Selective Targeted Therapy Designed To Destroy Cancer Cells

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Selective Targeted Therapy Designed To Destroy
Cancer Cells

• Prof.Motawa E.El-houseini

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Introduction

• Surgery , radiation and chemotherapy have led to
  increase survival rates for certain types of
  cancer. However, there are some types of cancer
  e.g. lung and G.I.T (liver cancer) cancers often
  do not respond well to such type of treatment ,in
  addition to the marked side effects that have
  been observed.Therefore additional cancer therapy
  is strongly recommended.The latter should be
  targeting therapy based on biochemical and
  biological approach.
• Novel promissing biological biochemical therapy
  for cancer
• 1-Bio-immunotherapy.
• 2-Anti-angiogenesis anti-metastasis inducer
  biomolecules.
• 3-Apoptosis inducer therapy.
• 4-Gene therapy 5-differentiation inducer
  therapy

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Prospects promissing Novel Therapy for cancer

• The rationale underlying this approach, called
  Immunotherapy one of the biological therapy
  approach. The former depends on the recognition
  of the tumor cells by the immune system, since
  tumor cells tend to exhibit cell surface antigens

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P. Lymphocytes

• Steven Rosenberg is a pioneer for attempting to
  utilize a persons own lymphocytes to destroy
  cancer cells
• He isolated lymphocytes from the blood of cancer
  patients and treated with IL-2(LAK cells)
• The latter were injected back into the patients
  from whom they were obtained

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P.Lymphocytes

• He observed tumor regression that occurred in
  about 20 of the patients
• This modest success led to the search for
  lymphocytes that were even more effective at
  killing cancer cellls

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Tumor infiltrating Lymphocytes (TILs)

• To achieve the previous aim, special lymphoid
  cells have been isolated from the tumor tissues
  themselves
• The latter suppose to have the highest
  concentration of lymphocytes ,that were therefore
  isolated from the tumors of cancer patients and
  grown in culture with IL-2 to stimulate the
  growth and cancer destroying properties of the
  cells.

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TILs

• TILs are isolated Killer T cells that are
  specifically targeted against the patients tumor
• It has been shown that 50 of cases showed tumor
  regression due to the TILs injection back into
  the patients from whom they were obtained

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Lymphocytes Activated killer cell (LAK) and TILS

• Both cell types are active lymphoid cells.
• TILs have an advantage over LAKs that they
• Possess a highly specific cytotoxcity against
  tumor cells (autologous type)
• A cell mixed culture of both previous mentioned
• Cells could enhance the the cytotoxcity of TILs
• Against tumor cells.

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TILS AS TARGETED THERAPY

• In a clinical trial to make TILs even more
  effective at killing cancer .Cells, recombinant
  DNA technique have been used so as to insert
  genes designed to enhance the therapeutic potency
  of the TILs e.g. TNF-a gene others.

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Design Targeted cancer Therapy

• It is exciting to see cancer therapies being
  developed that are based on a logical rationale
  for selectively destroying cancer cells depending
  on the recognition of Immune system

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• -Effector T cells fall into two subpopulations-
• Based on cytokine secretion i.e. type 1 cells
  secrete IFN-Gamma where as type 2
• cells secrete IL-4,IL-10 and GM-CSF..
• -NKCs represent a third subpopulation that
  secretes similar cytokines....

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Dendritic cell(DC)

• IT is the strongest antigen presenting cell(APC)
  .IT can present antigen to T lymphocytes in vivo
  and in vitro and induce cytotoxic T
  lymphocytes(CTL) reactions
• DCs were isolated from peripheral blood of the
  patients.
• DCs were stimulated by IL-4, Gm-CSF and tumor
  antigen.
  

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TILS and DCs

• - Co-cultivation of TILS and DCs could lead to
  cell population with very high killing activity
  against autogenous cancer cells -The killing
  rate was higher than that of TILs not
  stimulated by DCs.

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-DCs

• DCs are key antigen presenting cells that play an
  essential role in initiating and directing
  cellular and humoral immunity including
  anti-tumor responses.
• -Due to their critical role in cancer, induction
• of DCs apoptosis may be one of the central
• Mechanisms used by tumors to evade immune
  recognition.

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Immune suppression

• Inhibition of CD8 T cell Function due to
• an accumulation of CD4 T reg. within the
  tumor.
• Foxp3 is a transcription factor that highly
• Expressed in the naturally occuring CD4
• CD25 but ,it is not expressed in naïve CD4 CD25

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Diagramatic Representation for prespective
selective Biological Therapy of Patient with
Liver Cancer
Remove more tumor sample and blood sample
Remove tumor sample
Infuse TILs into patient
Assay for the genes

Transduction with genes or activation with
deferent agents
Culture in media
Culture cells with IL-2
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CONCOLUSION

• 1- TILs can be used as specific biological
  therapy designed for selectively destroy cancer
  cells after characterization of their
  subpopulations and activation with different ways
• 2-TIls activity should be tested at two levels
  before clinical trials first ex-vivo level
• second in-vivo level using experimental animal
  model namely Nude Mice

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Refeneces

• -Specifity of tumor cell stimulation of DNA
• Ihibitory cytokine production in vitro
• Jorgen Killer and Motawa EL-Houseini
• Anticancer Research 1 235-242(1981)
• -Clinical study on adoptive immunotherapy
• of bone metastatic neoplasm with
• tumor infiltrating lymphocytes
• article in chinese (1994 )
• -Tumor Infiltrating Lymphocytes and continuous
  infusion
• IL-2 after metastasectomy.in
  melanoma,colorectal and renal carcinoma patients
• Muller Fabbri et al
• Tumori 86 46 -52 (2000)
• -Finding a place for tumor-specific T Cells in
  Targeted cancer therapy
• Stanley R.Riddell
• J. Exp. Medicin 200 1533- 1537 (2004
  )
• -Studies on the mechanism of action of tumor
  Infiltrating Lymphmocytes(TILS)
• propagated Ex-Vivo
• Motawa E. EL-Houseini et al
• J. OF The Eg. NCI 15 NO.1 61-64 (
  2003 )