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1
CANCER AND IMMUNITY - THE NEXT FRONTIER IN CANCER TREATMENT
Zheng Cui, MD/PhD
Section of Tumor BiologyDepartment of PathologyWake Forest University
School of MedicineWinston-Salem, NC, USATelephone: 336-716-6185
Email: [email protected]
2
Acknowledgement
This presentation is made possible by:
Gailyn Waldron and Threshold, Inc.
Barbara Shook and the Barbara Ingalls Shook Foundation
3
Current cancer therapies:
SurgeriesRemove cancer
at early stage
ChemoKill growing cells
systemically
RadiationKill live cells
locally
ImmunotherapiesRepair a weak/bad
immune system
Targeted therapies:Herceptin, Gleevec
4
Cancer Stats:
Worldwide
~6,000,000,000
~6,000,000
~100/100K
Population:
Yearly cancer death:
Cancer mortality rate:(age-adjusted)
The US
300,000,000
600,000
~200/100K
US/W
1/20
1/10
2-fold
1950 2004
Heart disease
Cancer Death Rate
Mor
talit
y ra
te
(per
100
k po
pula
tion)
200
400
600CDC data
The outlook of cancer treatment is not so good!
>1600 cancer deaths a day in the US!
9
Smoking
General population Smokers
Lung cancer rate
0.08% 8%
Why don’t most smokers have lung cancer in the face of intense carcinogen exposure?
10
Cell Damage
Cell Damage
DNA repairClearance of cancer cells
Younger and healthier Older
Hostprotection
Hostprotection
Cause of cancer: cell damage and aging
11
Modeling cancer
in animals
Understanding Cancer
mechanisms
Finding Molecular
targets
TestingTargets
Developinghuman therapy
Pathway #1: why do we get cancer
Pathway #2: why don’t we get cancer
FindingCancer-
ResistantHumans
Developinghuman therapy
Pathways to cancer treatment
12
Modeling Cancers in mice
Spontaneous tumors at old age: 81% of laboratory mice have cancers at their natural deathbut often not aggressive
Carcinogen-induced cancersTakes months if not year
Genetically engineered tumorsTakes months if not year and often not malignant
Transplantable xenograft-human tumor cell linesOften not showing malignant properties
Transplantable mouse cancer cell linesToo aggressive, too lethal, too rapidS180, EL4, L5178, L1210, J774, LL2, MethA etc.
Aggressiveness
Survival time
Can
cer
type
13
CR WT
CR
Days After S180 Injections
WT WT WT WT WT
Bod
y W
eigh
t in
Gra
ms
0
10
20
30
40
1 9 17 25 33 41 49 57
Completely unexpected
No exception
Serendipitous discovery of a cancer-resistant mouse
CR=cancer-resistantWT=cancer-sensitive
14
Survival after cancer challenge is based on inheritance: it is all in the DNA
SR WT24 4037%
M 9 18F 15 22
20
Presenceof pathogens
Innate immunity:Natural Killer cells (NK)
Macrophages (MΦ)Neutrophils (PMN)
Complements(Within hours)
Adaptive Immunity:B cells (antibodies)
T cells (CTL)Dendritic cells (DC)
Macrophages(Weeks)
An overview of two arms of immune system
25
0
20
40
60
80
100
120
140
160
180
200
0 2 4 6 8 10 12 14 16 18 20Days After Cancer Establishment
Tu
mo
r V
olu
me
rela
tive
to
Co
ntr
ols
(%
)
WT-ATSR/CR-AT
AT
0
20
40
60
80
100
0 4 8 12 16 20 24 28 32 36 40 44
Days Post-Tumor Injection
Su
rviv
al (
%)
WT-AT, n=5SR-AT, n=7
AT (day 4)
0
500
1000
1500
2000
2500
1 3 5 7 9 11 13 15 17
Days after adoptive transfer of leukocytes
Tu
mo
r V
olu
me
(m
m3
)
SR/CR, n=14WT, n=8
AT
SR AT 1-day 8-day 12-day 18-day 23-day
Cure established cancers in WT mice by systemic WBC therapy
Still alive after 18 months
26
n=10
Cure of mouse prostate cancer by white cell infusion
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12
Age (Months)
Su
rviv
al %
No AT
SR/CR AT
White cell infusion
Cancer cell challenges
n=7
Dr. Yong ChenCancer Biology
WFUSM
28
Genetically defined
No need for further manipulation
Involves the innate immunity that has been mostly ignored
Highly effective: survival of million times more lethal doses
No side effect
Kill different cancers
Transferable to treat established cancers in ordinary mice
The innate immunity of cancer-resistant mice can cure cancer
29
Why do we have natural protection against cancers:Humans and other large, long-living animals must have
exceptional natural resistance and immunity against malignancy in order to survive beyond reproductive ages
Why don’t normal mice have meaningful resistance or immunity against malignancy?
Mouse Human Difference
Body size 25 g 75,000 g 3000 x
Lifespan 2.5 (<1) y 75 y 30 x
Pre-reproduction 8 w 800 w 100 x
% with ca at death 81% 25% 3.2 x
Cancer Surveillance ± +++++
Cancer-resistance and humans
30
Mice in the wild have a tough life and don’t live long enough to get cancer.Therefore, there was no natural selection for resistance against cancers.
31
If humans do have cancer-resistance, can we measure it?
Can we inject cancer cells into humans to find out?
Probably not!?
