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Immunotherapeutics is a fast growing area of research for cancer therapy. Unlike traditional chemotherapy given to cancer patients, which indiscriminately kills and rapidly multiplying cell, the use of immunotherapeutics allows for targeted killing of cancer cells, thus sparing healthy cells. A new therapeutic approach is being investigated that helps direct T cells to recognize and attack cancerous cells. Two types of T cells can be activated to help fight infections and cancer: CD4+ T cells, termed helper T cells, which activate other components of the immune system, and CD8+ T cells, termed cytolytic T cells, which can directly kill infected cells and cancer cells.

A company involved in developing monoclonal antibodies for treatment of cancer, New Jersey based Immunomedics, has recently released trial results showing success using a bispecific antibody to destroy cancer cells. The bispecific antibody can bind to two separate proteins: CD19, which is found on a type of white blood cell called B cells, and a portion of CD3, which is found on a separate type of white blood cell called T cells. CD19 is highly expressed on Non-Hodgkin Lymphoma cells, which are mutated, cancerous B cells. The bispecific antibody helps direct the T cells, which are immune cells involved in protecting the host from foreign invaders and cancerous cells, to CD19-expressing cancerous B cells. Once the T cells have been directed to the cancerous B cells, they can begin the process of cell mediated immunity. The T cells can lead to the direct killing of the cancer cell. Researchers at Immunomedics have shown that the bispecific antibodies are able to direct CD3-expressing T cells to kill CD19-expressing cells in vitro at very low concentrations.

The researchers then began to test the ability of the bispecific antibody to kill cancer cells in an animal model. The researchers tested to see if the bispecific antibody could function on solid tumors. Of the animals used in the study, 6 survived, with 5 of the 6 survivors being tumor free at the end of the study. After the successful animal trials of CD19 and CD3 the bispecific antibodies, researchers at Immunomedics produced three more bispecific antibodies, expressing CD3 along with three different cancer cell specific markers. Two of the three bispecific antibody complexes were able to induce T cell mediated anti-tumor activity in animal models of pancreatic cancer and human colon cancer.

The process of how the bispecific antibody can result in T cell mediated killing of cancer cells is not fully presented in the press release from Immunomedics. In order to become fully activated, T cells need to receive a variety of signals. First, antigen must be presented to a T cell that can specifically recognize and attack that antigen. Next, several costimulatory molecules on the T cell must also be activated, to tell the T cell the antigen is from a foreign invader or cancerous cell. This helps prevent the T cell from attacking normal host cells. If the costimulatory signals are not given to the T cell, it will not be able to function. Once all of the proper activation signals have been given, the T cell can then begin to perform its function. The bispecific antibody used in trials by Immunomedics contains an antibody against CD3, a molecule found on the surface of all T cells. When CD3 is bound, either by a costimulatory factor or antibody, it helps activate the T cell. This may not be sufficient, however, to properly activate the T cells to attack cancer cells, and could result in cancer-specific T cells becoming inactive.

Another potential problem that this strategy has is that the bispecific antibody would indiscriminately activate any cell expressing CD3. This would activate any T cell in the body, not just those specific for the cancer. While the bispecific antibody would help recruit T cells to cancer cells, it would not ensure that the T cell can act against the cancer cell. Because so many T cells would be activated in the body, this could also result in an excessively high level of cytokines, the proteins produced by T cells when they are trying to remove cancerous cells. In high levels, cytokines can actually be toxic to the body, causing high levels of inflammation and damage. Despite the promising pre-clinical results of the bispecific antibody system, it is important to remain cautious as work in this area progresses.

References:
http://www.nasdaq.com/article/immunomedi...Wldy0qRI4I

http://www.immunomedics.com/pdfs/news/20...122012.pdf