بسم ا الرحمن الرحـــــيم
TUMOUR VACCINES Review of current status Dr. Akram Al-Hilali 2009
08/16/14
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?WHAT IS A VACCINE Complete organism, cell or antigens thereof given to challenge the immune system and start, or boost, its action against that organism or cell. 08/16/14
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VACCINATION FOR CANCER Not prophylactic (mostly) Vaccines are given to recruit the help of the immune system to eliminate an existing tumour or prevent recurrence of a tumour treated with cytotoxic means. They are called vaccines because they challenge the immune system to help.
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ESSENTIAL QUESTION CAN THE BODY IMMUNE SYSTEM BE USED TO ELIMINATE, IN A NATURAL WAY, EXISTING CANCER OR PREVENT ITS RELAPSE AFTER ?SUCCESSFUL CHEMOTHERAPY
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SECOND QUESTION IF THE IMMUNE SYSTEM OF A PATIENT HAS ALLOWED THE CANCER TO ARISE AND GET ESTABLISHED, HOW COULD IT BE USED TO ELIMINATE IT? IN OTHER WORDS, HOW DID THE TUMOUR EVADE THE IMMUNE SURVEILANCE OF THE PATIENT IN THE FIRST PLACE? 08/16/14
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?ARE TUMOURS IMMUNOGENIC Do tumour cells carry antigens that are different from normal counterpart cells in the body? If they do, then why did the immune cells not attack them initially? If they don’t, then how can the immune system be induced to attack such cells? 08/16/14
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REASONS FOR FAILURE OF THE IMMUNE SYSTEM TO RESPOND TO TUMOURS
Weak immune system (suppression or deficiency) Weak antigenicity of the tumour (mostly selfantigens with little change). Lack of certain surface molecules needed for APC to recognize and T lymphocyte to be stimulated to kill.(e.g. the co-stimulatory molecules CD80 and CD86 on APC in CLL & CML) Low cytokines or abnormal mix of cytokines 08/16/14
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REASONS FOR FAILURE OF THE IMMUNE .SYSTEM TO RESPOND TO TUMOURS -Contd Modulation by chemical or virus. Suppression by factors secreted by the tumour. Immune tolerance gradually developing towards the established cancer. Depressed APC’s. All these weaknesses should be overcome for a vaccine to work.
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TUMOUR-INDUCED IMMUNE TOLERANCE
One explanation why immune system does not respond properly to tumours was shown in experiments: CD4+ cells change from naive to active in presence of tumour and then become inactive, as if they have started to recognize the tumour as “self”. APC process the tumour antigens and present them to T lymphocytes that become gradually tolerant. This tolerance should first be overcome for any vaccine to work. 08/16/14
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PHENOMENA SUGGESTING THAT IMMUNE SYSTEM PLAYS ANTI-CANCER ROLE
Higher cancer rate in the elderly Higher cancer rate in the immune-suppressed Higher cancer rate in the immune-deficient Some tumours are infiltrated by CD3 or B lymphocytes (Tumor infiltrating lymphocytes). Some tumours regress spontaneously (Melanoma, choriocarcinma) Increased relapse rate of leukaemia when BM is purged for T lymphocytes before transplantation Less relapse rate in allogeneic vs. autologous BMT. 08/16/14
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ENDOGENOUS IMMUNE RESPONSE TO TUMOURS
May not be detectable Does not seem to prevent growth of tumour, even if elicited. In cases where the immune response is detected, it may be playing a role in partial retardation of growth In the absence of sound immune system the growth could have been more vigorous. It is also possible that a large number of people get rid of their tumour cells early by immune response and tumour never establishes. Some controls do give positive results with antibodies or activated T lymphocytes against tumour antigens. 08/16/14
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CANCER PATIENTS PRODUCE ENDOGENOUS ANTIBODIES
