The immune system, infection, and the prevention of cancer Epidemiological clues from transplant recipients and people with AIDS Andrew Grulich UNSW Medical.

The immune system, infection, and The immune system, infection, and the prevention of cancer the prevention of cancer

Epidemiological clues from transplant Epidemiological clues from transplant recipients and people with AIDSrecipients and people with AIDS

Andrew GrulichAndrew Grulich

UNSW Medical Faculty Dean’s Lecture, September 2007 UNSW Medical Faculty Dean’s Lecture, September 2007

National Centre in HIV Epidemiology and Clinical Research, University of New National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia. South Wales, Sydney, Australia.

OutlineOutline

BackgroundThe known role of infection in the causation of cancer

What can we learn from immune deficient populations? Studies in transplant recipientsStudies in people with HIV/AIDS

Two examples What causes Kaposi’s sarcoma? What causes non-Hodgkin’s lymphoma?

Future directions and interventions

Viral agent IARC: Evidence of causality

Sufficient Limited Inconclusive

Hepatitis B Liver

Hepatitis C Liver

HTLV-1 Adult T-cell lymphoma

HHV8 Kaposi’s sarcoma

Primary effusion lymphoma

Epstein-Barr Nasopharynx Salivary gland

virus (EBV) Hodgkin’s disease Stomach

non-Hodgkin’s lymphomaa Lung

Established virus-cancer relationshipsEstablished virus-cancer relationships

aIn immune suppressed populations

Viral agent Evidence of causality


Human papillomavirus CervixAnusVulva

VaginaPenis

TongueTonsil

Non-melanoma skinPeri-ungal skin

LarynxEye

Nasal cavity

Colon

Lung

Breast

Ovary

Prostate

Bladder

Mouth

Oropharynx

Established virus-cancer relationshipsEstablished virus-cancer relationships

Agent IARC: Evidence of causality


Helicobacter pylori StomachGastric B-cell

MALT

Schistosoma haematobium

Bladder

Opisthorchis viverrini Cholangio-carcinoma

Other infective agents and cancer Other infective agents and cancer

The magnitude of the effectThe magnitude of the effectAgent 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

492,80053,88014,500

100% 5.2%

HBV and HCV Liver 535,000 85% 4.9%

EBV Nasopharynx Hodgkin lymphoma Burkitt lymphoma

78,10028,6006,700

98% 1.0%

HIV/HHV8 KS NHL

66,20036,100

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?How does infection cause cancer?

Direct effects of virally-encoded proteinsHPV

E6 inactivates P53 by inducing rapid degradationE7 activates cyclin dependent kinase 2

HTLV1Tax transcriptionally activates a variety of oncogenes

EBVLMP1 up-regulates BCL2 and a range of cellular oncogenes

Indirect effects HBV/HCV

Not directly oncogenicCarcinogenicity may depend on the immune response

H pylori and flukesNot directly oncogenic?chronic inflammation

Summary: the role of infection 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 Immune deficient populations

Impaired immunity can unmask the carcinogenic effects of infection

The interlinked effects of infection and immunityThe 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 cancerWhen the cancer arises from cells of the immune system

B lymphocytes (90% of lymphoma)T lymphocytes Others (rare)

Sir Frank Macfarlane Burnet

Nobel Prize, 1960

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.

1950’s: immune surveillance theoryImmunity essential for the recognition and elimination of emerging cancer clonesImpaired immunity should result in increased risk of all cancer types

1970: the advent of post-transplantation immune suppressionIncreased rates of Kaposi’s sarcoma and NHL noted immediatelyLittle evidence of other increases

1980: the advent of AIDSIncreased rates of Kaposi’s sarcoma and NHL noted immediatelyInconsistent evidence of other increases

2000+: larger populations of people with HIV and transplant recipientsAre other cancers associated with immune deficiency?Might these populations provide a way to allow new discoveries of infectious causes of cancer?

Immune deficiency and cancer: historyImmune deficiency and cancer: history

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” studiesLink identifiers of people with HIV/AIDS, or transplant recipients, with cancer registersCompare rates of cancer to those in the general population using the SIRWhere such databases exist, these effectively create a population-wide cohort study

Australia’s advantagelongstanding 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

Study design: immune suppression and cancerStudy design: immune suppression and cancer

Cancer in transplant recipients 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)

Methods Data linkage

Name-based, probabilistic

Retrospective population-wide cohort study, 1982-2002Data linkage between:

Australia and New Zealand Dialysis and Transplant Registry (ANZDATA)

Population-based register of renal transplantation, since 1960’sEnter 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

Cancer in Australian kidney transplant recipientsCancer in Australian kidney transplant recipients

MethodologyMethodologyStudy populationStudy population

ANZDATA extract n=31,446

Australian residents

Remove if no/partial follow-up in Australia (n=378)

Registered/alive during study period

Remove if registered/died prior to01/01/1982 (n=2,208)

Remove if registered after enddate (n=5)

n=31,068

n=28,855

ResultsResultsCohortCohort characteristics characteristics

Characteristics No. of registrants (%)

Person-years

Mean person-years

Mean age

Total 28,855 (100)

