Immunotherapy and CAR T:

from pills to cell and gene therapies

Carl June
March 3, 2020
 Fire with Fire Video
Emily Whitehead: Patient #1
 Conflict of Interest Statement

Declaration of financial interest due to intellectual property and patents in the

field of cell and gene therapy:
• Royalties and IPR: Novartis
• Scientific Advisory Board for Celldex, Cabaletta, Carisma, Kiadis, Viracta and
WIRB-Copernicus Group
• Scientific Founder and equity: Tmunity Therapeutics
Conflict of interest is managed in accordance with The University of
Pennsylvania policies and oversight
Chimeric

Antigen

Receptor

T Cells

CAR T Cells
Overview: the development of CAR T Cells

Lim WA, and June CH. The Principles of Engineering Immune Cells to Treat Cancer.
Cell. 2017;168(4):724-40.
 CAR T and TCR T

June and Sadelain, NEJM 2018

 CAR T Cells: the first living drug

• CAR T cells are

made for each
patient.
• The process takes
about 2 weeks “vein
to vein.”
• The cells can divide
and stay in the body
for years: preventing
cancer relapse!
Copyright of Novartis Pharmaceuticals Corporation. All rights reserved
 CAR T Cell Therapy: a process not a drug

• Autologous T cells

• Allogeneic “3rd party” T cells

• Cord blood

• Healthy donor

• iPSC

https://cen.acs.org/pharmaceuticals/oncology/Controlling-CAR-T-scientists-plan/96/i19
 Emily Whitehead: Patient #1

6 yo 14 yo
 CAR T Cells: First Cell and Gene Therapy

• Emily was treated on

my trial at U Penn in
2012.
• Novartis licensed the
CAR T made in my lab
and conducted an
international trial.
• The US FDA approved
the CAR T in August,
2017.
CT019 (tisagenlecleucel): Kymriah™ FDA approval August 30,2017
July 31, 2010
1st CART19 Infusion
Porter, 2011
Grupp, 2013
Maude, 2014
Garfall, 2015 Patient Donates
Cells Pediatric
Schuster, 2017
Oncology:
Maude, 2018
ALL Cytokine Release
Syndrome

Adult Oncology:
T cell transfusion ALL, CLL, DLBCL,
MCL, Myeloma

Genetic engineering
Expand T cells
Synthetic
Biology
CVPF
12
Genealogy of CAR T
Design Features of Tisagenlecleucel and Axicabtagene:
Differential Persistence
Cytokine Release Syndrome (CRS)

• High fever, flu-like

syndrome

• Emily almost died

from CRS: fever to
>40oC for 3 days –
unstable
hypotension and
comatose in ICU

• Only occurs in
responding patients

• Tocilizumab saved
her life Stephan Grupp, et al. NEJM 2013
The backstory that saved Emily’s Life: serendipity!

Sarah June Prof. Tada Kishimoto Emily Whitehead

JRA, 2001 2010 Pt #1 and Grade 4 CRS survivor!
Pharmacology and Pharmacodynamics of CAR T

CAR T cells are living drugs

▪ The cells that deliver effects may evolve in patients:

▪ Cells causing efficacy or toxicity may not be the same as
the product that was infused!
▪ Pharmacology of CAR T is very different from inert drugs
▪ Autologous cells are inherently safe
What Happens When Things Go
-Right
-Wrong
-Strange?
 Lessons From Outliers

• We studied patient #10 in detail:

why did
he have a delayed peak of CAR T cells in
blood?

• Why was he an outlier?

• It turned out that all of his CAR T cells were
the descendants of one super cell!

• This taught us that just one CAR T cell can

cure leukemia if it is “good enough”

CAR T cells in the blood of patients with leukemia

Fraietta et al Nature, 2018

Human Genome Editing: In Vitro and In Vivo

• There are an increasing number of “tools” to edit genomic DNA:

➢ Zinc finger nucleases
➢ TALENS
➢ Meganucleases
➢ CRISPR-Cas9
• Potential uses:
➢ Introduce disease resistance: HIV CCR5 deletion
➢ Enhance T cell function: PDCD1 (PD-1) deletion,
creating “checkpoint resistant” T cells
➢ Prevent GVHD: TCR deletion, creating “Universal CAR T cells”
• Germline gene editing banned:
National Academy of Sciences and Medicine, 2015
 Combining Gene Editing
with TCR T and CAR T
• In solid tumors, the tumor
microenvironment is toxic to
T cells
• Genome editing has the
potential to render T cells
resistant to the toxic effects
of the tumor
• CRISPR technology has a
high potential to improve T
cell function
IND 17297 and Clinicaltrials.gov NCT03399448
Sponsor: Tmunity and Parker Institute for Cancer Immunotherapy
 CAR T Success Leads to Massive Investment in Cell Therapy

Source:
Aditi Krishnamurthy, Michelle Teicher, Benjamin Leibowitz, Jim Tornatore, Filippo Petti & John Bishai (Wells Fargo)
 CAR T Cells Are Now World Wide

• CAR T Cell trials started in the US in

2006

• There are now more than 600 CAR T

trials

• Most CAR T cell trials are now in China!

