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

Newer cancer therapies IMMUNOTHERAPY

CD4+CD8+

7 th hallmark of cancer? Avoidance of immunosurveillance Nature Reviews Immunology 6, (October 2006)

Macrophage digesting a human prostate cancer cell Nature Protocols 1, (2006)

J. Clin. Invest. 117(5): (2007). How tumour cells avoid immunosurveillance

cells 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 immune responses. J. Clin. Invest. 118(6): (2008).

Immunotherapy Non-specific immunotherapy Non-specific immunotherapy BCG BCG Cytokines Cytokines Specific immunotherapy Active immunotherapy Antibody therapy Adoptive transfer of T cells Vaccine-based immunotherapy Tumour-based vaccines Virus-based vaccines Peptide-based vaccines others

Activating the Immune System Non-specific approach WB Coley observed tumour regression after bacterial infections WB Coley observed tumour regression after bacterial infections BCG vaccine to treat bladder carcinoma BCG vaccine to treat bladder carcinoma ’s – cytokines ’s – cytokines includes interferons, interleukins and tumor necrosis factor (TNF) includes interferons, interleukins and tumor necrosis factor (TNF) Limited success Limited success

Specific approach – The promise of antibody-based therapy Search for tumour specific antigens Search for tumour specific antigens Development of monoclonal antibodies Development of monoclonal antibodies 1975 Milstein and Kohler developed hybridoma technology 1975 Milstein and Kohler developed hybridoma technology antibody-producing cells could be made to survive indefinitely if they were fused with cancer cells antibody-producing cells could be made to survive indefinitely if they were fused with cancer cells

Adoptive immunotherapy stimulating T cells by exposing them to tumour cells or antigens in the laboratory and then injecting expanded populations of the treated cells into patients stimulating T cells by exposing them to tumour cells or antigens in the laboratory and then injecting expanded populations of the treated cells into patients Patient is both donor and recepient Patient is both donor and recepient

Adoptive immunotherapy Generation of dendritic cell vaccines from peripheral blood monocytes: 1)Monocytes cultured with GM-CSF +IL-4 to produce DCs 2)Matured with CD40 ligand 3)Pulsed with peptide or tumour lysate 4)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

Vaccines Tumour-based vaccines Tumour-based vaccines Use whole cell/crude extracts of tumours Use whole cell/crude extracts of tumours Virus-based vaccines Virus-based vaccines Use of viral oncolysate e.g. Vaccinia viruses expressing carcinoembryonic antigen (CEA) Use of viral oncolysate e.g. Vaccinia viruses expressing carcinoembryonic antigen (CEA) Peptide-based vaccines Peptide-based vaccines tumour-associated antigens (TAAs) epitopes bound directly to MHC on the cell surface can activate CTLs tumour-associated antigens (TAAs) epitopes bound directly to 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 specific antitumour immune response.

Approaches to antitumor vaccination APC – antigen presenting cellTAA – tumour associated antigen DC – dendritic cellMHC – major histocompatibility complex The Journal of Clinical Investigation Vol 113 ( 11) June 2004 pp 1515

Immunoconjugates RADIOACTIVE ISOTOPES: I 131 or yttrium 99 RADIOACTIVE ISOTOPES: I 131 or yttrium 99 TOXINS: Use of antibodies to deliver toxins to a tumor site. E.g. ricin (made from castor beans), which inhibits protein synthesis and stops tumour growth. TOXINS: Use of antibodies to deliver toxins to a tumor site. E.g. ricin (made from castor beans), which inhibits protein synthesis and stops tumour growth. CHEMOTHERAPEUTIC DRUGS: Reach tumours in larger and lethal doses when delivered by an antibody. CHEMOTHERAPEUTIC DRUGS: Reach tumours in larger and lethal doses when delivered by an antibody. ENZYMES: convert "prodrugs" into cytotoxins will home to tumors when attached to antibodies ENZYMES: convert "prodrugs" into cytotoxins will home to tumors when attached to antibodies GENETIC DRUGS: e.g. antisense DNA can be linked to antibodies directly or packaged into viral particles engineered to have targeting antibody on their surface. GENETIC DRUGS: e.g. antisense DNA can be linked to antibodies directly or packaged into viral particles engineered to have targeting antibody on their surface. INFLAMMATORY MOLECULES: tumour necrosis factor (TNF) and other messenger molecules of the immune system as well as certain microbial products, can bring about an inflammatory reaction that destroys tissues at the tumour site. INFLAMMATORY MOLECULES: tumour necrosis factor (TNF) and other messenger molecules of the immune system as well as certain microbial products, can bring about an inflammatory reaction that destroys tissues at the tumour site.

Clinical trials – Ab-based therapy A33, a 43k glycoprotein with selective expression in normal and malignant epithelium of the (gastrointestinal tract) A33, a 43k glycoprotein with selective expression in normal and malignant epithelium of the (gastrointestinal tract) G250, a glycoprotein expressed by a high percentage of renal cancers; G250, a glycoprotein expressed by a high percentage of renal cancers; LewisY (LeY), an oligosaccharide epitope expressed on glycolipids and glycoproteins by a wide range of epithelial cancers; LewisY (LeY), an oligosaccharide epitope expressed on glycolipids and glycoproteins by a wide range of epithelial cancers; GD3, a ganglioside with high expression in melanoma and other neuroectodermal tumors; GD3, a ganglioside with high expression in melanoma and other neuroectodermal tumors; FAP-alpha, a 95 k glycoprotein strongly expressed in the stromal fibroblasts of epithelial cancers; FAP-alpha, a 95 k glycoprotein strongly expressed in the stromal fibroblasts of epithelial cancers; Truncated EGF receptor, a 140 k form of the EGF receptor (deleted in exons 2-7), which is expressed by a proportion of brain cancers and other tumour types. Truncated EGF receptor, a 140 k form of the EGF receptor (deleted in exons 2-7), which is expressed by a proportion of brain cancers and other tumour types. antibodies have been genetically modified to provide chimeric (G250, GD3) or humanized (A33, LeY, F19) constructs

References Immunotherapy for cancer by L.J Old Immunotherapy for cancer by L.J Old Scientific American (Sept 1996) pg 102 Scientific American (Sept 1996) pg 102 Tumours: Immunotherapy by MP Rubinstein and D J Cole Tumours: Immunotherapy by MP Rubinstein and D J Cole Nature Reviews Immunology 6, (October 2006) Nature Reviews Immunology 6, (October 2006)