Natural HER-2/neu antibodies in 14% of patients with colorectal cancer. Negative in controls who have no cancer. Significantly higher in those with over-expression of HER-2 on tumour cells. It also shows in some breast cancers (30%) B cell infiltration and antibodies in some breast cancers Anti-viral antibodies produced when viral antigens are part of the tumour antigens
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IMMUNOTHERAPEUTICS FOR CANCER, past and present
Coley’s vaccine (bacterial extract) used for cancer management in the late 19th century Tumour lysate or killed tumour cells + adjuvant used later in the 20th century. In 1960’s :influenza virus infected tumour cells were injected after lysing (Lindenman & Klein) BCG therapy in CML. BCG is included within some current CML vaccines. Successful use of mAbs (anti CD20, rituximab) for B-NHL Promising effect of Trastuzamab for breast cancer. Anti-TMEFF2 antibodies against prostate cancer Antileukaemic effect of donor lymphocytes injection (DLI) after BMT and PBSCT Blood Tx causes drop in leukemic cell count prior to any therapy in some leukemic patients. 08/16/14
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WILL CANCER PATIENTS ?RESPOND TO VACCINES
In other words, is the immune system sound in cancer patients? Response of most cancer patients to new antigen (primary immune response) not different from normal controls. Response to recall antigens (secondary immune response) not different from normal controls in most cancer patients Many cancer patients do have CTL, helper T cells and antibodies directed against some of the antigens in their tumours, regardless of vaccination.
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CANCER ANTIGENS Examples
Two melanoma antigens (MAGE & MART) CEA PSA HER-2 (in 20% of adenocarcinomas and breast cancers)
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P53 Ras Muc-1 in adenocarcinoma Viral antigens like EBV and HPV Jak-2
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Cancer Antigens More than 500 such antigens have now been discovered, mainly by T cell clones derived from cancer patients. Their categories are:
Differentiation
antigens Mutation, fusion and splice variant antigens Amplified or over-expressed antigens Cancer Testis (CT) antigens- expressed only in normal germ line cells and cancer cells Viral antigens produced by viruses incorporated in tumors. 08/16/14
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CNCER ANTIGENS EXAMPLES OF EACH CATEGORY 1. Differentiation: Melanin, Cytokeratin 2. Antigens of modified genes Unique: antigen of bcr-abl fusion gene of CML, DEK-CAN fusion peptide from t(6;9) in some AML, AML/ETO rearrangement protein in some AML, AML/RAR alpha rearrangement protein in PML and rearrangement in Ig genes in B cell lymphoma and myeloma (idiotype) Shared: MAGE, BAGE, LAGE and GAGE- especially expressed in myeloma and some in melanoma 3. Overexpressed:(PR3) of neutrophils in AML and CML. WT-1 in most leukemias. Mucin-1 in solid epithelial tumours. 4. Cancer Testis: (CT) like carcino-embryonic antigen. 5. Virus-associated: EBV in tx-associated LPD. HPV in cervical cancer. These antigens are expressed by cancer, not necessarily the cause of the disease 08/16/14
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TUMOUR VACCINES GENERAL STRATEGIES FOR TUMOUR VACCINE FORMULATION
Recognize tumour antigen/s, preferably those involved in malignant transformation Make it more immunogenic by augmenting the antigen/s, using gene transmission. Add cytokines or cytokine gene to tumour cell or a bystander cell to produce cytokines Expose to APC (multiplied ex vivo), . Add CD4+ cells to the preparation. Inject the vaccine. Strategy allows use of antigen of autologous or allogeneic origin.
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IDEAL TUMOUR VACCINE
Should be able to produce active systemic immune response in the host. This immune response should be able to specifically reject the tumour. The response should not be directed against the normal counterpart cells in the body. The vaccine should produce long-lived memory protecting the patient from relapse of the cancer. No real breakthrough as yet in the field.
