Immunotherapy and cancer

These slides provide an overview of immunotherapy in cancer

Dr. Momna Hejmadi, University of Bath

N.B. Some images used in these slides are from the textbooks listed and are not covered under the Creative Commons license as yet

This resource created by Dr. Momna Hejmadi, University of Bath, 2010, is licensed under the Creative Commons Attribution-Non-Commercial-Share Alike 2.0 UK: England & Wales License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/2.0/uk/

Newer cancer therapiesNewer cancer therapies

IMMUNOTHERAPY IMMUNOTHERAPY

CD4+ CD8+

77thth hallmark of cancer? hallmark of cancer?Avoidance of immunosurveillanceAvoidance of immunosurveillance

Nature Reviews Immunology 6, 715-727 (October 2006)

Macrophage digesting a human prostate cancer cellMacrophage digesting a human prostate cancer cell

Nature Protocols 1, 928 - 935 (2006)

J. Clin. Invest. 117(5): 1137-1146 (2007).

How tumour cells avoid immunosurveillanceHow tumour cells avoid immunosurveillance

How tumour cells avoid immunosurveillanceHow tumour cells avoid immunosurveillancecells escape innate and adaptive immune response by immunoselection/ editing (selection of non-

immunogenic tumour-cell variants) by immunosubversion (that is, active suppression

of the immune response) By Hiding from the Immune Response:

immunoprivileged sites By Outpacing the Immune Response: Tumour cells

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

Impact of conventional anticancer therapies on Impact of conventional anticancer therapies on immune responses.immune responses.

J. Clin. Invest. 118(6): 1991-2001 (2008).

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

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

1892 - WB Coley observed tumour regression 1892 - WB Coley observed tumour regression after bacterial infectionsafter 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

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 cultured with GM-CSF +IL-4 to produce DCs2) 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

VaccinesVaccines

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

Virus-Virus-based vaccines 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) PeptidePeptide-based vaccines -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

OthersOthers 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

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

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. ricin : Use of antibodies to deliver toxins to a tumor site. E.g. ricin

(made from castor beans), which inhibits protein synthesis and (made from castor beans), which inhibits protein synthesis and stops tumour growth. stops tumour growth.

CHEMOTHERAPEUTIC DRUGSCHEMOTHERAPEUTIC DRUGS: Reach tumours in larger and lethal : Reach tumours in larger and lethal doses when delivered by an antibody. 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: GENETIC DRUGS: e.g. antisense DNA can be linked to antibodies e.g. antisense DNA can be linked to antibodies directly or packaged into viral particles engineered to have targeting directly or packaged into viral particles engineered to have targeting antibody on their surface. antibody on their surface.

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

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

malignant epithelium of the (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 glycolipids an oligosaccharide epitope expressed on glycolipids

and glycoproteins by a wide range of 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 other and other

neuroectodermal tumors; neuroectodermal tumors; FAP-alphaFAP-alpha, a 95 k glycoprotein strongly expressed in the stromal , a 95 k glycoprotein strongly expressed in the stromal

fibroblasts of 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

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

Nature Reviews ImmunologyNature Reviews Immunology 6, 715-727 (October 6, 715-727 (October 2006) 2006)