Newer cancer therapiesNewer cancer therapies

Immunotherapy Immunotherapy

ImmunotherapyImmunotherapy

Non-specific Non-specific immunotherapyimmunotherapy BCG BCG CytokinesCytokines

Specific immunotherapySpecific immunotherapy Active immunotherapyActive immunotherapy

Antibody therapyAntibody therapy Adoptive transfer of T cellsAdoptive transfer of T cells

Vaccine-based Vaccine-based immunotherapyimmunotherapy

Tumour-based vaccinesTumour-based vaccines Virus-based vaccinesVirus-based vaccines Peptide-based vaccinesPeptide-based vaccines othersothers

Key immune cells in cancerKey immune cells in cancerThe main immune cells that play a role in the protection against The main immune cells that play a role in the protection against

tumours and their rejection aretumours and their rejection are Cytotoxic T-lymphocytes (CTLs)Cytotoxic T-lymphocytes (CTLs)

MHC restricted - recognize only small endogenously processed MHC restricted - recognize only small endogenously processed protein fragments (peptides) that must be presented in a surface protein fragments (peptides) that must be presented in a surface protein called the major histocompatibilty complex (MHC)protein called the major histocompatibilty complex (MHC)

Natural Killer (NK) cellsNatural Killer (NK) cells: : toxicity without prior sensitization and without MHC restriction. toxicity without prior sensitization and without MHC restriction.

Usually activated when T cells cannot be activated Usually activated when T cells cannot be activated

Macrophages: Macrophages: usually activated by bacterial / viral infections leading to tumour usually activated by bacterial / viral infections leading to tumour

cell deathcell death Stimulates secretion of the tumour necrosis factor (TNF)Stimulates secretion of the tumour necrosis factor (TNF)

Cytotoxic T-lymphocytes (CTLs)Cytotoxic T-lymphocytes (CTLs)

Macrophage engulfing a Macrophage engulfing a bacillusbacillus

class I MHC antigen processing pathwayclass I MHC antigen processing pathway

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How tumour cells avoid How tumour cells avoid immunosurveillanceimmunosurveillance

Altering Their CharacteristicsAltering Their Characteristics : G : Generate variants lacking antigens enerate variants lacking antigens normally detected by CTL, NK cells and antibodies. Tumour cells may normally detected by CTL, NK cells and antibodies. Tumour cells may also lack co-stimulatory molecules, which activate T cells, and signaling also lack co-stimulatory molecules, which activate T cells, and signaling molecules needed to respond to cytokines, such as gamma-interferon, molecules needed to respond to cytokines, such as gamma-interferon, that promote tumour cell killing by immune mechanisms. that promote tumour cell killing by immune mechanisms.

Suppressing the Immune ResponseSuppressing the Immune Response : : Tumour cells inappropriate or Tumour cells inappropriate or ineffective signals to CTL, or secreting TGF-beta etcineffective signals to CTL, or secreting TGF-beta etc

Hiding from the Immune ResponseHiding from the Immune Response : : Immunoprivileged sitesImmunoprivileged sites Exploiting the Immune System's IgnoranceExploiting the Immune System's Ignorance: G: Growth without eliciting rowth without eliciting

any immune response. any immune response. Outpacing the Immune Response:Outpacing the Immune Response: Tumour cells can simply proliferate Tumour cells can simply proliferate

so quickly that the immune response is not fast enough to keep their so quickly that the immune response is not fast enough to keep their growth in checkgrowth in check

Immune escape mechanisms of tumour cellsImmune escape mechanisms of tumour cells

Downregulation or inactivation of any of the signalling cascade molecules leads to tumour cell death.However, tumour cell will not be recognised ifPeptides are not released from a protein orPeptides not loaded onto the MHC molecule Expression of Fas ligand on tumour cells may induce apoptosis in the specific T cell

ImmunotherapyImmunotherapy

Activating the Immune SystemActivating the Immune SystemNon-specific approachNon-specific approach

1892 - WB Coley observed tumour 1892 - WB Coley observed tumour regression after bacterial infectionsregression after bacterial infections

BCG vaccine to treat bladder carcinomaBCG vaccine to treat bladder carcinoma 1970-80’s – cytokines 1970-80’s – cytokines

includes interferons, interleukins and tumor includes interferons, interleukins and tumor necrosis factor (TNF)necrosis factor (TNF)

Limited success Limited success

Specific approach – The promise of Specific approach – The promise of antibody-based therapyantibody-based therapy

Search for tumour specific Search for tumour specific antigensantigens

Development of Development of monoclonal antibodiesmonoclonal antibodies

1975 Milstein and Kohler 1975 Milstein and Kohler developed hybridoma developed hybridoma technology technology antibody-producing cells antibody-producing cells

could be made to survive could be made to survive indefinitely if they were indefinitely if they were fused with cancer cellsfused with cancer cells

The problems of antibody-based The problems of antibody-based therapytherapy

virtually all these antigens are also found on virtually all these antigens are also found on normal cells!normal cells!

