FDA Symposium: “Assessment of CV Toxicities in … am Venture Partners (Palo Alto, CA) Co-Founder,...
Transcript of FDA Symposium: “Assessment of CV Toxicities in … am Venture Partners (Palo Alto, CA) Co-Founder,...
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FDA Symposium:“Assessment of CV Toxicities in
Immuno Oncology Trials
“Autoimmunity Associated With Therapies”
PJ Utz, MDProfessor of Medicine
Stanford University School of Medicine
December 1, 2017
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Utz Conflict of Interest Disclosure (2012-2017):
Consultant:Genentech (South SF, CA)Gilead Sciences (Foster City, CA)Gerson Lehrman Group (Boston, MA)U.S.F.D.A. Arthritis Drugs Advisory CommitteeResolve Therapeutics (Seattle, WA)
SAB:Genentech (South SF, CA)GSK (London, UK)UCB (Belgium)Baxter Healthcare (Germany)DNAX/Merck (Palo Alto, CA)DynaVax (Berkeley, CA)Genzyme (Cambridge, MA)Novartis (Cambridge, MA)Third Rock Ventures (Boston, MA)5 am Venture Partners (Palo Alto, CA)
Co-Founder, Consultant:BayHill Therapeutics (Palo Alto, CA)Cardinal Therapeutics (Palo Alto, CA)Tolerion, Inc (Portola Valley, CA)
Sponsored Research:AMP RA/Lupus – Leadership Center and STAMP Tech CenterAmgen, Genentech, Intel, GSK, Sanofi-Aventis, TakedaNovo Nordisk Fellowship Program
Private Stock Ownership: Gilead Sciences
Part Time Caddie: Dodge Kemmer
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Utz Conflict of Interest Disclosure (2012-2017):
Consultant:Genentech (South SF, CA)Gilead Sciences (Foster City, CA)Gerson Lehrman Group (Boston, MA)U.S.F.D.A. Arthritis Drugs Advisory CommitteeResolve Therapeutics (Seattle, WA)
SAB:Genentech (South SF, CA)GSK (London, UK)UCB (Belgium)Baxter Healthcare (Germany)DNAX/Merck (Palo Alto, CA)DynaVax (Berkeley, CA)Genzyme (Cambridge, MA)Novartis (Cambridge, MA)Third Rock Ventures (Boston, MA)5 am Venture Partners (Palo Alto, CA)
Co-Founder, Consultant:BayHill Therapeutics (Palo Alto, CA)Cardinal Therapeutics (Palo Alto, CA)Tolerion, Inc (Portola Valley, CA)
Sponsored Research:AMP RA/Lupus – Leadership Center and STAMP Tech CenterAmgen, Genentech, Intel, GSK, Sanofi-Aventis, TakedaNovo Nordisk Fellowship Program
Private Stock Ownership: Gilead Sciences
Part Time Caddie: Dodge Kemmer
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Overview of Talk
• Background on Tolerance and Autoimmunity
• Literature Review of Associated Autoimmune andRheumatic Diseases
• Diagnostic and Treatment Recommendations
• Preclinical vs Clinical Autoimmunity
• Recommendations
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A selective lack of an immune response to targeted antigen(s) while leaving the normal
immune response intact.
Tolerance
A breakage of tolerance in the immune system that results in the immune response attacking
the body's own cells and tissues.
Autoimmunity
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Where Tolerance and Autoimmunity Fit in with Immunology
Magnitude of Immune Response
Immunodeficiency
Cancer
Protective Immunity
Transplant Rejection
Autoimmunity
Allergy
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Central Tolerance vs Peripheral Tolerance
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Peripheral Tolerance: Immunotherapies = Trading Cancer for Autoimmune Diseases
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Literature Review (255 papers 12/1/17)
GI EndocrineColitis Primary adrenal failureHepatitis HypophysitisEsophagitis Thyroid diseaseGastritis T1D
Neuro RenalCNS Vasculitis Acute GNLimbic encephalitis Interstitial nephritis
HuContactin-associated protein-like 2 Heme
MS Pure red cell aplasiaMyasthenia Gravis (New, Flare) Hemolytic anemia
Derm MiscellaneousPsoriasis UveitisPsoriasiform dermatitis Autoimmune inner ear diseaseAlopecia areata Severe myocarditisBullous pemphigoid flare PneumonitisVitiligo Vasculitis (GCA, uterine, retinal)
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Diseases a Rheumatologist Might Encounter
• Polyarthritis/Arthralgia– RA– PMR– Psoriatic Arthritis
• Vasculitis – Uterine– Retinal– GCA
• Connective Tissue Diseases– Systemic Sclerosis (Scleroderma)– Myositis– Eosinophilic fasciitis– SLE – associated manifestations, eg GN, IN, HA– Sicca (mimicking Sjögren’s Disease)
• Sarcoidosis
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RA and PMR
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Inflammatory Arthritis and Sicca Syndrome
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Vasculitis
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Systemic Sclerosis (Scleroderma)
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Clinical Management
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De Novo Autoimmunity vs Evolution of Preclinical Autoimmunity?
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Arbuckle et al,NEJM, 2003349(16):1526-33
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Take Home Points • Clear clinical association of rheumatic diseases and tumor immunotherapies
• Incidence will increase due to combination therapy, no longer excluding autoimmunity
• Autoimmune diseases (eg T1D, TA, SLE) clearly evolve over time and have preclinical phase
• Clinical autoantibody testing may predict adverse events
• What the field needs: - Registry of patients and baseline clinical samples
- Serum- Plasma- PBMCs- RNA- DNA
- Baseline tissue- Matching samples after adverse event (including controls)- Technologies to identify autoantigens, markers and predictors
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