Breakthrough in genetic and cellular therapy in cancer

There is a recent breakthrough in genetic and cell therapy that could lead to a dramatic difference in the management of cancers; A team from University of Pennsylvania have been able to genetically modify the T cells of patients with B cell Chronic Lymphocytic Leukemia with a “chimeric antigen receptor” CAR targeting a CD 19 molecule on CLL cells.

How the therapy works:

  • Autologous T cells are immune cells taken from a
    patient’s own blood stream. These cells are then modified to express an
    antibody on their surface that will recognize and bind to a protein called
    CD19. (the genetic engineering bit)
  • This CD19 protein is on most B-cell CLL cells
    and B-cell non-Hodgkin lymphoma (NHL) cells.
  • These modified T cells are then grown (expanded)
    in the laboratory and given back to patients in an attempt to treat their
    leukemia. (the cell therapy bit)
  • When the patient’s own T-cells recognize and
    bind to the CLL cell, they have the ability to become activated and kill the
    leukemia cell. {{{0}}}

Initial Results

While only treated a small number of patients, the results were a breakthrough:

  • That a patient’s modified T-cells can survive
    for many months after administration, and have the ability to grow in the body
    in large quantities.
  • And they have been able to kill large quantities
    of CLL cells in all 3 patients treated.
  • Unfortunately, as CD19 antigen is expressed even
    in normal B lymphocyte cells, new clones of normal B cells that replace the B
    CLL cells are also killed and thus patients require immune support for the
    length of the observed successful treatment period, in one patient as long as
    one year. The investigators are now watching if the modified T cells will
    diminish and disappear over time since the work has been done. It is also not
    clear if the effect will last after that.

Another approach to modify the T cells is been explored in Israel at the lab of Vaxil Biotherapeutics where a breakthrough technology is applied to produce T cell therapeutic and preventive cancer vaccine.

 

The thrust of the technology is to identify good target cancer antigen and manipulate it with genetic engineering to reactivate the cell mediated immune response that have been obtunded by cancer cells.:Elicit the needed T-helper immune modulating response via the interaction of cancer antigen with MHC Class II surface antigen on antigen presenting cells such as dendritic cells that allows the complex interaction with CD4 T helper cells. The activation of these cells is

needed to provide the appropriate signals via cytokines to mobilise and activate the T cytotoxic cells. Foreign or invading antigens are processed after combining with ubiquitin in the cytoplasm by proteosome and would usually break the antigen to the TH via the endosomes and CTL epitopes via the endoplasmic reticulum to be combined with MHC Class II and Class I respectively.

  1. Elicit the T cytotoxic cells activation via expression of the canc er antigen with MHC Class I on the DC surface that allows recognition by T cytotoxic cells that will expand and activate leading to the lysis of target cells. The processing of the CTL epitopes in the endoplasmic
    reticulum is mediated by either Transport Associated Antigen Processing peptide
    (TAP) dependent or non TAP dependent channels. Many cancer cells are able to
    escape CTL immune response by modify the TAP channel.

The unique technology of Vaxil is in the antigen used as the cancer vaccine. The MU1 antigen that is expressed in more than 90% of solid and non-solid cancers. The first indication is in multiple myeloma. Trial started in September 2010 at the Hadassah Medical Center in Jerusalem under the
direction of Dr Michael Shapira.

Unlike the CAR approach, the T cells are not genetically engineered to express anti CD19 on their surface. The unique genetically engineered cancer antigen enhances the T cell immune response by a better Antigen Presenting and processing technology that would reactivate the body’s  own immune response; The breakthrough is in obliterating the mechanism to obtund the natural T cell mediated immune response by the cancer cells through its unique antigen presenting and processing technology.

The unique characteristic of the target antigen

  • The target antigen is the basis for every vaccine and will dictate its efficacy more than the delivery system or the adjuvant.
  • The immune system (in particular T cells) recognize the target antigen via binding to a set of molecules called MHC class I and MHC class II. There are hundreds of different types and  every individual has a different set of between 6 and 12 individual MHC molecules.
  • For a therapeutic vaccine to work it must be able to find and bind these MHC molecules which vary widely amongst different people.

There are 2 approaches:

  • Approach 1: use the entire antigen/pathogen/cancer cell as statistically this should bind an individual’s set of MHC molecules. However, this significantly reduces the specificity of  the immune response which may lead to reduced efficacy and higher side-effects.
  • Approach 2: identify a small section of the target antigen that bind to a single MHC molecule. This leads to a specific but weak immune response, applicable only to a small proportion of the population.
  • Vaxil offers a third revolutionary combined approach – VaxHit – which identifies and uses the  Key sequence of the target antigen which has the following major advantages:
    • Small & defined sequences which generate a highly specific immune response with less likelihood of side-effects.
    • Binds a very large proportion of the potential combinations of an individual’s MHC molecules. Hence it is more potent and applicable for the majority of the population and will thus be more effective.

The VaxHit technology can identify potential vaccines for many indications (cancer and infectious diseases). VaxHit vaccines have the unique ability to overcome the tumor/pathogens ability to evade and resist the efforts of the immune system to eliminate them. This is called the TAP
deficiency.

VaxHit vaccines are potent without a dedicated delivery system or adjuvant and are non TAP dependent.

Sources:

  1. http://penncancer.org/cart-19
  2. http://unitedwithisrael.org/israel-develops-cancer-vaccine/

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