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CANCER AND IMMUNITY - THE NEXT FRONTIER IN CANCER TREATMENT
Zheng Cui, MD/PhD
Section of Tumor Biology
Department of Pathology
Wake Forest University
School of Medicine
Winston-Salem, NC, USA
Telephone: 336-716-6185
Email: [email protected]
1
Acknowledgement
This presentation is made possible by:
Gailyn Waldron and Threshold, Inc.
Barbara Shook and the Barbara Ingalls Shook Foundation
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Current cancer therapies:
Chemo
Surgeries
Kill growing cells
systemically
Remove cancer
at early stage
Immunotherapies
Repair a weak/bad
immune system
Radiation
Kill live cells
locally
Targeted therapies:
Herceptin, Gleevec
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Cancer Stats:
The US
Population:
~6,000,000,000
300,000,000
1/20
Yearly cancer death:
~6,000,000
600,000
1/10
Cancer mortality rate:
(age-adjusted)
~100/100K
~200/100K
The outlook of cancer
treatment is not so good!
>1600 cancer deaths a day in the US!
Mortality rate
(per 100k population)
Worldwide
600
400
US/W
2-fold
CDC data
Heart disease
200
Cancer Death Rate
1950
2004
4
May 8th, 2006
5
May 8th, 2006
The second most blogged news story in May, 2006
6
The most blogged news story in May: Britney Spears!
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Since then, she continues to make news….
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Lung cancer rate
0.08%
8%
Smoking
General population
Smokers
Why don’t most smokers have lung cancer
in the face of intense carcinogen exposure?
9
Cause of cancer: cell damage and aging
Host
protection
Cell
Damage
DNA repair
Clearance of cancer cells
Cell
Damage
Host
protection
10
Younger and healthier
Older
Pathways to cancer treatment
Pathway #1: why do we get cancer
Modeling
cancer
in animals
Understanding
Cancer
mechanisms
Finding
Molecular
targets
Testing
Targets
Developing
human
therapy
Pathway #2: why don’t we get cancer
Finding
CancerResistant
Humans
Developing
human
therapy
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Modeling Cancers in mice
Aggressiveness
Transplantable mouse cancer cell lines
Too aggressive, too lethal, too rapid
S180, EL4, L5178, L1210, J774, LL2, MethA etc.
Cancer type
Carcinogen-induced cancers
Takes months if not year
Genetically engineered tumors
Takes months if not year and often not malignant
Transplantable xenograft-human tumor cell lines
Often not showing malignant properties
Spontaneous tumors at old age:
81% of laboratory mice have cancers at their natural death
but often not aggressive
Survival time
12
Serendipitous discovery of a cancer-resistant mouse
Body Weight in Grams
No exception
40
WT
WT
WT
WT
WT
30
20
CR
10
WT
0
1
9
17
25
33
41
Days After S180 Injections
49
57
CR=cancer-resistant
WT=cancer-sensitive
Completely unexpected
CR
13
Survival after cancer challenge is based on inheritance:
it is all in the DNA
M
F
SR
24
37%
9
15
WT
40
18
22
14
From a single mouse to a great legacy!
Finally, they are available free to research community! 15
Cancer cells are specifically killed
by white cells that formed “rosettes”
16
Cancer cell killing is dependent on cell-cell contact.
17
Natural killer cells form rosettes and aggregates with tumor cells
18
The surface of cancer cell is damaged before dying
19
An overview of two arms of immune system
Presence
of 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)
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White cells are tracking down cancer cells
Cell aggregation
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Cancer cells are ruptured by white cells
Mixed pop-rosettes
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Cancer cells are ruptured by white cells
Mixed pop
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A much larger cancer cell killed by a small white cell (neutrophil)
Pmn-apop
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SR/CR, n=14
WT, n=8
2500
Tumor Volume (mm3)
Tumor Volume relative to Controls (%)
Cure established cancers in WT mice by systemic WBC therapy
2000
1500
AT
1000
500
0
1
3
5
7
9
11
13
15
Days after adoptive transfer of leukocytes
200
WT-AT
SR/CR-AT
180
160
AT
140
120
100
80
60
40
20
0
17
0
2
4
100
Survival (%)
80
6
8
10
12
14
16
18
20
Days After Cancer Establishment
Still alive after 18 months
AT (day 4)
WT-AT, n=5
SR-AT, n=7
60
40
20
0
0
4
8
12
16
20
24
28
32
36
40
44
Days Post-Tumor Injection
SR AT
1-day
8-day
12-day
18-day
23-day
25
Cure of mouse prostate cancer by white cell infusion
White cell infusion
Cancer cell challenges
n=7
Dr. Yong Chen
Cancer Biology
WFUSM
SR/CR AT
100
Survival %
80
60
No AT
40
n=10
20
0
0
1
2
3
4
5
6
7
8
Age (Months)
9
10 11 12
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It is a permanent, complete cure of cancer!