273,407

9.5 49.2

Time periods

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

Results: virusesResults: viruses

All cancersUnspecified

LeukemiaNon-Hodgkin lymphoma

Hodgkin diseaseThyroid

BrainEye

TestisProstate

PenisOvary

Corpus uteriCervix uteri

VulvaBreast

Connective tissueKaposi sarcoma

MesotheliomaMelanoma

LungLarynx

PancreasGallbladder

LiverAnus

RectumColon

Small intestineStomach

EsophagusSalivary gland

MouthTongue

Lip

.01 .1 1 10 100 1000 .01 .1 1 10 100 1000 .01 .1 1 10 100 1000

Prior to RRT During dialysis After transplantationS

ite

SIR

Sufficient evidence Limited evidence Inconclusive evidenceVajdic et al, JAMA, 2006

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

Summary

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 HIVAnal 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 matchA cancer is judged as AIDS-related if

SIR increased for the entire period from 5 years before until 2 years after AIDSIncreasing trend of SIRS pre to post AIDS

Many cancers increased overallfew had an increasing trend from early to late stagesproblem: 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 studiesHIV-cancer studies

Grulich et al, Lancet, 2007

Transplant studiesTransplant studies


Infection-related cancersInfection-related cancers


Infection-related cancers 2: HPVInfection-related cancers 2: HPV

Common epithelial cancersCommon epithelial cancers


Other cancers increased in one or bothOther cancers increased in one or both


ConclusionConclusionA 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 sarcomaKaposi’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 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 activityA history of sexually transmissible infections

Consistent with a sexually transmissible agent

The cause of KS: human herpesvirus 8The cause of KS: human herpesvirus 8

Discovered in KS tissue in 1994

Discovered by a molecular biologist-epidemiologist team

A gamma herpesvirus, found in close to 100% of KS tissue, rarely described in control tissueinfection 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

Chang et al, Science, 1994

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 KSGrulich et al, J AIDS & HR, 1999

PathogenesisPathogenesis

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 proteinbcl 2 like protein that prevents apoptosis.G protein coupled receptoran inhibitor of apoptosis mediated by the FLICE pathway an inhibitor of the interferon signalling pathwayIL-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 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 countriesKS is essentially an opportunistic infection associated with loss of cell-mediated immunity against HHV-8HHV-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 regressionThis 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, 1972-99KS in SE Sydney, 1972-99

0

5

10

15

20

72 74 76 78 80 82 84 86 88 90 92 94 96 98

Rat

e p

er 1

00,0

00

KS incidence

1. Age standardised to Australian population 1991

Source: NSW Cancer Council

Sexually a51.951.453.757.648.556.556.9

HIV epidemic

KS mainly in homosexual men

KS and sexual transmission

Discovery of HHV-8

Combination therapy

What causes non-Hodgkin lymphoma?

Non Hodgkin LymphomaNon 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

3-5% of AIDS-defining illnessesprobably 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

NHL in AIDSNHL in AIDS

Risk factors: NSW case-control studyRisk 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 reviewSerial CD4 countsLong term markers of B cell stimulation (serum Ig, globulin)Therapies active against EBV

Grulich et al, AIDS, 2000

CD 4 count one year prior to match date

CD4 count Odds Ratio 95 %CI<20 1.020-99 1.04 0.51-2.12100-199 0.51 0.24-1.05200-499 0.50 0.25-0.99500 0.48 0.19-1.16

p trend 0.003

Duration of immune deficiency Duration of immune deficiency

Grulich et al, AIDS, 2000

Long term B cell stimulationLong term B cell stimulation

30

32

34

36

38

40

0 1 2 3 4 5

Years prior to match date

Mea

n se

rum

glo

bulin

Cases Controls

n cases 216 108 67 47 28 20

n controls 201 110 63 42 23 16

Grulich et al, AIDS, 2000-

Indices of the role of EBVIndices of the role of EBV

Anti-herpes drugs in the previous year Acyclovir OR 1.06 (95% CI 0.65-1.71)

no dose effectno 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 therapyAIDS-NHL in the era of effective ARV therapy

Incidence decliningCNS 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 rapidlyNo longer universally fatalAim to treat HIV (HAART) and NHL (chemotherapy) at the same time if at all possible

An unanswered question: what causes NHL?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 dysfunctionAuto-immune disease (increased risk)Atopic disease (decreased risk)

Grulich et al, JNCI, 2005Grulich et al, CEBP, 2007

InterLYMPHInterLYMPH– – member studiesmember studies

Next meeting: Sydney July 2008Next meeting: Sydney July 2008

Future directionsFuture 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 HPVDoes 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 cancerLip cancerMelanomaThyroid cancer (in ESRD and kidney transplant patients)

Cancer in other conditions of dysregulated immunityPrimary 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?

NCHECR, SydneyProfessor John Kaldor

Dr Claire VajdicDr Matthew Law

Yueming LiMarina van Leeuwen

Michael Falster

NSW Cancer CouncilDr Xinan Wan

Professor Bruce ArmstrongDr Anne Kricker

Dr Margaret McCredieAnne-Maree Hughes

Marylon Coates

ANZDATAProf Jeremy ChapmanDr 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

AcknowledgementsAcknowledgements

The immune system, infection, and the prevention of cancer Epidemiological clues from transplant recipients and people with AIDS Andrew Grulich UNSW Medical.

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