33
Manual test of cancer cell killing activity:How well the white cells can kill cancer cells in test tubes
Control: cancer cells without white cells(100% survival)
Cancer cells with white cells (Ratio at 50:1)(some survival)
34
21 42 63 84 105
Hela + non-killing control cells: 1:20
Automated real-time recording of cancer cells killed by WBC
Hela control
Hela + WBC: 1:20
Time in hTime point of manual assays
Addition of effector cells
1
3
2
1
3
2
=0% kill
=30% kill
=50% kill
Plating target cells
35
1
2
3
4
5
6
7
Killing inTest tubes
-+
+
+--
-
Resistant/Survival after challengeLitter mates
Identifying cancer-resistant mice without a cancer cell challenge
36
12.5
25.0
37.5
50.0
75.0
62.5
87.5
In v
itro
canc
er k
ill a
ctiv
ity
(tar
get
cells
kill
ed %
)
100.0
0WT Mice SR mice
Test-tube cancer resistance results using cancer-resistant and non-resistant mice
37
12.5
25.0
37.5
50.0
75.0
62.5
87.5In
vitr
o ca
ncer
kill
act
ivity
(S
180
cells
kill
ed %
)
100.0
0WT Mice Young
SR miceOld
SR miceOld SR mice cancer cells
S180 cells
Mouse cancer-resistance by age
38
12.5
25.0
37.5
50.0
75.0
62.5
87.5
In v
itro
canc
er k
ill a
ctiv
ity
(tar
get
cells
kill
ed %
)100.0
0WT Mice Humans
>50y, CaSR mice Humans
>50yHumans
<50y
Hela cells
Human cancer-resistance by age
39
White cells that don’t kill cancer cells White cells that kill cancer cells
Automated recording of cancer cell kill
40Cancer patientNo rosettes
Hela cellsHuman WBC
Mouse S180 cellsSR mouse WBC
Rosette formation leading to cancer cell kill
43
Stability of cancer-killing activity in human WBC
100
80
60
40
20
02 4 6 8 10 12 14 16
% o
f ca
nce
r ce
lls k
illed
Time span in weeks
Stress
Recovery in 3 days
44
Stability of cancer-killing activity in human WBC
100
80
60
40
20
02 4 6 8 10 12 14 16
% o
f ca
nce
r ce
lls k
illed
Time span in weeks
Stress
Recovery in 3 months
45
Seasonality of CKA activity?
100
80
60
40
20
0Aug Sep Oct Nov Dec Jan Feb Mar
% o
f ca
nce
r ce
lls k
illed
Northern Hemisphere:Shorter daylightLower intensity of sunlight radiationLower temperatureVitamin D deficiency
Higher mortality rate in elderlyInfluenza seasonLower immune responsesSevere mood swing (SAD)
46
Injecting human subjects (Inmates and ca patients) with live cancer cells
Ethical and legal problems
Elected to the president of AACR in 1968
Chester Southam:
Healthy humans were resistant to cancer cells.Cancer patients lost cancer resistance while retained antimicrobeial resistance.
Science 25 January 1957 125: 158-160
48
Anticancer protection can be lost due to:
1. Genetics
2. Aging
3. Stress
4. Seasonal changes
5. Too many cancer cells (increased carcinogenesis)
6. Too few immune cells (immune suppression)
49
A new cancer treatment concept:
To replace a weak/bad immune system with a validated, functional one rather than to repair it
51
Donor selection: CKA, Availability, ABO, Virus status
Patient selection: reasonable condition
Dose escalation
Safety control: GVHD
Routes of delivery: systemic, local
Combination with existing therapies
The new cancer treatment concept
52
Uniqueness of this treatment:
No drug involved
Technology- and knowledge-based
Minimal side-effect is expected
Involves innate immunity (macrophages and neutrophils)but not adaptive immunity (T cells)
53
*n=14
Adoptive Transfer in different age groups
0
20
40
60
80
100
0 20 40 60 80 100 120
Days after S180
Su
rviv
al
Pe
rce
nta
ge
Young to Young (n=16)
Young to Old (n=15)
Old to Young (n=16)
Old to Old (n=16)
Old cells Young cells
100
80
60
40
20
0
Old
re
cipi
ents
Old
re
cipi
ents
You
ng
reci
pien
ts
You
ng
reci
pien
ts
Old cells Young cells
100
80
60
40
20
0
Old
re
cipi
ents
Old
re
cipi
ents
You
ng
reci
pien
ts
You
ng
reci
pien
ts
Young=3-6 months
Old=22-26 months
54
0
20
40
60
80
100
Per
cen
t S
urv
ival
Control Sex
Mismatch
MHC
Mismatch
Sex+MHC
Mismatch
Mismatched Adoptive Transfer in Mice
Male recipients
Female recipients
n=12 in each group
10083.3
58.341.7
0
20
40
60
80
100
Pe
rcen
t S
urv
ival
55
Why hasn't this treatment for cancer been tested yet?Differences with conventional funding philosophy
No mechanism: rational design vs empirical approach. (Pathways of development)
A radical departure from textbook: innate immunity vs adaptive immunity
Too good to be true
Not from a well-known establishment
Worsening funding environment
56
$10 million is needed for:
Clinical trials in humans for different cancers
Clinical trials in dogs
Developing techniques for long-term storage of cancer-killing white cells
Refinement of CKA assay: automation
Funding requirements to treat human cancer patients
57
Cancer and Immunity: the Next Frontier in Cancer Treatment
The Promise
No more disfiguring surgeryNo more toxic chemotherapy
No more damaging radiation therapiesNo more cancer recurrence
Permanent cures for cancer using the immune system
We can cure cancer using what we have learned from cancer-resistant mice
59
Many thanks again to:
Gailyn Waldron and Threshold, Inc.
Barbara Shook and the Barbara Ingalls Shook Foundation