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Immune System: Immune-Modulators
We have spent the last several issues of Tidbits discussing the relationship between CLL and the immune system. (Links to previous articles can be found in the side bar to the left.) Researchers have spent many years studying the biology of CLL cells (malignant B-cells) and their relationship with the immune system. Several methods are under investigation to reverse the ways that CLL cells negatively affect the immune system. We will explore some of the mechanisms being targeted and drugs being tested.
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Immune cells (blue) attacking cancer cell (yellow). Imaged obtained from oncosec.com.
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CLL Cell Mobilization from Sanctuary Sites: CLL cells hang out in the lymph nodes for protection and nourishment. When CLL cells are forced into the blood stream, they are more susceptible to death. Ibrutinib and idelalisib (formerly known as GS-1101 and CAL-101) are becoming well-known for their dramatic results in reducing lymph node sizes and eliminating CLL cells. These and other similar drugs block adhesion proteins which enable the CLL cells to stay in the lymph nodes, and thus push the CLL cells into the bloodstream.
Enhanced T-cell Co-Stimulation:A major component of immune dysfunction in CLL is defective T-cells, which are important immune cells. In a healthy individual, T-cells and B-cells work together to keep the body free from foreign invaders. B-cells and T-cells stimulate, or activate, each other through shared signals. Studies have demonstrated that CLL cells prevent T-cells from properly functioning, but this relationship is not fully understood.
Lenalidomide is a relatively newer treatment offered for CLL patients. It is considered an immune modulator, meaning that it enhances the capabilities of the immune system. It offers several benefits for CLL patients, including reversing the defects of T-cells. Researchers do not fully understand how lenalidomide does this in CLL patients. It is not yet FDA approved for CLL and is not appropriate for all patients.
The B-cell and T-cell relationship is an appealing way to target CLL cells. Teaching T-cells to attack malignant cells is something researchers have been studying for years. Chimeric antigen receptors (CARs) may be a solution. CARs are receptors that are genetically inserted into T-cells and then expressed on their surface. CARs enable T-cells to seek out a specific molecule and stimulate the T-cells to attack and kill the cell expressing the target molecule found on CLL cells.
Repair of CLL B-cell Antigen Presenting Function: B-cells are producers of antibodies. Before a B-cell is capable of producing antibodies, it first functions as an antigen presenting cell. This means that the B-cell encounters an antigen, or foreign invader, and takes the antigen to "present" to a T-cell which in turn helps the B-cell multiply and produce antibodies against the specific type of antigen (see image below). CLL cells are poor antigen presenters, and there are few healthy B-cells in a CLL patient, so there are lower levels of antibodies being produced.
In addition to what was mentioned above, lenalidomide can also repair the antigen presentation function in CLL cells. Once again, the exact mechanisms of lenalidomide in CLL are not well understood. But, researchers do know that it enhances immunity against CLL cells and at the same time reduces the survival mechanisms used by the CLL cells.
Gene therapy is another mode of repairing the antigen presenting function in CLL cells and also serves as a targeted therapy. Gene therapy is a process where a gene is inserted into a cell to change how the cell operates. A gene can be inserted into a CLL cell so that the cell develops an antigen on its surface and subsequently presents this antigen to a T-cell. The T-cell then destroys the CLL cell. Basically, the gene makes the CLL cell mark itself as a target for destruction. Phase I clinical trials using gene therapy for CLL were successfully conducted a few years ago, but further action has yet to be taken.
T-cell therapy:T-cell therapy also capitalizes on the relationship between B-cells and T-cells. Allogeneic stem cell transplantation, where a donor supplies stem cells to a patient, is currently the only FDA approved therapy that utilizes T-cells to target CLL cells. A transplant basically replaces the patient's immune system with a healthy immune system which should recognize the cancer and kill the cancer cells. There can be significant side effects and toxicity associated with a stem cell transplant, although management of the side effects is improving.
T-cells are primarily responsible for eradicating cancer cells as part of a transplant. This knowledge prompted the development of CARs (mentioned above). By eliminating the other cell types infused in a stem cell transplant, and teaching the T-cells to only target specific molecules, there should be a significant reduction in risk. CARs are being tested in early stage clinical trials.
Information for this article retrieved from: Riches, J.C., et al. Immune Reconstitution in Chronic Lymphocytic Leukemia. Current Hematologic Malignancy Reports. 2012;7(1):13-20.
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CLL Global Alliance members gathered in Houston on January 26 and 27, 2013 for the semi-annual Alliance meeting. The Alliance is a collaborative group of CLL investigators from the United States and Europe. Members have been actively participating since 2008, and during this time a true sense of camaraderie and trust has developed which accelerates new collaborations and ideas for research approaches.