Clinical trials.gov search term “chimeric antigen receptor”

633 trials listed as of February, 2020
 Historic Decline in Cancer Death Rates in US

ACS, January 9, 2020

Curative Therapies for Many Previously Untreatable Diseases are on
the Horizon
 Social Challenges: Making CAR T Less Expensive
• The number of new myeloma patients
in the US in 2017: ~30,000
• At current standard of care: total
lifetime costs to treat all patients
diagnosed in 2017: $22.4B
• The average cost of cancer drugs
approved in the US in 2017: 150,000
Rajkumar, ASCO 2018
Ways to make CAR T cheaper:
• Better manufacturing: Robotics
and automation
• Use “3rd Party” CAR T made from
cord blood or stem cells. Current
CAR T are made from each
patient
• Manufacture CAR T in India!
Cost Curve of Disruptive Therapies: Implications for CMS
In the European Union, a disease is defined as rare
when it affects fewer than 1 in 2,000 people. There
may be as many as 7,000 rare diseases. The total
number of Americans living with a rare disease is
estimated at between 25-30 million.

Orphan diseases are not rare!

 Sickle Cell Anemia

An inherited and ultimately fatal disease of

the bone marrow producing defective red
blood cells

About 100,000 people in the US

About 1 in 13 African-Americans have the

trait (1 of 2 chromosomes)

The disease is disabling leading to pain,

increased incidence of narcotic addition,
and early death
Cost Curve of Disruptive Therapies: Implications for CMS
Moving new therapies outside of specialized centers is challenging
Disruptive vs. Sustaining Technologies

Disruptive technologies cause problems

because they do not initially satisfy the
demands of even the high end of the
market. Because of that, large companies
choose to overlook disruptive technologies
until they become more attractive profit-
wise. Disruptive technologies, however,
eventually surpass sustaining technologies in
satisfying market demand with lower costs.
Currently: The most expensive drugs are for non-curative therapies:
autoimmune
(arthritis and diabetes)

This equation will change if cancer patients live longer!

Will CAR T Become a Curative Therapy for Autoimmune Disorders?
 Synthetic Biology: A Call to Action
CAR T Cells and Cell and Gene Therapies
Clinicians
Cell Biologists
Immunologists
Informatics, Big Data Biomedical and
Computer Scientists Chemical Engineers

Cooperative,
Electrical Engineers Not competitive
Manufacturing and
Mechanical Engineers Research Industrial Engineers
Manufacturing of High Quality
Healthcare delivery, Cells at Low Cost
Regulatory
Health Policy, IT Organization

Insurance, Standards
Patient Organization
Reimbursement
Advocates
 Outscaling CAR Manufacturing
Robotic and Automated Cell Culture: costs will fall by 10x
CAR: Sedan CAR: CD19

Bead
addition

Bead
removal

T cell
infusion
 Robots and Automation:
Lessons from Detroit

Performance characteristics of assembly systems following different

assembly principles (Heilala, J. Modular Reconfigurable Flexible
Final Assembly Systems, Assembly Automation, 21/1: 20–28, 2001)
 Should Cell and Gene Therapies be
a Government-Industry-Philanthropic Partnership?

Therapies of the State:

• Tremendous benefit to public health → “Cure” for cancer
and other chronic and incurable diseases
• Potential for significant reduction in long-term healthcare
cost
• Benefit to economy and job creation in biotechnology
• Philanthropic “moonshots” to de-risk a nascent industry
• Enable innovation globally
• Education of lay public and physicians of impending
disruption
• Bring stakeholders together → Ensure Sustainability
Beth Schachter, Nature Biotechnology 32, 736-741 (2014)
Summary: CAR T and Gene Therapies

▪ CAR T cells have potent and durable efficacy in ALL, CLL, DLBCL and myeloma
▪ CAR T cells have some activity in solid tumors
▪ Multiplex editing of TCR T cells using CRISPR/Cas9 is safe and feasible in 3
patients
▪ Cell and Gene Therapies have potential to be “one and done” curative therapies.
This disrupts the medical industry
▪ On the near horizon: many non-curable diseases will become curable. Issues of
economic disparities and access. Sickle cell anemia and other
hemoglobinopathies on the 5-year horizon.