioning approaches, including antibody-drug conjugates (ADCs). Depending on …

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Organ-specific microenvironments drive divergent T cell evolution in acute Graft-Versus-Host Disease 3176

Kayleigh Ingersoll Omdahl, Rene S. Bermea, Ryan L. Fleming, Kyle Kimler et autres

Abstract Description Tissue-specific T cell immune responses play a critical role in maintaining organ health, but can also drive immune pathology during both auto- and alloimmunity. The mechanisms controlling intra-tissue T cell programming remain unclear. Here, we leverage a non-human primate model …

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PTPN2-KO CAR-T Cells Demonstrate Enhanced Effector Function, CNS Infiltration, and Toxicity in a Non-Human Primate CAR-T Model

Francesca Alvarez Calderon, Ryan A. Fleming, Marlana Winschel, Lev Gorfinkel et autres

Abstract B-cell targeting CAR-T cell therapies achieve high remission rates, yet durable responses occur in fewer than 40% of patients. Deletion of negative T-cell regulators, such as PTPN2, a key inhibitor of TCR and cytokine signaling, represents a promising strategy to enhance …

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Graft Survival and Rejection Risk with TNX-1500 as Monotherapy or in Combination with Conventional IS Agents in Nonhuman Primate Heart Transplants

Kohei Kinoshita, A. Maenaka, Steve K. Takemoto, Ryan Chaban et autres

Purpose: TNX-1500 (TNX) is a humanized IgG4 αCD154 mAb engineered to down-modulate FcγR2 binding to reduce the thromboembolism risk associated with ruplizumab (hu5c8 IgG1). Here in a NHP allo heart transplant model we report an expanded series of weekly dose TNX therapy …

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A single dose of a CD137 antibody–drug conjugate protects rhesus macaque allogeneic HCT recipients against acute GVHD

Ulrike Gerdemann, Kyle Kimler, Connor McGuckin, Ryan A. Fleming et autres

ABSTRACT: Rapid CD137 upregulation on alloreactive T cells upon allogeneic stimulation suggests that their selective elimination could prevent acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HCT). Here, we developed a novel aGVHD prophylactic regimen consisting of a single dose …

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Organ-specific microenvironments drive divergent T cell evolution in acute graft-versus-host disease

Kayleigh Ingersoll Omdahl, Rene S. Bermea, Ryan L. Fleming, Kyle Kimler et autres

Tissue-specific T cell immune responses play a critical role in maintaining organ health but can also drive immune pathology during both autoimmunity and alloimmunity. The mechanisms controlling intratissue T cell programming remain unclear. Here, we leveraged a nonhuman primate model of acute …

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Enhanced Costimulation Blockade With αCD154, αCD2, and αCD28 to Promote Heart Allograft Tolerance in Nonhuman Primates

Ryan Chaban, Ikechukwu Ileka, Kohei Kinoshita, Gannon McGrath et autres

BACKGROUND: Long-term renal allograft acceptance has been achieved in macaques using a transient mixed hematopoetic chimerism protocol, but similar regimens have proven unsuccessful in heart allograft recipients unless a kidney transplant was performed simultaneously. Here, we test whether a modified protocol based …

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