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TYPES OF VACCINES A. ANTIGEN-SPECIFIC
MUC-144 or cancer testis antigens Over-expressed PR-3 in AML. WT-1 vaccine for AML, CML and some solid tumours. PRAME antigen for AML PML-RAR α antigen for PML bcr-abl fusion gene(p210) with its specific amino acid sequence. 08/16/14
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B.TUMOUR-CELL-BASED VACCINES )POLYVALENT NON-ANTIGEN SPECIFIC(
Cells have normal as well as tumour specific antigens on surface. Response is supposed to be stronger to tumour selective antigens. Genetically altered tumour cells to augment or modify immunologically relevant antigens. Presently: Tumour cells are modified to secrete cytokines, express stronger antigens or express new antigens, like co-stimulatory or adhesion molecules. This kind of vaccine avoids relapse due to variation of antigen in type A vaccine ( immune escape) 08/16/14
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EXAMPLES OF TUMOUR CELLBASED VACCINES TRIED
Melacine Vaccine 2
cell lines lysed + Detox adjuvant. Approved for stage IV melanoma in Canada The cell line contains many melanoma antigens Same vaccine used for stage II resected
Plasmid Vaccines (intra-tumour) Allovectin
for melanoma (1% response) Leuvectin for renal cell carcinoma stage 0 or I
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C. DENDRITIC CELL BASED VACCINES
DC derived from peripheral blood mononuclears collected by apheresis and then cultured, or Derived from monocytes (CD14+) or stem cells (CD34+) cells The DC may be primed with Id and given several times. Transfer of genes encoding tumour antigens to DC. DC can be leukemic as in CML. Encouraging early clinical results. 08/16/14
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EXAMPLES OF DC-BASED VACCINES TRIED Against myeloma. Antigens added include MART-1, MAGE-3, gp-100 and tyrosinase. Against myeloma. Id added. Against glioma. Glioma peptides added. Against prostatic cancer. GM-CSF and PAP added.
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D. ANTI-IDIOTYPE VACCINES
Idiotype is specific in antigen. Anti-idiotype is specific part of antibody for the antigen (variable region) Anti-idiotype is used to identify the idiotype of the antigen and produce vaccine against it. Anti-idiotype vaccine in NHL- with KLH and GM-CSF adjuvants in some. Anti-idiotype vaccine for myeloma- with alum, IL-2 or GM-CSF added. 08/16/14
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E. DNA VACCINES
DNA molecules responsible for encoding the tumour antigens are desired to keep up the antigenicity of the tumour. These can be injected directly into the tumour or transferred by a vector virus. (Chicken pox and Fowl pox viruses have been successfully used). Bacteria have also been used as vectors Genes for cytokines can also be inserted to activate immune reaction. 08/16/14
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TRANSFERRED MOLECULES Genes for Cytokines Genes for MHC molecules Genes for other surface molecules
All can be transferred into tumour cells ex-vivo and then the cells are injected as vaccine, or can be transferred directly into the tumour (in vivo). Inflammatory reaction to the gene in modified cells release antigens to other, non transduced cells. They can be transferred to muscle or skin and then the antigen is released and taken by DC.
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ADOPTIVE IMMUNOTHERAPY ANOTHER VACCINE STRATEGY
Recently tried ex vivo approach by Ball and his group in California. AML cells with T cells obtained by aphaeresis from patient’s blood. IL-4 & GM-CSF added to the cells in culture leading to appearance of DC (differentiated from AML cells). Then IL-2 added to culture causing increase in CD3 cells. Pure T cells specific to AML stay in the culture. These T cells kill the AML cells in culture, autologous and others, which decrease gradually as T cells increase. T cells are then injected into patient. 08/16/14
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PROPHYLACTIC VACCINATION AGAINST CANCER
This is a field that is completely different from “Tumour vaccines” Vaccines are prophylactically given against viruses that are potentially oncogenic. Patient should not have been exposed to the virus before. HPV-16 is the latest example and has been reported to be successful. HBV vaccination is an older example. 08/16/14
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