Transcript National Centre in HIV Epidemiology and Clinical Research

The immune system, infection, and
the prevention of cancer
Epidemiological clues from transplant
recipients and people with AIDS
Andrew Grulich
UNSW Medical Faculty Dean’s Lecture, September 2007
National Centre in HIV Epidemiology and Clinical Research, University of New
South Wales, Sydney, Australia.
Outline
Background
The known role of infection in the causation of cancer
What can we learn from immune deficient populations?
Studies in transplant recipients
Studies in people with HIV/AIDS
Two examples
What causes Kaposi’s sarcoma?
What causes non-Hodgkin’s lymphoma?
Future directions and interventions
Established virus-cancer relationships
Viral agent
IARC: Evidence of causality
Sufficient
Hepatitis B
Liver
Hepatitis C
Liver
HTLV-1
HHV8
Limited
Inconclusive
Adult T-cell lymphoma
Kaposi’s sarcoma
Primary effusion
lymphoma
Epstein-Barr
virus (EBV)
Nasopharynx
Salivary gland
Hodgkin’s disease
Stomach
non-Hodgkin’s lymphomaa
Lung
aIn
immune suppressed populations
Established virus-cancer relationships
Viral agent
Evidence of causality
Sufficient
Human papillomavirus
Limited
Inconclusive
Cervix
NonAnus melanoma skin
Vulva Peri-ungal skin
Vagina
Larynx
Penis
Eye
Nasal cavity
Colon
Lung
Breast
Ovary
Prostate
Bladder
Tongue
Tonsil
Mouth
Oropharynx
Other infective agents and cancer
Agent
IARC: Evidence of causality
Sufficient
Helicobacter pylori
Schistosoma
haematobium
Opisthorchis viverrini
Stomach
Gastric B-cell
MALT
Bladder
Cholangiocarcinoma
Limited
Inconclusive
The magnitude of the effect
Agent
Cancer
No. of
cases
% of cancers
at that site
% of all
cancers
H pylori
Stomach
Lymphoma
592,000
11,500
63%
75%
5.5%
HPV
Cervix
Anogenital
Mouth, pharynx
492,800
53,880
14,500
100%
5.2%
HBV and HCV
Liver
535,000
85%
4.9%
EBV
Nasopharynx
78,100
Hodgkin lymphoma 28,600
Burkitt lymphoma
6,700
98%
1.0%
HIV/HHV8
KS
NHL
66,200
36,100
100%
0.9%
Schistosomes
Bladder
10,600
3%
0.1%
HTLV-1
ATL
3,300
>90%
0.03%
Liver Flukes
Cholangio-carcinoma 2,500
0.02%
Parkin et al, Int J Cancer, 2006
How does infection cause cancer?
Direct effects of virally-encoded proteins
HPV
E6 inactivates P53 by inducing rapid degradation
E7 activates cyclin dependent kinase 2
HTLV1
Tax transcriptionally activates a variety of oncogenes
EBV
LMP1 up-regulates BCL2 and a range of cellular oncogenes
Indirect effects
HBV/HCV
Not directly oncogenic
Carcinogenicity may depend on the immune response
H pylori and flukes
Not directly oncogenic
?chronic inflammation
Summary: the role of infection
Infection is acknowledged as having an important role in
the causation of cancer
Over the past 25 years, the proportion of all cancers
thought to be infection-related has increased from
around 5% to close to 20%
Discoveries have arisen mainly from the study of single
agent-single cancer associations
What can the study of immune deficient populations
add?
Immune deficient populations
Impaired immunity can unmask the carcinogenic effects of
infection
The interlinked effects of infection and immunity
The effects of infection and of impaired immunity are
linked
Impaired immunity leads to increased clinical expression
of infectious diseases
Increased replication of infective agents and
an increased risk of those cancers related to infection
The relationship may be more complex
when carcinogenesis depends on a robust immune response
eg liver cancer, stomach cancer
When the cancer arises from cells of the immune system
B lymphocytes (90% of lymphoma)
T lymphocytes
Others (rare)
Immunological surveillance:
“small accumulations of tumour
cells may develop, and because of
their possession of new antigenic
potentialities, provoke an effective
immunological reaction with
regression of the tumour, and no
clinical hint of its existence”
Cancer - a biological approach, 1957.
Sir Frank Macfarlane Burnet
Nobel Prize, 1960
Immune deficiency and cancer: history
1950’s: immune surveillance theory
Immunity essential for the recognition and elimination of emerging cancer clones
Impaired immunity should result in increased risk of all cancer types
1970: the advent of post-transplantation immune suppression
Increased rates of Kaposi’s sarcoma and NHL noted immediately
Little evidence of other increases
1980: the advent of AIDS
Increased rates of Kaposi’s sarcoma and NHL noted immediately
Inconsistent evidence of other increases
2000+: larger populations of people with HIV and transplant recipients
Are other cancers associated with immune deficiency?
