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Potential New Stem Cell Approach to Fighting Cancer

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  • Michael Korns
    The immune system is a remarkable defense mechanism, able to defend the body against a lifetime s worth of pathogens and pathogen attractors -- bacteria and
    Message 1 of 1 , Mar 31, 2005
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      The immune system is a remarkable defense mechanism, able to defend
      the body against a lifetime's worth of pathogens and pathogen
      attractors -- bacteria and viruses, toxins and parasites, splinters
      and cuts -- everything, that is, except cancer. Although the immune
      system handles most of these disease-causing organisms and insults
      well, it does a poor job of suppressing the growth of tumors.

      A major goal of cancer immunotherapy has been to bolster the immune
      system by generating large numbers of white blood cells (T cells)
      that could specifically seek and destroy cancer cells. Now, two
      scientists from the California Institute of Technology have come up
      with a novel and promising approach to antitumor immunotherapy.
      Reporting in the online edition of the Proceedings of the National
      Academy of Sciences (http://www.pnas.org/papbyrecent.shtml), Lili
      Yang, a postdoctoral scholar, and David Baltimore, professor of
      biology, Caltech president, and Nobel Prize recipient, have developed
      a new methodology they are calling "instructive immunotherapy" that
      someday may fight human cancer.

      In mice and humans, hematopoietic stem cells (HSC) form both red
      blood cells and immune system cells. In mice, Yang and Baltimore
      succeeded in altering some HSCs so that they would generate specific
      kinds of T cells that aggressively attack and destroy specific cancer
      cells. Once the mouse immune system received this enhancement, it
      became able to generate its own cancer-specific T cells on a long-
      term basis. When helped by dendritic cells (another type of immune
      system cell) carrying a piece of the tumor's marker protein, the
      methodology achieved the complete elimination of large, established
      tumors. While the work is preliminary and was done with mice, says
      Baltimore, instructive immunotherapy could eventually be used for
      controlling the growth of tumors in humans.

      "We've achieved something that could one day prove important," says
      Baltimore, who was awarded the 1975 Nobel Prize in Physiology or
      Medicine, "but the first caveat is that this is all with mice, and
      mice are often not predictive of behavior in humans." Still, he
      notes, "everything we have done is in principle possible to do in
      humans, so we plan to try to develop a system for optimizing the
      ability to program human stem cells."

      Yang, a former graduate student of Dr. Baltimore, says current cancer
      strategies fall into two categories: developing a cancer vaccine, or
      developing a drug that can be given when cancer is diagnosed. "Our
      strategy is threefold," she says, "a combination of gene therapy,
      stem cell therapy, and immunotherapy. When these three methodologies
      work together, it is possible to provide life-long immunity."

      In addition to making billions of new blood cells each day, HSCs are
      responsible for providing immune protection of every cell type in the
      body. In fact, HSC transplants are routinely used to treat patients
      with cancers. In their case, Yang and Baltimore chose to manipulate
      HSCs for three reasons--because HSCs normally make T cells, they make
      them by the billions, and they exist in humans through their lifetime.

      The first step was to design a retrovirus vector that could deliver
      genes for both chains of the T cell receptor to HSCs. This was
      actually the key to the whole study. For this work, two vectors
      delivering two sets of genes were developed. The HSCs then gave rise
      to both of the major types of T cells known as CD4 helper cells and
      CD8 killer cells. Together, these two cell types can recognize the
      foreign nature of the test cancer cells used in the study and can
      kill them. The researchers were successful in programming up to a
      quarter of the mouse's T cells to react to the model tumor. Even
      better, once modified, the mouse's immune system continued to produce
      these antigen-specific T cells on its own. However, with this method
      alone, Yang and Baltimore found that mice were only partially
      resistant to the tumor cells.

      To achieve complete protection required boosting the animal's immune
      system with dendritic cells carrying a fragment of the tumor cell's
      marker protein. These dendritic cells are thought to use their long
      tentacle-like branches (called dendrites) to stimulate the T cells
      and make them more active. With this combination, Yang and Baltimore
      were able to achieve the complete shrinkage and suppression of even
      large, well-established tumors.

      Dr. Yang recalled her reaction to the first positive results: "It was
      a great surprise that the method worked so well. This level of
      efficacy makes us believe that the method may have real therapeutic

      The next step, says Yang, will be to repeat the experiment, this time
      using conditions that more closely approximate human tumors. After
      that, if things hold up, the next step will be to start thinking
      about human trials.

      "Producing a state of antitumor immunity has been a dream of
      immunologists for years, but has been unrealized in humans," says
      Baltimore. "Here we've developed a methodology that provides a new
      opportunity to realize this goal. We certainly hope that it will
      prove to be effective in humans."
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