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Harnessing Killer T Cells
Julie Nielsen, PhD
BC Cancer Agency
May 2, 2015
Overview
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The immune response to cancer
What T cells are & how they work
Immune-based therapies for cancer
Using T cells to target patient-specific
mutations
• Targeting MYD88 with T cells
The immune system actively
responds to cancer
Tumor cells
Killer T cells
Helper T cells
OvCa image
courtesy of Katy Milne
Tumor-infiltrating T cells are
associated with patient survival
% overall survival
Killer T cells present
Killer T cells absent
100
VGH/BCCA cohort
HGSC OvCa
optimally de-bulked
n = 200
p = 0.0008
50
0
0
5
10
Years 
15
Clarke, B. et al. 2009
Milne, K. et al. 2009
Basics of the immune system
• Includes many kinds of cells that help
eliminate foreign invaders (e.g. viruses) and
abnormal cells (e.g. cancer)
• Cells circulate throughout the body looking for
trouble
• Each cell type uses a unique strategy
– Some cells produce antibodies (IgM)
– Others engulf foreign invaders
– Killer T cells directly destroy abnormal cells
How do killer T cells work?
• Components of cells or
viruses are cut into fragments
inside the cell
• These fragments are then
taken to the cell surface
where they are displayed for T
cells to survey
• T cells recognize these
fragments using their “T cell
receptor” (lock & key)
• If T cells recognize something
abnormal, they will kill the cell
• ~25 million different T cell receptors
How does cancer evade the
immune system?
• Cancer cells are similar to normal cells in
many ways – this makes it difficult for the
immune system to recognize cancer
• The immune system is tightly regulated to
prevent autoimmunity – cancer cells can take
advantage of this & “put the brakes” on T cells
Strategies to enhance the immune
response to cancer
• Rituximab
• Drugs that “release the brakes” on T cells
• T cell therapy
Isolate T cells
Identify T cells that
recognize cancer
Re-infuse T
cells into
patient
Grow large
numbers
CD19 CAR T cells
• CD19 is a protein found on WM & many other
lymphomas & leukemias
• T cells can be engineered to recognize CD19 via a
“chimeric antigen receptor” (CAR)
• CD19 CAR T cells have been used to treat ~100
patients with leukemia or lymphoma
• Clinical results demonstrated in many types of cancer
(most effective in acute lymphoblastic leukemia)
• Numerous clinical trials underway
• One disadvantage: CD19 is also found on normal B
cells, so they are also eliminated by CAR T cells
Tumor-specific targets
• Cancer is caused by accumulation of
mutations (mistakes) in DNA
• Bad news: these mutations give cells
abnormal growth properties
• Good news: T cells can detect these
mutations and destroy cells that have them
Identifying T cells that recognize
patient-specific mutations
• Recent advances in DNA sequencing make it possible
to sequence tumors from many patients
• Some mutations are very common in specific types of
cancer, but most mutations are unique to each patient
• Our research involves identifying mutations that are
recognized by T cells in order to develop T cell-based
therapies
Patients & controls
• Over 100 patients and 75 cancer-free controls
enrolled in the study
• Sample requirements:
– Tumor samples for identifying mutations
– Annual blood samples (200ml/draw) for screening
T cells
• Patients with WM or follicular lymphoma
Study overview
Obtain
tumor samples
Identify tumor-specific
sequences
Assess
T cell responses
Develop personalized
T cell-based therapies
• Every mutation
has the potential
to create a new
T cell target
Not all mutations are recognized
• Mutated protein must be
processed to generate
fragment of interest
• Fragment must bind to the
patient’s MHC molecules on
the cell surface
• T cells with the appropriate
T cell receptor must exist
How do we determine which
mutations are recognized?
Obtain tumor &
matched blood
Mutant
peptides
Identify
mutations
Peptides
10 days
14 days
Test T cell
responses
14 days
T cells
T cells in follicular lymphoma
25
Somatic mutations in a
cohort of FL patients
20
15
10
5
0
C
R
EB
B
EZ P
M H2
E
FO F 2 B
C XO
A 1
R
D
1
PI 1
EP M1
30
IR 0
C F4
C
N
C D3
D
79
B
Number of patients
• 53 follicular lymphoma patients
• Looked for mutations in 10 genes known to have
JS Nielsen et al., Figure 1
mutations in lymphomas
• Identified mutations in 80% of patients
Mutant gene
T cells in follicular lymphoma
4000
3000
IROL017 REP225
*
2000
1000
0
M
oc
kt
Irr ran
e s
M WT lev fec
ut M an te
an E t d
M DM t M F2 RN
ut S E B A
an O F2 R
t M (N B NA
EF o a R N
2B nti A
g
pe en
pt )
id
e
Spots per 106 cells
• Assessed T cell responses to proteins derived from
mutations
• Identified T cells that recognized patient-specific
mutations in 25% of patients
Targeting mutations in WM
• A mutation in MYD88 has been found in most
patients with WM (Dr. Treon 2012 NEJM)
• We have identified T cells that recognize fragments
of mutated MYD88
Individual peptides
T cells specifically recognize
mutated MYD88
Mutant
100pM
1nM
10nM
100nM
1uM
10uM
WT
Peptide concentration
T cells recognize mutated
MYD88 in B cells
Future directions
• Can MYD88-specific T cells recognize WM?
• If so, develop & test T cell-based therapy
Isolate patient’s
T cells
MYD88L265Pspecific TCR
Express TCR in patient’s
T cells & select MYD88specific cells
Re-infuse T cells
into patient
Expand T
cells
Summary
• The immune system can recognize & eliminate
tumors
• The presence of killer T cells in tumors is associated
with increased patient survival
• Immune-based therapies are being tested in clinical
trials (CAR T cells, strategies that remove the brakes
from T cells)
• T cells can recognize proteins derived from patientspecific mutations
• T cells can recognize mutant MYD88
• Future work will show whether T cells targeting
MYD88 will be effective therapeutically
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Acknowledgements
Brad Nelson, PhD
Nicol Macpherson, MD PhD
Colin Sedgwick
Andrew Chang
Patients & controls
Collaborators
• Ryan Morin, PhD
• Brian Berry, MD
• Steve Treon, MD PhD
• Joe Connors, MD
• Randy Gascoyne, MD
• Zabrina Brumme, PhD
• Marco Marra, PhD
Funding
• BC Cancer Foundation
• International Waldenstrom’s Macroglobulinemia Foundation
• Waldenstrom’s Macroglobulinemia Foundation of Canada
• Canadian Cancer Society Research Institute
• Lymphoma Foundation Canada