Might these populations provide a way to allow new discoveries of infectious
causes of cancer?
Study design: immune suppression and cancer
How do we study whether cancer occurs at increased rates in people with
immune deficiency?
Clinical cohort studies
Relatively expensive, of limited power thus far
“Linkage” studies
Link identifiers of people with HIV/AIDS, or transplant recipients, with cancer registers
Compare rates of cancer to those in the general population using the SIR
Where such databases exist, these effectively create a population-wide cohort study
Australia’s advantage
longstanding and nationwide HIV and transplant registration and cancer registration
A comparison of the pattern of cancer in transplant recipients with cancer in
people with HIV/AIDS has the potential to help guide our thinking about which
cancers we might expect to occur at increased risks in people with impaired
immunity
Cancer in transplant recipients
By the year 2000, there was
General agreement that there are markedly increased rates of
Kaposi’s sarcoma and non-Hodgkin lymphoma
A study from Sweden in the late 1990’s suggested a wider range
of cancers occur at increased rates
There was a lack of agreement on which cancers occur at
increased rates, and whether or not these might be related to
factors which also caused end stage renal disease
New, potentially less carcinogenic compounds being trialled for
use in immune suppression (m-TOR inhibitors)
Cancer in Australian kidney transplant recipients
Methods
Data linkage
Name-based, probabilistic
Retrospective population-wide cohort study, 1982-2002
Data linkage between:
Australia and New Zealand Dialysis and Transplant
Registry (ANZDATA)
Population-based register of renal transplantation,
since 1960’s
Enter register at dialysis for end stage renal disease
National Death Index (NDI)
Population-based register of all deaths in Australia
National Cancer Statistics Clearing House (NCSCH)
Population-based register of cancers occurring
nationally, since 1982
Methodology
Study population
ANZDATA e xtract
n=31,446
Remove if no/partial followup in Australia (n=378)
Aus tralian re s ide nts
n=31,068
Remove if registered/died prior to
01/01/1982 (n=2,208)
Remove if registered after end
date (n=5)
Re gis te re d/alive during s tudy pe riod
n=28,855
Results
Cohort characteristics
Characteristics
No. of
registrants
(%)
Person- Mean
years
personyears
Mean
age
Total
28,855 (100) 273,407
9.5
49.2
Prior to treatment
25,685 (89)
119,279
4.6
49.5
Dialysis
24,926 (86)
67,231
2.7
54.2
After transplantation 10,180 (35)
86,898
8.5
41.0
Time periods
Results: viruses
Site
Prior to RRT
During dialysis
After transplantation
Lip
Tongue
Mouth
Salivary gland
Esophagus
Stomach
Small intestine
Colon
Rectum
Anus
Liver
Gallbladder
Pancreas
Larynx
Lung
Melanoma
Mesothelioma
Kaposi sarcoma
Connective tissue
Breast
Vulva
Cervix uteri
Corpus uteri
Ovary
Penis
Prostate
Testis
Eye
Brain
Thyroid
Hodgkin disease
Non-Hodgkin lymphoma
Leukemia
Unspecified
All cancers
.01
.1
1
10
100
1000
.01
.1
1
10
100
1000
.01
.1
1
10
100
1000
SIR
Sufficient evidence
Limited evidence
Inconclusive evidence
Vajdic et al, JAMA, 2006
Summary
Kidney transplantation is associated with increased
cancer risk across a number of sites
For most of these, cancer risk was not increased
prior to transplantation
Most, but not all, were cancers with a known or
suspected viral cause
These data suggest an important role of the
interaction between common viral infections and the
immune system in the aetiology of a large variety of
types of cancer
How does this compare to HIV?
NHL, KS and cervical cancer are recognised as part of the definition of
AIDS
A variety of other cancers occur at increased rates in people with HIV
Anal Cancer (RR 40, only in gay men)
Leiomyosarcoma in children (RR > 50)
SCC of the conjunctiva (RR 10-20)
Hodgkin disease (RR about 10)
Lip cancer (RR at least 5)
Grulich et al, AIDS, 1999; Engels et al, AIDS, 2006.
Based on the largest single study, the US AIDS-cancer match, these were
not associated with immune deficiency
The authors concluded that lifestyle factors , and not immune deficiency,
likely explain these increased risks
Frisch et al, JAMA, 2001.
Are these cancers associated with i-deficiency?
US AIDS-cancer match
A cancer is judged as AIDS-related if
SIR increased for the entire period from 5 years before until 2 years after AIDS
Increasing trend of SIRS pre to post AIDS
Many cancers increased overall
few had an increasing trend from early to late stages
problem: in the era of effective HIV therapy a pre-post AIDS comparison
may not represent increasing immune deficiency
A new approach
Which cancers occur at increased rates in people with HIV?
