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S10‐086 (XA): In vivo and in vitro expansion of T regulatory cells
Inventors: Elizabeth D. Mellins, and Khoa D Nguyen
Team 403/22/2016
Our Team
Dr. Eric Schuur, PhD in Molecular Biology, President/CEO at HepatxCorporation
Dr. Meredith Warshaw, PhD in Physiology/Biophysics, Consultant at Conscensus and Transforia, Inc.
Dr. Sanjay Malhotra, Faculty in Radiation Oncology and Stanford Cancer Institute
Lusi Chien, MBA Stanford Business School, VP of Marketing & Strategy at TenexHealth
Angelica Parente, PhD candidate in Biophysics, VP of Events at Stanford Biotech Group
Mentors
InflammationThe process of inflammation initiates fromtissue injury or from foreign presence.
• Inflammation is a normal response toinfection or injury and is considered oneof the body’s defensive mechanisms.
• The classical signs of acute inflammationare pain, heat, redness, swelling, and lossof function.
Pathways of Inflammation
Immunology Primer
Issues arise when…
• Immune system reacts to
self auto‐immunity and
auto‐inflammation.
• Immune system does it’s
job when we don’t want it
to, ie. Transplant rejection.
Role of regulatory T cells in the promotion of transplant tolerance
International Liver Transplantation Society (2012), 18(7), 761‐70.
S10‐086 (XA): Serum amyloid A (SAA)
A novel anti‐inflammatory role of SAA in the induction of a micro‐environment that attracts and supports regulatory T cells (Treg)expansion at sites of infection or tissue injury, likely to curb (auto)‐inflammatory responses.
Current Development Stage
• SAA, produced in inflamed tissues, leads to the proliferation of Treg cells &
suppression of Teffector (Teff) cells in…
• Ex vivo ‐ Plasma from normal human controls and Systemic Juvenile
Idiopathic Arthritis (SJIA) patients, an auto‐inflammatory disease
• In vivo – Treg proliferation at injection site after peritoneal injection
(abdominal cavity) in male mice
Systemic response to inflammation
SAA high = TeffSAA low = Treg
Treg Transplantation
Treg Applications: Cell Transplantation
Cells from a foreign source can cause an immune response
Co‐administration of stem cells with Treg cells is ongoing in clinical trials
Applications to chimeric antigen receptor T‐cell (CAR‐T) therapies
Treg injections to inhibit cytokine release syndrome caused by CAR‐T therapies for immuno‐oncology
Prevent GVHD for allogeneic CAR‐T
Treg Applications: Organ Transplant Rejection
Over 28,000 people get transplants in the U.S. every year.
After an organ transplant, people need to take immunosuppressant (anti‐rejection) drugs. These drugs help prevent your immune system from attacking ("rejecting") the new organ. Typically, they must be taken for the lifetime of your transplanted organ which can cause severe side effects.
Treg therapies for transplant rejection being developed by Meyer group at Stanford
Treg Applications: Auto‐Immune & Auto‐Inflammatory Disease
A disease in which the body's immune system attacks healthy cells. E.g. Celiac disease, lupus, rheumatoid arthritis, type I diabetes (T1D), multiple sclerosis, allergies, etc.
50 million people = 20% of the population suffer from some type of auto‐immune disease in the US
Similar but different are auto‐inflammatory diseases E.g. Inflammatory bowel syndrome, crohn’s disease
Autologous ex vivo T‐cell engineering proliferation and re‐administration being applied to T1D, Crohn’s/IBD, & more
Treg Applications: Type I Diabetes >200,000 cases in the U.S. every year.
