8:00 am Coffee & Registration

8:55 am Chair’s Opening Remarks

FURTHERING THE UNDERSTANDING OF TREG CELL BIOLOGY TO ENHANCE TREG THERAPIES

9:00 am Tissue Tregs: Phenotype & Function

Synopsis

  • Non-lymphoid tissues host Treg populations with distinct transcriptomes and TCR repertoires
  • Besides controlling local immune responses, “tissue-Tregs” regulate local homeostatic processes such as metabolism and tissue repair
  • Specifically targeting tissue-Tregs stands to improve outcomes by, first, being more effective and, second, avoiding generalized immunosuppression

9:30 am Empowering Treg Cells in Disease

Synopsis

  • Restitution of regulatory T cells function in potency using exogenous interleukin-2 appears promising in the treatment of autoimmune diseases and transplant rejection, appropriate consideration should be given to biochemical events which compromise the response of regulatory T cells to interleukin-2
  • Identification of such processes should enable the use of additional approaches to maximize current approaches aimed at the activation of regulatory T cells

10:00 am IL-2 & Regulatory T Cells: From Basic Mechanisms to a Therapy for Autoimmune Diseases

Synopsis

  • Contribution of IL-2R signaling for Treg development and homeostasis
  • Mechanisms for selective responses of human Tregs to low-dose IL-2
  • Enhancing low-dose IL-2 therapy by using a long-lasting novel IL-2-based fusion protein

10:30 am Morning Refreshments

EXPLORING TECHNIQUES TO ENGINEER ANTIGEN-SPECIFIC TREG CELLS

11:00 am Making Antigen-Specific Tregs to Treat Autoimmunity & Obesity

Synopsis

  • Cellular and molecular mechanisms of Treg generation
  • In vivo generation of autoantigen-specific Tregs for treatment of autoimmunity
  • Link of apoptosis to the generation of Tregs in autoimmunity
  • Establishment of in vitro essay to identify antigen-specific Tregs
  • Alternative pathway to generate Tregs to treat obesity

11:30 am Bench to Bedside Regulatory T Cell Therapy in Autoimmune Liver Diseases

  • Ye Oo Medical Research Council Clinician Scientist, University of Birmingham

Synopsis

  • Intrahepatic T effector and Regulatory T cells in human liver
  • Inflamed liver microenvironment
  • Homing mechanism of Treg to human liver
  • Polyclonal and antigen specific Treg therapies in autoimmune liver diseases

12:00 pm Lunch & Networking

DISCUSSING STRATEGIES TO MANIPULATE THE IL-2 PATHWAY

1:00 pm IL-2 & Treg Cell Therapies: In or Out?

Synopsis

  • IL-2 is the key cytokine for Treg survival and function
  • Treg cell products are cultured in ultra-high dose of IL-2, becoming IL-2 addicted, which impacts their survival and function in patients
  • We generated IL-2 sufficient super-Tregs expressing either wild type or mutated
  • IL-2 under various promoters
  • These cells survive in IL-2 deprived environments and have improved in vitro and in vivo suppressive function
  • IL-2 self-sufficiency should be implemented to improve the potency of any Treg cell therapy, including CAR Tregs

1:30 pm Two Receptor Stimulation of CD4+FoxP3+ T cells in vivo: TNFRSF25 & CD25 Regulation of Treg Compartments

Synopsis

  • In vivo regulation of Tregs in the lymphoid and GI tract
  • Combinatorial targeting of TNFRSF25 and CD25 in vivo with agonistic reagents modifies Tregs and innate lymphoid cells
  • Manipulating the recipient and donor Treg compartments for regulation of GVHD

2:00 pm A Novel Defect in IL-2R Signaling in Tregs of Patients with Inflammatory Autoimmune & Allergic Diseases

Synopsis

  • This defect, which affects the inhibition of desensitization of the IL-2R pathway required for prolonged pSTAT5 activation and transcription of the genes required for Treg function is druggable
  • Clinical benefit was seen in treating mouse models of SLE, T1D, MS and asthma using a novel protein drug conjugate of an IL-2 fusion protein to which several copies of a small molecule drug that restores endogenous Treg function were attached.
  • This represents a paradigm shift from immunosuppression to restoration of endogenous immune regulation to treat autoimmune and inflammatory diseases

2:30 pm PTX-35: A Novel TNFRSF25-Agonist for Regulatory T-cell Expansion

Synopsis

  • TNFRSF25-engagment by PTX-35 can expand regulatory T-cells in vivo and reduce disease severity in several animal models of GVHD & inflammatory disease
  • Favorable safety profile in monkeys; target engagement confirms Treg expansion
  • Plans for new indications & modalities – opportunities for partnerships
  • Global program status update

3:00 pm Afternoon Refreshments

HEARING ALTERNATIVE APPROACHES TO DIRECT TREG CELLS

3:30 pm Pharmacologic Approaches to Enhance Foxp3+ Treg Production & Function in Autoimmunity & Transplantation

Synopsis

  • Our genetic and pharmacologic studies show that Foxp3 is subject to post-translational modifications such as cetylation/deacetylation, ubiquitination/ deubiquitination and phosphorylation/dephosphorylation.
  • Small molecules that increase Foxp3 stability and/or function can be used to promote Treg function in the context of autoimmunity or transplantation
  • Small molecules offer considerable advantages over Treg cell therapy, including cost, convenience, ability to treat repeatedly and/or indefinitely and most importantly, proven efficacy

4:00 pm From Mice to Man: Successful Translation of a Treg-dependent Tolerogenic Therapy for Treatment of Celiac Disease Using Gliadin- Encapsulating PLG Nanoparticles

Synopsis

  • Tolerance induction using antigen-encapsulating PLG nanoparticles (Ag-PLG) recapitulates how self-tolerance is induced and maintained in the hematopoietic system
  • Ag-PLG uptake by splenic marginal zone and liver APCs confers a tolerogenic phenotype
  • Ag-PLG induces the induction of CD4+Foxp3+, CD4+ Tr1, and CD8+CD122+regulatory T cells

4:30 pm Activation of the Aryl Hydrocarbon Receptor by Antigen-Specific Tolerogenic Nanoparticles for the Treatment of Autoimmune Diseases

Synopsis

  • Targeted activation of the Aryl Hydrocarbon Receptor induces FoxP3+ and IL10+Regulatory T cells
  • Antigen-specific nano-liposomes targeting dendritic cells induces tolerance and suppresses disease in multiple pre-clinical mouse models
  • AhR activation by liposomes suppresses pro-inflammatory signaling pathways in tissue-resident innate immune cells

5:00 pm Chair’s Closing Remarks & Close of Summit