Ab therapy may still be used becauseAb therapy may still be used because the antigen in normal tissues may not be the antigen in normal tissues may not be

accessible to blood-borne antibodiesaccessible to blood-borne antibodies the cancer cells may express more antigen than the cancer cells may express more antigen than

normal cells donormal cells do antibody-induced injury of normal cells may be antibody-induced injury of normal cells may be

reversible.reversible.

Clinical trials – Ab-based therapyClinical trials – Ab-based therapy A33A33, a 43k glycoprotein with selective expression in normal , a 43k glycoprotein with selective expression in normal

and malignant epithelium of the (and malignant epithelium of the (gastrointestinal tractgastrointestinal tract)) G250G250, a glycoprotein expressed by a high percentage of renal , a glycoprotein expressed by a high percentage of renal

cancers; cancers; LewisY (LeY),LewisY (LeY), an oligosaccharide epitope expressed on an oligosaccharide epitope expressed on

glycolipids and glycoproteins by a wide range of glycolipids and glycoproteins by a wide range of epithelialepithelial cancers; cancers;

GD3GD3, a ganglioside with high expression in , a ganglioside with high expression in melanomamelanoma and and other neuroectodermal tumors; other neuroectodermal tumors;

FAP-alphaFAP-alpha, a 95 k glycoprotein strongly expressed in the , a 95 k glycoprotein strongly expressed in the stromal fibroblasts of stromal fibroblasts of epithelial cancersepithelial cancers; ;

Truncated EGF receptorTruncated EGF receptor, a 140 k form of the EGF receptor , a 140 k form of the EGF receptor (deleted in exons 2-7), which is expressed by a proportion of (deleted in exons 2-7), which is expressed by a proportion of brain cancersbrain cancers and other tumour types. and other tumour types.

antibodies have been genetically modified to provide chimeric (G250, GD3) or humanized (A33, LeY, F19) constructs

Adoptive immunotherapyAdoptive immunotherapy

stimulating T cells by exposing them to stimulating T cells by exposing them to tumour cells or antigens in the laboratory tumour cells or antigens in the laboratory and then injecting expanded populations of and then injecting expanded populations of the treated cells into patientsthe treated cells into patients

Patient is both donor and recepient Patient is both donor and recepient

Adoptive immunotherapyAdoptive immunotherapy

Generation of dendritic cell vaccines from peripheral blood monocytes:

1)Monocytes cultures with GM-CSF +IL-4 to produce DCs

2)Matured with CD40 ligand3)Pulsed with peptide or tumour lysate4)Re-injected as vaccine to induce T-cell immune

response against tumour

The Journal of Clinical Investigation Vol 113 Number 11 June 2004 pp 1515

Vaccine-based immunotherapy Vaccine-based immunotherapy

1940-50’s, tumour immunogeneity seen in mice1940-50’s, tumour immunogeneity seen in mice the tumors bore antigens that could immunize the tumors bore antigens that could immunize

other mice of the same strain against other mice of the same strain against transplants of the tumors. transplants of the tumors.

T lymphocytes from immunized animals could T lymphocytes from immunized animals could transfer immunity against tumours to healthy transfer immunity against tumours to healthy animals of the same strain. animals of the same strain.

T cells from the immunized mice could kill T cells from the immunized mice could kill tumour cells in vitro.tumour cells in vitro.