Type I diabetes is an auto‐immune disease
Treg cells are defective in disease settings, so efforts to repair or replace them may reverse auto‐immunity
Jeff Bluestone group at USCF working on this, a potential collaboration
Current modality for Therapeutic TregProduction
Current expansion modalities are inadequate because they are too toxic in vivo and produce heterogeneous Treg populations Rapamycin IL‐2 CD‐3 and CD‐28 antibody coated beads
Umbilical cord blood is a potential source without need for expansion Fixed amount, limited source that can’t be used for additional infusions if needed
Immune responses of cord blood derived cells differ from peripheral blood
Outstanding need: “Efficacy is dependent in part on infusion of a high number of these cells, especially polyclonal ones, but obtaining high numbers of polycloncal Treg from a single donor remains a problem” – Hurdles in TregTherapy Review, Science Translational Medicine 2015
Potentially Competing Technology
Tumor Necrosis Factor Receptor 2 Agonist –Denise Faustman Lab, Mass General BCG – an approved TB vaccine & TNF inducer
T1D ‐ Showed increase in/restoration of pancreatic insulin secretion after BCG vaccination and Treg induction in small PI trial
PII study underway TNFR2 antibody agonist discovered through studying BCG mechanism only used ex vivo Specific ‐ 14 cell surface markers characterized
Navacim ‐ Parvus Therapeutics• Nanoparticle coated in major
histocompatibility complex 2 (MHCII)• Induces FoxP3‐ Treg cells vs. FoxP3+ with SAA and TNFR2 agonist
• Already working in mouse models of multiple sclerosis, rheumatoid arthritis, & T1D
• Currently going after T1D, MS, and liver autoimmune disease (pre‐IND for T1D and POC stage for MS and liver autoimmune disease)
Current Industry Treg Therapy Trials
Drug Development Pipeline
Targets Therapeutics
12‐16 years
Treg Regulatory Hurdles• No Treg therapies are currently on the market• Regulatory protocols are still in the process of being designed, assays not yet standardized
• Trials are further along in the EU than the US• cGMP manufacturing of Treg cells and required reagents can be difficult• Characterization in clinical trials
• Possible Treg cells convert to Teff cells after injection• Possible Tregmay not be anergic/viable after injection• Risk of concominant use of immunosuppressants interfering with Treg• Dosing – possible therapeutic levels may suppress too well and prevent immune response for cancer or infection
• Treg survival and distribution post‐injection
SWOT Analysis
Strengths Weaknesses
ThreatsOpportunities
o Treg specifico Recombinant form
availableo Receptors it binds
to knowno Already tested in
mice/on human cells
o Dosing unknowno At high concentrations
becomes non‐specifico May have use in vivo
but dosing and potentially delivery are unanswered questions
o Production of Treg cell therapies
o Potential uses in vivo if dosing is figured out
o May work synergistically with “competing” tech
o Terminally differentiated?
o cGMP manufacturing may be difficult
o Regulatory protocols not yet established
o Competitors may be further along
Licensing Opportunities Explored
We explored several partnership opportunities but ultimately feel that the technology is too early stage for them
Companies we explored include:‐ Fate Therapeutics: expressed interest in 2014 but no longer interested in TReg Therapies
‐ TxCell: potential, French public company ‐ Caladrius: struggling financially, but has a subsidiary for immunotherapy manufacturing (PCT) that has contracted with TxCell
‐ Juno: not going after Treg‐ Kite Pharma: not going after Treg
Next Developmental Stages• Collaborations are necessary to answer open questions and evaluate clinical applications
• Collaboration initiated with Everett Meyer’s group to see if SAA can proliferate their
engineered Treg for transplant rejection
• Potential collaboration with Negrin lab to study SAA and in vivo/ex vivo proliferation of
Treg in GVHD mouse model
• Dr. Mellins hired a post‐doc familiar with these experiments to complete next steps
• Potentially looking for a company to fund pilot studies to..
• further characterize SAA‐induced Treg phenotype
• compare SAA with competing technologies in a side‐by‐side expansion assay
Backup Slides
Current Academic Treg Therapy Trials
REGULATORY ANALYSIS (Hurdles and Timeline)
Currently the scientific development of Treg based immunotherapy is at its infancy
Steps for approval by the regulatory body (Food and Drug Administration FDA)
(1) Investigational New Drug (IND) filing requires data on the product based the following studies – (~ 2yr)(a) Determine whether a mechanism of action defined in experimental systems can also be observed in humans
(e.g., a binding property or inhibition of an enzyme) (b) Provide important information on pharmacokinetics (PK) (c) Identify the most promising lead product (candidate) designed to interact with a particular therapeutic target
in humans, based on PK or pharmacodynamics (PD) properties (d) Explore a product’s bio‐distribution characteristics (e.g. using various imaging technologies) The primary purpose of the IND submission is to ensure that subjects will not face undue risk of harm.
Investigator/Applicant must submitted:
(A) Information on a clinical development plan
‐ Clinical studies of pharmacokinetics or imaging
‐ Clinical trials to study pharmacologically relevant doses
‐ Clinical studies of MOAs related to efficacy
(B) Chemistry, manufacturing, and controls information
(C) Pharmacology and toxicology information
(D) Previous human experience with the investigational candidate or related compounds, if there is any available.
REGULATORY ANALYSIS (Hurdles and Timeline)
(2) New Drug Application (NDA). Once phase III is complete, the manufacturer files an New Drug Application (NDA). Review of the NDA typically lasts one to two years, bringing total drug development and approval (i.e. the IND and NDA stages) to approximately nine years. During the NDA stage, the FDA consults advisory committees made of experts to obtain a broader range of advice on drug safety, effectiveness, and labeling. Once approved, the drug may be marketed with FDA regulated labeling. The FDA also gathers safety information as the drug is used and adverse events are reported, and it will occasionally request changesin a labeling or will submit press releases as new contraindications arise.
Overall, the License Application must contain the following: ‐ GLP Compliance‐ Pre‐clinical studies‐ Human clinical studies‐Manufacturing details‐ Labeling‐ Additional information
FDA’s Review Process (to decide if product is approved or not approvable)‐ Bioequivalence Review‐ Plant Inspection‐ Chemistry/Micro/Product Review‐ Labeling Review
REGULATORY ANALYSIS (Hurdles and Timeline)