How does this compare to transplant recipients?
If the pattern is similar, then it is likely to be immune deficiency, and not
shared lifestyle factors, which increase cancer risk
HIV-cancer studies
Grulich et al, Lancet, 2007
Transplant studies
Grulich et al, Lancet, 2007
Infection-related cancers
Grulich et al, Lancet, 2007
Infection-related cancers 2: HPV
Common epithelial cancers
Grulich et al, Lancet, 2007
Other cancers increased in one or both
Grulich et al, Lancet, 2007
Conclusion
A new approach to determine the range of immune deficiency-related
cancer
A much larger range of cancers than previously appreciated is associated
with transplant and HIV-associated immune deficiency
Most, but not of all of these, are infection-related, and HPV plays a
prominent role
The lack of association with immune deficiency in the US AIDS-cancer
match may mean that these cancers occur at relatively preserved CD4
counts
The association with degree of immune deficiency may well not be linear, and
appears to be different for different cancers
Considerations of increased cancer risk in mild immune deficiency may
influence the question of “when to start” HIV therapy.
What causes Kaposi’s sarcoma?
Kaposi’s sarcoma
A malignancy arising from lymphatic endothelial cells
Gives rise to darkly pigmented lesions of the skin and mucous
membranes
Lesions can occur anywhere on skin, and are frequently disfiguring
Involvement of internal organs (respiratory and GI tract) can lead to
bleeding and death
KS in AIDS
KS was the harbinger of the AIDS epidemic
Relative risk of 50,000 or more
Percent of AIDS defining illnesses
Developed countries
male homosexuals 30-40%
all others < 5%
African heterosexuals 20% +
Risk of KS is raised in homosexual men who report
More sexual activity
A history of sexually transmissible infections
Consistent with a sexually transmissible agent
The cause of KS: human herpesvirus 8
Discovered in KS tissue in 1994
Chang et al, Science, 1994
Discovered by a molecular biologist-epidemiologist team
A gamma herpesvirus,
found in close to 100% of KS tissue,
rarely described in control tissue
infection precedes development of KS
HHV-8/KSHV is now recognised as the cause of KS
Close relatives found in African green monkeys, other primates
Closest human relative is Epstein Barr Virus
Probably an ancient cross species transmission
Risk factors for HHV8 in people with HIV
Homosexual men with serological evidence of HHV-8 infection:
Report more STDs
Report twice as many casual partners
Significantly more likely to report sexual risk behaviours with casual
partners
More likely to be HSV2 IgG positive
ie a sexually transmissible infection
HHV-8 serology predicts future development of KS
Grulich et al, J AIDS & HR, 1999
Pathogenesis
HHV-8 is the necessary cause of KS.
It contains a several recognisable host genes (“molecular piracy”).
The proteins encoded by these genes include some that are homologous to
human oncoproteins.
a cyclin that inhibits retinoblastoma protein
bcl 2 like protein that prevents apoptosis.
G protein coupled receptor
an inhibitor of apoptosis mediated by the FLICE pathway
an inhibitor of the interferon signalling pathway
IL-6 (induces B cell proliferation)
three functional chemokines (?Angiogenic)
Products encoded by viral genes directly de-rail cell cycle control
Stopping HHV8 replication should stop carcinogenesis
KS: a story (almost) solved
The extra-ordinarily distinctive epidemiology of immune deficiency and of
infection with HHV-8 among people with KS led us to the cause
Incidence has plummeted in developed countries
KS is essentially an opportunistic infection associated with loss of cell-mediated
immunity against HHV-8
HHV-8 is under very close control by the immune system: maintenance of
immunity prevents KS development
When KS presents clinically in a person with HIV, first line therapy is usually
anti-retroviral therapy (ARV)
Restoration of anti-HHV-8 immunity mostly results in tumour regression
This challenges our concept of what is a malignancy
KS remains an enormous issue in those sub-Saharan African countries
where ARV therapy access is poor and HHV-8 seroprevalence is high
Now the most common cancer in sub-Saharan Africa
KS in SE Sydney, 1972-99
Discovery of HHV-8
Rate per 100,000
20
15
10
KS and sexual transmission
KS mainly in homosexual men
Sexually a
51.9
51.4
53.7
57.6
48.5
56.5
56.9
5
HIV epidemic
Combination therapy
0
72 74 76 78 80 82 84 86 88 90 92 94 96 98
KS incidence
1. Age standardised to Australian population 1991
Source: NSW Cancer Council
What causes non-Hodgkin lymphoma?