Antibodies failed to transfer immunity Antibodies failed to transfer immunity

VaccinesVaccines

Tumour-based vaccinesTumour-based vaccines Use whole cell/crude extracts of tumoursUse whole cell/crude extracts of tumours

Virus-based vaccines Virus-based vaccines Use of viral oncolysate e.g. Vaccinia viruses expressing Use of viral oncolysate e.g. Vaccinia viruses expressing

carcinoembryonic antigen (CEA) carcinoembryonic antigen (CEA) Peptide-based vaccines Peptide-based vaccines

tumour-associated antigens (TAAs) epitopes bound directly tumour-associated antigens (TAAs) epitopes bound directly to MHC on the cell surface can activate CTLsto MHC on the cell surface can activate CTLs

Others: Others: humoral responses e.g. Her2-neu, CEA, TP53, gangliosides humoral responses e.g. Her2-neu, CEA, TP53, gangliosides

administration of some form of antigen to induce a administration of some form of antigen to induce a specific antitumour immune response.specific antitumour immune response.

Approaches to antitumor vaccinationApproaches to antitumor vaccination

APC – antigen presenting cell TAA – tumour associated antigenDC – dendritic cell MHC – major histocompatibility complex

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Immunoconjugates Immunoconjugates RADIOACTIVE ISOTOPESRADIOACTIVE ISOTOPES: I: I131131 or yttrium 99 or yttrium 99 TOXINSTOXINS: Use of antibodies to deliver toxins to a tumor site. E.g. : Use of antibodies to deliver toxins to a tumor site. E.g.

ricin (made from castor beans), which inhibits protein synthesis and ricin (made from castor beans), which inhibits protein synthesis and thwarts tumor growth. thwarts tumor growth.

CHEMOTHERAPEUTIC DRUGSCHEMOTHERAPEUTIC DRUGS: Reach tumours in larger and : Reach tumours in larger and lethal doses when delivered by an antibody. lethal doses when delivered by an antibody.

ENZYMESENZYMES: convert "prodrugs" into cytotoxins will home to tumors : convert "prodrugs" into cytotoxins will home to tumors when attached to antibodieswhen attached to antibodies

GENETIC DRUGS: e.g. antisense DNA can be linked to antibodies GENETIC DRUGS: e.g. antisense DNA can be linked to antibodies directly or packageddirectly or packaged into viral particles engineered to have targeting into viral particles engineered to have targeting antibody on their surface. antibody on their surface.

INFLAMMATORY MOLECULESINFLAMMATORY MOLECULES: tumour necrosis factor (TNF) : tumour necrosis factor (TNF) and other messenger molecules of the immune system as well as and other messenger molecules of the immune system as well as certain microbial products, can bring about an inflammatory reaction certain microbial products, can bring about an inflammatory reaction that destroys tissues at the tumour site.that destroys tissues at the tumour site.

ImmunotherapyImmunotherapy

ImmunotherapyImmunotherapy

Hormone therapyHormone therapy

Hormone sensitive cancers (Breast cancer in females and Hormone sensitive cancers (Breast cancer in females and prostate cancer in males) are susceptible to deprivation of prostate cancer in males) are susceptible to deprivation of the corresponding mitogenic hormone. the corresponding mitogenic hormone.

Treatment of either involvesTreatment of either involves direct inhibition of steroid synthesis : E.g. using either LHRH direct inhibition of steroid synthesis : E.g. using either LHRH

superagonists or aromatase inhibitors in breast cancersuperagonists or aromatase inhibitors in breast cancer blocking their effects at the target cell level through the blocking their effects at the target cell level through the

receptors: Steroid receptor antagonists block receptor receptors: Steroid receptor antagonists block receptor activity. E.g. tamoxifen is an oestrogen receptor antagonist. activity. E.g. tamoxifen is an oestrogen receptor antagonist.

Problems with hormone therapy include sexual dysfunction Problems with hormone therapy include sexual dysfunction (e.g.ovulation), secondary cancers etc(e.g.ovulation), secondary cancers etc

Hormone therapyHormone therapy

ReferencesReferences Immunotherapy for cancer by Immunotherapy for cancer by L.J OldL.J Old

Scientific American (Sept 1996) pg 102Scientific American (Sept 1996) pg 102

Tumours: Immunotherapy Tumours: Immunotherapy MP Rubinstein and D J Cole MP Rubinstein and D J Cole www.els.netwww.els.net

Progress on new vaccine strategies for the Progress on new vaccine strategies for the immunotherapy and prevention of cancer immunotherapy and prevention of cancer

Jay A. Berzofsky, et alJay A. Berzofsky, et al The Journal of Clinical The Journal of Clinical InvestigationInvestigation Volume 113 Number 11 Volume 113 Number 11 June 2004June 2004 1515-15251515-1525