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Newer cancer therapies Immunotherapy

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Presentation on theme: "Newer cancer therapies Immunotherapy"— Presentation transcript:

1 Newer cancer therapies Immunotherapy

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4 APC, including dendritic cells and macrophages

5 Immunotherapy Non-specific immunotherapy 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

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) 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: toxicity without prior sensitization and without MHC restriction. Usually activated when T cells cannot be activated Macrophages: usually activated by bacterial / viral infections leading to tumour cell death Stimulates secretion of the tumour necrosis factor (TNF) CTLs - recognize only small endogenously processed protein fragments (peptides) that must be presented in a surface protein called the major histocompatibilty complex (MHC) to be recognized. Therefore, T cells are ‘MHC restricted’ Cytotoxic T lymphocytes (CTL) recognize surface markers on other cells in the body that label those cells for destruction. In this way, CTLs help to keep virus-infected or malignant cells in check. Here, a smaller CTL (arrow) is attacking and killing a much larger influenza virus-infected target. The sequence represents 30 minutes elapsed time.

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

8 class I MHC antigen processing pathway
The class I MHC antigen processing pathway acting as an internal surveillance mechanism to detect any abnormal or foreign protein synthesized in the cell. Tumor antigens encoded in the endogenous DNA of the tumor cell, or encoded in a DNA plasmid or viral vector vaccine taken up by an APC, are synthesized and cleaved by the 26S proteasome into fragments that are transported by TAP, the transporter associated with antigen processing, into the endoplasmic reticulum, where they are loaded onto newly synthesized class I MHC molecules that transport them to the cell surface for recognition by the T cell receptor. 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. Suppressing the Immune Response : Tumour cells inappropriate or ineffective signals to CTL, or secreting TGF-beta etc Hiding from the Immune Response : Immunoprivileged sites 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 CTLs - recognize only small endogenously processed protein fragments (peptides) that must be presented in a surface protein called the major histocompatibilty complex (MHC) to be recognized. Therefore, T cells are ‘MHC restricted’

10 Immune escape mechanisms of tumour cells
Figure 1 Immune escape mechanisms of tumour cells. Recognition of tumour cells by T cells requires a tumour-associated peptide (pep) to be presentedby a major histocompatibility complex (MHC) molecule and recognition of this peptide–MHCcomplex by the T-cell receptor (TCR) and ligation withCD4/CD8 molecules. The TCR consists of an ab chain, and recognition leads to a signal through the CD3 complex (g, Z (two), d and x (two) chains). To activate the T cell, the signal needs to reach the nucleus through downstream molecules such as p56 lck, p59 fyn and zeta-associated protein of 70 kDa(ZAP-70). Downregulation or inactivation of any of the molecules involved in this cascade will prevent T-cell activation and lead to subsequent killing of the tumour cell. Inability to release peptides from a protein, or to load the peptide on the MHC molecule, will prevent recognition of the tumour cell. Finally, expression of Fas ligand on tumour cells may induce apoptosis (programmed cell death) in the specific T cell, which prevents the tumour cell from being eradicated. 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
WB Coley observed tumour regression after bacterial infections BCG vaccine to treat bladder carcinoma ’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 The problems of antibody-based therapy
virtually all these antigens are also found on normal cells! Ab therapy may still be used because the antigen in normal tissues may not be accessible to blood-borne antibodies the cancer cells may express more antigen than normal cells do 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) 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

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 Patient is both donor and recepient

17 Adoptive immunotherapy
The Journal of Clinical Investigation Vol 113 Number 11 June 2004 pp 1515 Generation of antitumor DC vaccines from peripheral blood monocytes. Elutriated monocytes from a leukapheresis are cultured with GM-CSF and IL-4 to produce DCs, which are then matured with CD40 ligand (CD40L) or other agents, pulsed with peptide or tumor lysate, or transduced with an expression vector and then injected into the patient as an autologous DC vaccine to induce a T cell immune response against the tumor. Generation of dendritic cell vaccines from peripheral blood monocytes: Monocytes cultures 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

18 Vaccine-based immunotherapy
’s, tumour immunogeneity seen in mice 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 cells from the immunized mice could kill tumour cells in vitro. Antibodies failed to transfer immunity chemicals or viruses induced tumors in mice, the tumors bore antigens that could immunize other mice of the same strain against transplants of the tumors. Subsequent studies showed that immune system cells known as T lymphocytes taken from immunized animals could transfer immunity against tumors to healthy animals of the same strain. And workers devised techniques to show that the T cells from the immunized mice could kill tumor cells grown in test tubes as well. In contrast, antibodies elicited by the tumor cells generally failed to transfer immunity or kill tumor cells.

19 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 Tumour example: colonic cancer recurrence risk reduced by 61% when injected with tumour-BCG follog operative surgery

20 Approaches to antitumor vaccination
Approaches to antitumor vaccination. (A) Irradiated tumor cells transduced with a viral gene transfer vector encoding a cytokine such as GM-CSF attract APCs (DCs) that acquire, process, and present tumor-associated antigens (TAAs) encoded by the vector in the context of MHC. (B) DCs can be directly loaded by incubation with tumor protein lysates or peptides with sequences based on expressed tumor antigens, or by viral gene transfer vectors expressing TAAs. (C) TAAs can be locally supplied to DCs by the direct injection of peptides, viral gene expression vectors, or naked DNA expression plasmids. DCs migrate to secondary lymphoid tissues where they present the antigen epitopes to T cells to generate an antitumor cytolytic T cell response. 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

21 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 thwarts tumor 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.

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 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
Scientific American (Sept 1996) pg 102 Tumours: Immunotherapy MP Rubinstein and D J Cole 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


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