WT
Normal
PTEN-KO
PTEN-KO + SR
Cancer
Scars
27
The innate immunity of cancer-resistant mice can cure cancer
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
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Cancer-resistance and humans
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
Mouse
Human
Difference
Body size
25 g
75,000 g
3000 x
Lifespan
2.5 (<1) y
75 y
30 x
Pre-reproduction
8w
800 w
100 x
% with ca at death
81%
25%
3.2 x
Cancer Surveillance
±
+++++
Why don’t normal mice have meaningful resistance or immunity against malignancy?
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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.
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If humans do have cancer-resistance, can we measure it?
Can we inject cancer cells into humans to find out?
Probably not!?
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Cancer Cells
White blood cells
Incubation
% killed
70
30
40 / 70 = 57.3% Killed
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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)
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Automated real-time recording
of cancer cells killed by WBC
Hela + non-killing control cells: 1:20
Hela control
1
Hela + WBC: 1:20
2
3
21
42
63
84
105
Time in h
Plating target cells
Time point of manual assays 1 =0% kill
2 =30% kill
Addition of effector cells
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3 =50% kill
Identifying cancer-resistant mice without a cancer cell challenge
Litter mates
Killing in
Test tubes
1
+
+
+
2
3
4
5
6
7
Resistant/Survival after challenge
35
Test-tube cancer resistance results using
cancer-resistant and non-resistant mice
100.0
87.5
In vitro cancer kill activity
(target cells killed %)
75.0
62.5
50.0
37.5
25.0
12.5
0
WT Mice
SR mice
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Mouse cancer-resistance by age
100.0
S180 cells
87.5
In vitro cancer kill activity
(S180 cells killed %)
75.0
62.5
50.0
37.5
25.0
12.5
0
WT Mice
Young
SR mice
Old
SR mice
Old SR mice
cancer cells
37
Human cancer-resistance by age
100.0
87.5
Hela cells
In vitro cancer kill activity
(target cells killed %)
75.0
62.5
50.0
37.5
25.0
12.5
0
WT Mice
SR mice
Humans
<50y
Humans
>50y
Humans
>50y, Ca
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Automated recording of cancer cell kill
White cells that don’t kill cancer cells
White cells that kill cancer cells
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Rosette formation leading to cancer cell kill
Mouse S180 cells
SR mouse WBC
Hela cells
Human WBC
Cancer patient
No rosettes
40
Surveillance by human white cells
41
Cancer cell killed by a smart bomb (white cell)
42
Stability of cancer-killing activity in human WBC
Recovery in 3 days
100
% of cancer cells killed
80
60
40
20
0
2
4
6
8
10
12
14
16
Time span in weeks
43
Stress
Stability of cancer-killing activity in human WBC
Recovery in 3 months
100
% of cancer cells killed
80
60
40
20
0
2
4
6
8
10
12
14
16
Time span in weeks
Stress
44
Seasonality of CKA activity?
100
% of cancer cells killed
80
60
Higher mortality rate in elderly
Influenza season
Lower immune responses
Severe mood swing (SAD)
40
20
0
Aug
Sep
Oct
Nov
Dec
Jan
Feb
Mar
Northern Hemisphere:
Shorter daylight
Lower intensity of sunlight radiation
Lower temperature
Vitamin D deficiency
45
Chester Southam:
Injecting human subjects (Inmates and ca patients) with live cancer cells
Healthy humans were resistant to cancer cells.
Cancer patients lost cancer resistance
while retained antimicrobeial resistance.
Ethical and legal problems
Elected to the president of AACR in 1968
Science 25 January 1957 125: 158-160
46
Possible effects of aging and stress on CKA of human WBC
75%
25%
47
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)
48
A new cancer treatment concept:
To replace a weak/bad immune system with
a validated, functional one rather than to repair it
49
Healthy volunteers
CKA screening
White cells
50
The new cancer treatment concept
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
51
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)
52
Adoptive Transfer in different age groups
Young=3-6 months
Old=22-26 months
80
Young to Young (n=16)
60
*n=14
40
Old to Young (n=16)
20
Young to Old (n=15)
Old to Old (n=16)
0
0
20
40
120
20
Old recipients
Young recipients
40
Old recipients
60
Young recipients
20
Young recipients
40
100
80
Old recipients
60
Young recipients
80
60
80
Days after S180
100
100
Old recipients
Survival Percentage
100
0
0
Old cells
Young cells
Old cells
Young cells
53
Percent Survival
Mismatched Adoptive Transfer in Mice
n=12 in each group
100
80
60
100
40
83.3
58.3
41.7
20
Percent Survival
0
100
80
Male recipients
60
Female recipients
40
20
0
Control
Sex
Mismatch
MHC
Mismatch
Sex+MHC
Mismatch
54
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
55
Funding requirements to treat human cancer patients
$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
56
Cancer and Immunity: the Next Frontier in Cancer Treatment
The Promise
No more disfiguring surgery
No more toxic chemotherapy
No more damaging radiation therapies
No more cancer recurrence
Permanent cures for cancer using the immune system
We can cure cancer using what we have
learned from cancer-resistant mice
57
Funding:
CRI
NCI
WFU
Charlotte Geyer
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Many thanks again to:
Gailyn Waldron and Threshold, Inc.
Barbara Shook and the Barbara Ingalls Shook Foundation
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