Non Hodgkin Lymphoma
A cancer arising from lymphocytes and presenting as
a mass
If presenting in the blood = leukaemia
Common cause of cancer death with incidence rapidly
increasing (?recent plateau)
6th most common cause of cancer death in Western countries
It mainly involves B, not T, lymphocytes (also in HIV)
ie not the target cells for HIV infection
Risk factors largely unknown; immune deficiency
important
Rate increased 10 fold in immune suppressed transplant
recipients
NHL in AIDS
3-5% of AIDS-defining illnesses
probably more than 10% of AIDS deaths in Western settings
50-100x more common than general population
Unusual subtypes, aggressive (“high grade”) and
often rapidly fatal
Burkitt’s: mild immune deficiency
(median CD4 300+)
Large cell-immunoblastic: severe i-deficiency
(CD4 50)
Primary CNS: profound immune deficiency
(CD4 10)
EBV present in 20% of Burkitt’s lymphoma, 50%+ of
LCI NHL and 100% of CNS NHL
Little variation in risk with route of HIV infection
Therefore unlikely to be due to a STI or a BBV
Risk factors: NSW case-control study
Design
Cases: 219 people with AIDS NHL in Sydney, 1984-94
Controls: 219 people with HIV infection without NHL
Matched: degree of immune deficiency (CD4 count)
Data: medical record review
Serial CD4 counts
Long term markers of B cell stimulation (serum Ig, globulin)
Therapies active against EBV
Grulich et al, AIDS, 2000
Duration of immune deficiency
CD 4 count one year prior to match date
CD4 count
Odds Ratio
95 %CI
<20
20-99
100-199
200-499
500
1.0
1.04
0.51
0.50
0.48
0.51-2.12
0.24-1.05
0.25-0.99
0.19-1.16
p trend 0.003
Grulich et al, AIDS, 2000
Long term B cell stimulation
Mean serum globulin
40
Cases
Controls
38
36
34
32
30
0
1
2
3
4
5
Years prior to match date
n cases
216
108
67
47
28
n controls
201
110
63
42
23
20
16
Grulich et al, AIDS, 2000-
Indices of the role of EBV
Anti-herpes drugs in the previous year
Acyclovir
OR 1.06 (95% CI 0.65-1.71)
no dose effect
no subtype effect
Ganciclovir
OR 0.51 (95 % CI 0.20-1.25)
Effective anti-EBV therapy does not prevent AIDS-NHL
Grulich & Law, Clin Inf Dis, 2001
AIDS-NHL in the era of effective ARV therapy
Incidence declining
CNS NHL is disappearing in areas where HAART
access is universal
an opportunistic infection due to lack of cell mediated immunity
against EBV.
restoration of CMI against EBV prevents, and in some cases
cures, CNS NHL
Immunoblastic lymphoma declining less
Burkitt’s Lymphoma ?not declining
Treatment of NHL is improving rapidly
No longer universally fatal
Aim to treat HIV (HAART) and NHL (chemotherapy) at
the same time if at all possible
An unanswered question: what causes NHL?
Why has the incidence of NHL increased rapidly in the
developed world over the last 50 years?
What is the role of EBV in the non immune-deficient population?
What is the role of immune deficiency?
Could a mild, sub-clinical form of immune deficiency explain much
of the risk of NHL?
Other immune dysfunction
Auto-immune disease (increased risk)
Atopic disease (decreased risk)
Grulich et al, JNCI, 2005
Grulich et al, CEBP, 2007
InterLYMPH– member studies
Next meeting: Sydney July 2008
Future directions
Are these cancer-immunity associations reversible?
Would earlier therapy of HIV reduce cancer risk?
Does cancer risk return to normal on the cessation of immune suppression?
Is cancer risk lower among recipients of m-TOR inhibitors?
The role of HPV
Does the wider than expected role of HPV in these settings reflect an important role for HPV
in upper aero-digestive cancers in the general population?
Should we be vaccinating men?
What explains the increased rate of specific cancers?
Lung cancer
Lip cancer
Melanoma
Thyroid cancer (in ESRD and kidney transplant patients)
Cancer in other conditions of dysregulated immunity
Primary immune deficiency
Is there a highly prevalent but mild form of immune deficiency or immune dysfunction
that could explain why NHL has increased so much?
Acknowledgements
NCHECR, Sydney
Professor John Kaldor
Dr Claire Vajdic
Dr Matthew Law
Yueming Li
Marina van Leeuwen
Michael Falster
NSW Cancer Council
Dr Xinan Wan
Professor Bruce Armstrong
Dr Anne Kricker
Dr Margaret McCredie
Anne-Maree Hughes
Marylon Coates
ANZDATA
Prof Jeremy Chapman
Dr Stephen Macdonald
Dr Angela Webster
St Vincent’s Hospital
Dr Sam Milliken
Dr Jenny Turner
Columbia University, USA
Professor Patrick Moore
Dr Yuan Chang
Viral Epidemiology Laboratory, NCI
Dr Denise Whitby
Interlymph immunology sub-group
Dr Wendy Cozen, UCLA