Learning Objectives: Intro on the premise of modern cancer - - PDF document

1 | [footer text here] James Lee, MD/MHS October 10th, 2019

UCSF Continuing Medical Education

2019 Asian Health Symposium San Francisco, CA

Future of Cancer Therapy: Intro to CAR T cells

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Disclosure

I have no relevant financial relationships with any companies related to the content of this course.

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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

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STAGE IV CANCER SURVIVAL

Traditional Therapies Immunotherapy

1 0 0 % 0 %

% of Treated Patients Alive Time

Patients ultimately succumb to their disease

Traditional Cancer Therapies

1 0 0 % 0 % Long Term Benefit Traditional Therapies

% of Treated Patients Alive Time

Immunotherapy Combinations of Immunotherapy What used to a hypothetical curve is now a reality

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Not helpful ! Won’t remember!!

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In the beginning…the sabre-toothed tiger

(image: Getty) https://www.mirror.co.uk

Need context:

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The innate immunity

• Macrophages
• Neutrophils
• Basophils
• Eosinophils
• Dendritic cell
• Natural Killer cell

The adaptive immunity

• T cells
• B cells

Response time Hours Days

Receptor recognizes set patterns, Co-evolved, only changes through evolution Receptor can recognize 1015 possible patterns, dynamic change depending on exposure through 1 lifetime

Defense against “non-self” invaders

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Annu Rev Med. 1999;50:369-86. Daud et al, CIR, 2017

Ok, but can they recognize cancer?

Self ? Or non-self??

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Tu Tumor antigen

Ok, but can they recognize cancer?

Na Native T cell receptor

T cell biology T cell Tumor cell

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T cell Biology- priority is self preservation

MHC I/II CD4/8 αβ ζ ζ CD3

Tumor/virus infected cell

T cell

tumor peptide Signal 1 = Activation and proliferation Signal 2 +

CD28 4-1BB OX40 CD80 4-1BBL OX40L

APC

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Chimeric Antigen Receptor T-cell Therapy

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T cell genetically modified with CAR to go after “self”

• Specificity of a

monoclonal antibody

• Not dependent on

MHC

• Activates T cells

with Signals 1 & 2

Maus et al, Frontiers, 2018

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• 2. T cell

transduction

• 1. T cell

isolation by leukapheresis

• 3. T cell expansion

Tumor specific CAR gene introduction

Chimeric Antigen Receptor

Na Native TCR CR CAR

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Courtesy of Michael Jensen, MD, www.washington.edu

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*Lymphodepletion chemo followed by 5x107-5x108 cells

CAR T cell clinical schema

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First ideal cancer target – CD19

CD19 as ideal target because:

Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

preB-ALL B cell lymphomas and leukemias myelomas Stem Cell pre B immature B mature B plasma cell pro B

CD19 CD22 CD20 BCMA

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r/r ALL

• CR 80-90%

r/r DLBCL

• CR 40-60%

FDA approved CAR T cell products Kymriah (tisagenlecleucel) Yescarta (axicabtagene cilelucel)

Response rate

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r/r ALL

• CR 80-90%
• 25-40%
• 35-45%

r/r DLBCL

• CR 40-60%
• 15-25%
• 15-25%

FDA approved CAR T cell products Kymriah (tisagenlecleucel) Yescarta (axicabtagene cilelucel)

Response rate

Cytokine Release Syndrome (sCRS) Neurotoxicity (sNT)

r/r MM

• similar

to DLBCL (prelim) *FDA

• rphan

Drug status

Anti-CD19 CAR Anti-BCMA CAR

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Cytokine Release Syndrome

Symptoms / Signs CRS Grade 1

(mild)

CRS Grade 2

(moderate)

CRS Grade 3

(severe)

CRS Grade 4

(life- threatening) Vital Signs Temperature ≥ 38.5 ºC / 101.3 ºF Yes Any Any Any Systolic blood pressure (SBP) ≤ 90 mmHg N/A Responds to intravenous (IV) fluids or single low- dose vasopressor Needs high- dosea or multiple vasopressors Life- threatening Need for oxygen to reach oxygen saturation (SaO2) > 90% N/A Fraction of inspired

• xygen (FiO2)

< 40% FiO2 ≥ 40% Needs ventilator support Organ Toxicity N/A Grade 2 Grade 3 or transaminitis Grade 4 Grade 4 (excluding transaminitis)

Adapted from Lee, Blood, 2014

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Cytokine Release Syndrome

CRS Key Risk Factors/Features:

• 1. High disease burden
• 2. Intensity of pre-conditioning chemo
• 3. Occult infection (viral, bacterial, fungal)
• 4. Younger age
• 5. Usually begins within 14 days post infusion
• 6. Elevated inflammatory lab value- CRP

, Ferritin

• 7. Due to cytokine production (IFNg->IL-6->others)

Treatment: 1.Tocilizumab (anti-IL6)

• 2. +/- Corticosteroids
• 3. R/o and treat underlying infection

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CAR T cell Neurotoxicity

Neurotoxicity Key Risk Factors/Features:

• 1. A.k.a. cytokine release encephalopathy

syndrome, immune cell associated neutrotoxicity syndrome (CRES, ICANS).

• 2. AMS, aphasia, seizures, cerebral edema.
• 3. Median onset 4-5 days after infusion,
• ften following CRS

Treatment/management:

• 1. Serial CARTOX-10 exam
• 2. High dose corticosteroids
• 3. +/- Tocilizumab
• 4. +/- Keppra seizure prophylaxis

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CARTOX-10 Assessment

Shpall et al, Nat Rev Clin Onc, 2018

Each task = 1 point.

• 1. Orientation: current year, month, city,

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)

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CAR T cell Kinetics

Day 0 Day 7 Day 14 Day 30 CRS ICANS CAR T cell expansion B cell aplasia/autoimmunity Peak circulating CAR T cell number

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CAR T cell Kinetics

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CD19 CAR T cell relapses

CD19 negative: cancer cells downregulate CD19 target. CD19 positive: possibly due to suppressive TME or novel mechanisms,

• ften result in loss of CAR T persistence.

20-50% rate

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Future of CAR T cell therapy- solid tumors?

No trials for solid tumors has shown similar success as CD19 CARS:

• 1. Pediatric neuroblastoma (GD2 CAR)
• 2. Adult sarcoma (HER2 CAR).
• 3. Prostate cancer (PSMA CAR)
• 4. Gliobastoma (IL13R, EGFR CAR)
• 5. Mesothelioma/Panc Ca (Meso CAR)

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Future of CAR T cell therapy- solid tumors?

Maus et al, Frontiers, 2018

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 Key challenge: The immune system’s priority is self preservation and maintain homeostasis, CAR T cells will trigger suppressive feedback.

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Thank you

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