Disclosure Future of Cancer Therapy: I have no relevant financial relationships with any companies related to the content of Intro to CAR T cells this course. UCSF Continuing Medical Education 2019 Asian Health Symposium San Francisco, CA James Lee, MD/MHS October 10 th , 2019 1 2 Learning Objectives: § Intro on the premise of modern cancer immunotherapy § Basic scientific background of CAR T cell therapy § Clinical indications for CAR T cell therapy § CAR T cell therapy toxicity and management § Recognize why immunology is so cool 3 4 1 | [footer text here]
STAGE IV CANCER SURVIVAL Not helpful ! Won’t remember!! Traditional Therapies Immunotherapy 1 0 0 % 1 0 0 % Long Term Benefit % of Treated Patients Alive % of Treated Patients Alive Combinations of Traditional Immunotherapy Cancer Therapies Immunotherapy Traditional Therapies 0 % 0 % Time Time Patients ultimately What used to a hypothetical succumb to their disease curve is now a reality 5 6 Defense against “non-self” invaders Need context: In the beginning…the sabre-toothed tiger The innate immunity The adaptive immunity -Macrophages -T cells -Neutrophils -B cells -Basophils Receptor can recognize 10 15 -Eosinophils possible patterns, dynamic -Dendritic cell change depending on exposure through 1 lifetime -Natural Killer cell Receptor recognizes set patterns, Co-evolved, only changes through evolution Hours Days Response time (image: Getty) https://www.mirror.co.uk 7 8 2 | [footer text here]
Ok, but can they recognize cancer? Ok, but can they recognize cancer? Self ? Or non-self?? Na Native T cell receptor T cell biology T cell Tumor cell Tu Tumor antigen Annu Rev Med. 1999;50:369-86. Daud et al, CIR, 2017 9 10 T cell Biology- priority is self preservation C himeric Tumor/virus infected cell MHC I/II APC A ntigen CD80 4-1BBL OX40L tumor peptide R eceptor CD28 4-1BB T-cell Therapy OX40 αβ CD4/8 ζ ζ CD3 T cell Signal 2 + Signal 1 = Activation and proliferation 11 12 3 | [footer text here]
T cell genetically Chimeric Antigen Receptor modified with CAR to go after “self” Tumor specific CAR gene introduction 1. T cell 3. T cell expansion • Specificity of a isolation by monoclonal leukapheresis antibody Maus et al, Frontiers, 2018 • Not dependent on MHC CAR • Activates T cells with Signals 1 & 2 Na Native TCR CR 2. T cell transduction 13 14 CAR T cell clinical schema www.washington.edu Courtesy of Michael Jensen, MD, *Lymphodepletion chemo followed by 5x10 7 -5x10 8 cells 15 16 4 | [footer text here]
First ideal cancer target – CD19 FDA approved CAR T cell products Kymriah (tisagenlecleucel) CD19 as ideal target because: Yescarta (axicabtagene cilelucel) B cell lymphomas and myelomas preB-ALL leukemias Y Y r/r ALL r/r DLBCL Y Y Y Y Y Y Y Y Y Y Y Y -CR 80-90% -CR 40-60% Response rate Y Y Y Y Stem Cell pro B pre B immature B mature B plasma cell CD19 BCMA CD22 CD20 17 18 Cytokine Release Syndrome FDA approved CAR T cell products Kymriah (tisagenlecleucel) Symptoms / CRS CRS CRS CRS Yescarta (axicabtagene cilelucel) Grade 1 Grade 2 Grade 3 Grade 4 Signs (mild) (moderate) (severe) (life- threatening) Anti-CD19 CAR Anti-BCMA CAR Vital Temperature Yes Any Any Any Signs ≥ 38.5 ºC / 101.3 ºF Systolic blood N/A Responds to Needs high- Life- r/r ALL r/r DLBCL r/r MM pressure (SBP) intravenous dose a or threatening (IV) fluids or multiple ≤ 90 mmHg single low- vasopressors dose Response rate -CR 80-90% -CR 40-60% -similar vasopressor to DLBCL Need for oxygen to N/A Fraction of FiO 2 ≥ 40% Needs reach oxygen inspired ventilator (prelim) Cytokine Release saturation (SaO 2 ) > oxygen (FiO 2 ) support -25-40% -15-25% 90% < 40% Syndrome (sCRS) *FDA N/A Grade 2 Grade 3 or Grade 4 Organ orphan transaminitis (excluding Toxicity Neurotoxicity -35-45% -15-25% Grade 4 transaminitis) Drug status (sNT) Adapted from Lee, Blood, 2014 19 20 5 | [footer text here]
Cytokine Release Syndrome CAR T cell Neurotoxicity CRS Key Risk Factors/Features: Neurotoxicity Key Risk Factors/Features: 1. High disease burden 1. A.k.a. cytokine release encephalopathy 2. Intensity of pre-conditioning chemo syndrome, immune cell associated 3. Occult infection (viral, bacterial, fungal) neutrotoxicity syndrome (CRES, ICANS). 4. Younger age 2. AMS, aphasia, seizures, cerebral edema. 5. Usually begins within 14 days post infusion 3. Median onset 4-5 days after infusion, 6. Elevated inflammatory lab value- CRP , Ferritin often following CRS 7. Due to cytokine production (IFNg->IL-6->others) Treatment: Treatment/management: 1.Tocilizumab (anti-IL6) 1. Serial CARTOX-10 exam 2. +/- Corticosteroids 2. High dose corticosteroids 3. R/o and treat underlying infection 3. +/- Tocilizumab 4. +/- Keppra seizure prophylaxis 21 22 CARTOX-10 Assessment CAR T cell Kinetics Peak circulating CAR Each task = 1 point. T cell number CAR T cell expansion 1. Orientation: current year, month, city, Shpall et al, Nat Rev Clin Onc, 2018 hospital, president (5 points) 2. Naming: 3 objects (3 points) 3. Writing: ask patient to write a standard sentence (1 point) 4. Counting/Attention: count backwards from 10 to 1 (1 point) Day 30 Day 0 Day 7 Day 14 CRS B cell aplasia/autoimmunity ICANS 23 24 6 | [footer text here]
CAR T cell Kinetics CD19 CAR T cell relapses 20-50% rate CD19 negative: cancer cells downregulate CD19 target. CD19 positive: possibly due to suppressive TME or novel mechanisms, often result in loss of CAR T persistence. 25 26 Future of CAR T cell therapy- solid tumors? Future of CAR T cell therapy- solid tumors? Key challenge: The immune No trials for solid tumors has shown system’s similar success as CD19 CARS: priority is self preservation and 1. Pediatric neuroblastoma (GD2 CAR) Maus et al, Frontiers, 2018 maintain 2. Adult sarcoma (HER2 CAR). homeostasis, CAR T cells will 3. Prostate cancer (PSMA CAR) trigger 4. Gliobastoma (IL13R, EGFR CAR) suppressive feedback. 5. Mesothelioma/Panc Ca (Meso CAR) Notable works in progress: 1. Improving CAR costim signal to amplify function, persistence 2. Make CAR T cells deliver cytokines to modify TME, cheaper? 3. Remote controlled CAR that can shut down 4. CARs that can recognize more than 1 antigen (synNotch, Tandem CAR) 5. CRISPR for function and make safer / off-the-shelf universal donor CARs 27 28 7 | [footer text here]
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