Immunotherapy and cancer

1. Immunotherapy and cancer These slides provide an overview of immunotherapy in cancer Dr. Momna Hejmadi, University of Bath 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/ N.B. Some images used in these slides are from the textbooks listed and are not covered under the Creative Commons license as yet

2. Newer cancer therapiesIMMUNOTHERAPY

4. CD4+ CD8+

6. 7th hallmark of cancer? Avoidance of immunosurveillance Nature Reviews Immunology6, 715-727(October 2006)

7. Nature Protocols 1, 928 - 935 (2006) Macrophage digesting a human prostate cancer cell

8. J. Clin. Invest.117(5): 1137-1146 (2007). How tumour cells avoid immunosurveillance

9. 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

10. Impact of conventional anticancer therapies on immune responses. J. Clin. Invest. 118(6): 1991-2001 (2008).

11. Non-specific immunotherapy BCG 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 Immunotherapy

12. Activating the Immune SystemNon-specific approach • 1892 - WB Coley observed tumour regression after bacterial infections • BCG vaccine to treat bladder carcinoma • 1970-80’s – cytokines • includes interferons, interleukins and tumor necrosis factor (TNF) • Limited success

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

14. 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 • Patient is both donor and recepient

15. Adoptive immunotherapy The Journal of Clinical Investigation Vol 113 Number 11 June 2004 pp 1515 • Generation of dendritic cell vaccines from peripheral blood monocytes: • Monocytes cultured with GM-CSF +IL-4 to produce DCs • Matured with CD40 ligand • Pulsed with peptide or tumour lysate • Re-injected as vaccine to induce T-cell immune response against tumour

16. Vaccines administration of some form of antigen to induce a specific antitumour immune response. • Tumour-based vaccines • Use whole cell/crude extracts of tumours • Virus-based vaccines • Use of viral oncolysate e.g. Vaccinia viruses expressing carcinoembryonic antigen (CEA) • Peptide-based vaccines • tumour-associated antigens (TAAs) epitopes bound directly to MHC on the cell surface can activate CTLs • Others • humoral responses e.g. Her2-neu, CEA, TP53, gangliosides

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

18. Immunoconjugates • RADIOACTIVE ISOTOPES: I131 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. • 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 • 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.

19. Clinical trials – Ab-based therapy • 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; • 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; • 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. antibodies have been genetically modified to provide chimeric (G250, GD3) or humanized (A33, LeY, F19) constructs

20. References • Immunotherapy for cancer by L.J Old • Scientific American (Sept 1996) pg 102 • Tumours: Immunotherapy by MP Rubinstein and D J Cole www.els.net • Nature Reviews Immunology 6, 715-727 (October 2006)