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Newer cancer therapies Immunotherapy. Immunotherapy Non-specific immunotherapy Non-specific immunotherapy BCG BCG Cytokines Cytokines Specific immunotherapy.

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Presentation on theme: "Newer cancer therapies Immunotherapy. Immunotherapy Non-specific immunotherapy Non-specific immunotherapy BCG BCG Cytokines Cytokines Specific immunotherapy."— Presentation transcript:

1 Newer cancer therapies Immunotherapy

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5 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

6 Key immune cells in cancer The main immune cells that play a role in the protection against tumours and their rejection are Cytotoxic T-lymphocytes (CTLs) Cytotoxic T-lymphocytes (CTLs) MHC restricted - recognize only small endogenously processed protein fragments (peptides) that must be presented in a surface protein called the major histocompatibilty complex (MHC) MHC restricted - recognize only small endogenously processed protein fragments (peptides) that must be presented in a surface protein called the major histocompatibilty complex (MHC) Natural Killer (NK) cells: Natural Killer (NK) cells: toxicity without prior sensitization and without MHC restriction. Usually activated when T cells cannot be activated toxicity without prior sensitization and without MHC restriction. Usually activated when T cells cannot be activated Macrophages: Macrophages: usually activated by bacterial / viral infections leading to tumour cell death usually activated by bacterial / viral infections leading to tumour cell death Stimulates secretion of the tumour necrosis factor (TNF) Stimulates secretion of the tumour necrosis factor (TNF)

7 Cytotoxic T-lymphocytes (CTLs) Macrophage engulfing a bacillus

8 class I MHC antigen processing pathway The Journal of Clinical Investigation Vol 113 Number 11 June 2004 pp 1515

9 How tumour cells avoid immunosurveillance Altering Their Characteristics : Generate variants lacking antigens normally detected by CTL, NK cells and antibodies. Tumour cells may also lack co-stimulatory molecules, which activate T cells, and signaling molecules needed to respond to cytokines, such as gamma-interferon, that promote tumour cell killing by immune mechanisms. Altering Their Characteristics : Generate variants lacking antigens normally detected by CTL, NK cells and antibodies. Tumour cells may also lack co-stimulatory molecules, which activate T cells, and signaling molecules needed to respond to cytokines, such as gamma-interferon, that promote tumour cell killing by immune mechanisms. Suppressing the Immune Response : Tumour cells inappropriate or ineffective signals to CTL, or secreting TGF-beta etc Suppressing the Immune Response : Tumour cells inappropriate or ineffective signals to CTL, or secreting TGF-beta etc Hiding from the Immune Response : Immunoprivileged sites Hiding from the Immune Response : Immunoprivileged sites Exploiting the Immune System's Ignorance: Growth without eliciting any immune response. Exploiting the Immune System's Ignorance: Growth without eliciting any immune response. 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 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 Immune 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 if Peptides are not released from a protein or Peptides not loaded onto the MHC molecule Expression of Fas ligand on tumour cells may induce apoptosis in the specific T cell

11 Immunotherapy

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

13 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

14 The problems of antibody-based therapy virtually all these antigens are also found on normal cells! virtually all these antigens are also found on normal cells! Ab therapy may still be used because Ab therapy may still be used because the antigen in normal tissues may not be accessible to blood-borne antibodies the antigen in normal tissues may not be accessible to blood-borne antibodies the cancer cells may express more antigen than normal cells do the cancer cells may express more antigen than normal cells do antibody-induced injury of normal cells may be reversible. antibody-induced injury of normal cells may be reversible.

15 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

16 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

17 Adoptive 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 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

18 Vaccine-based immunotherapy 1940-50s, tumour immunogeneity seen in mice 1940-50s, tumour immunogeneity seen in mice the tumors bore antigens that could immunize other mice of the same strain against transplants of the tumors. the tumors bore antigens that could immunize other mice of the same strain against transplants of the tumors. T lymphocytes from immunized animals could transfer immunity against tumours to healthy animals of the same strain. T lymphocytes from immunized animals could transfer immunity against tumours to healthy animals of the same strain. T cells from the immunized mice could kill tumour cells in vitro. T cells from the immunized mice could kill tumour cells in vitro. Antibodies failed to transfer immunity Antibodies failed to transfer immunity

19 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.

20 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

21 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 thwarts tumor growth. TOXINS: Use of antibodies to deliver toxins to a tumor site. E.g. ricin (made from castor beans), which inhibits protein synthesis and thwarts tumor 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.

22 Immunotherapy

23 Immunotherapy

24 Hormone therapy Hormone sensitive cancers (Breast cancer in females and prostate cancer in males) are susceptible to deprivation of the corresponding mitogenic hormone. Treatment of either involves direct inhibition of steroid synthesis : E.g. using either LHRH superagonists or aromatase inhibitors in breast cancer direct inhibition of steroid synthesis : E.g. using either LHRH superagonists or aromatase inhibitors in breast cancer blocking their effects at the target cell level through the receptors: Steroid receptor antagonists block receptor activity. E.g. tamoxifen is an oestrogen receptor antagonist. blocking their effects at the target cell level through the receptors: Steroid receptor antagonists block receptor activity. E.g. tamoxifen is an oestrogen receptor antagonist. Problems with hormone therapy include sexual dysfunction (e.g.ovulation), secondary cancers etc

25 Hormone therapy

26 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 Tumours: Immunotherapy MP Rubinstein and D J Cole www.els.net MP Rubinstein and D J Cole www.els.netwww.els.net Progress on new vaccine strategies for the immunotherapy and prevention of cancer Progress on new vaccine strategies for the immunotherapy and prevention of cancer Jay A. Berzofsky, et al The Journal of Clinical Investigation Volume 113 Number 11 June 2004 1515-1525 Jay A. Berzofsky, et al The Journal of Clinical Investigation Volume 113 Number 11 June 2004 1515-1525


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