CLL cells are particularly inept at stimulating immune responses. Indeed, CLL cells appear to suppress immune function by turning off T lymphocytes, the cells of the immune system that marshal our immune response against infection. This might account in part for the increased susceptibility of CLL patients to certain infections.
We found that infection of leukemia cells with a modified cold-virus, called Ad-ISF35, could reverse the immune suppressive nature of CLL cells. CLL cells infected with Ad-ISF35 make a protein called ISF35, which is found on the surface of CLL cells. This protein can interact with another surface protein called CD40, an important trigger on the CLL cell for converting the leukemia cell into a cell that can stimulate T cells and induce anti-leukemia immune responses.
We can remove leukemia cells from the blood of patients via a process call “leukopheresis.” Leukopheresis removes blood typically from one arm, separates the white blood cells from the red blood cells and the liquid portion of the blood called plasma. It removes the white blood cells from blood and then returns the red blood cells and plasma back to the patient, generally in another arm. Leukopheresis can remove billions of leukemia cells at a time, particularly from patients who have high leukemia cell counts in the blood.
Using the leukemia cells harvested via this process, we could generate cellular vaccines that could be given back to the same patient. Leukemia cells treated with Ad-ISF35 are examined for their ability to make ISF35 on their surface. As noted, this causes the leukemia cell to become much more effective in stimulating T cells to make anti-leukemia immune responses.
When patients are given back their own leukemia cells that have been treated with this approach, they develop flu-like symptoms that lasting a few days. These symptoms are caused by activation of the immune system, similar to how the body responds to any infection. Surprisingly, we found that patients had early reductions in leukemia cell counts and decreases in the size of lymph nodes and spleen. Such reductions appear to be too early to be due to activation of an immune response against the leukemia. Rather, it appears that this treatment activates a so-call “innate immune response.”
We also found that this treatment could cause changes in the leukemia cells that make them more sensitive to some of the drugs that are used to treat this disease. This is particularly the case for patients who have leukemia cells with the 17p- deletion that often is associated with defects in the gene making a protein called P53.
P53, an important protein, polices the cell against genetic damage. When a cell is damaged, P53 causes the cell to stop growing and to repair the damage. However, if repair does not occur quickly, then P53 triggers the cell’s demise. Recent studies have found that most of the drugs that are used to treat cancer trigger P53 and it is P53 that actually causes the cancer cell to die. Having a defective P53 makes the tumor cell resistant to many anti-cancer drugs.
This resistance problem is underscored by the finding that P53 is defective in half of all human cancers. Also, CLL patients who develop drug resistance to anti-cancer drugs are often found to have acquired defects in P53. A surprising discovery has been that leukemia cells that have defective P53 can be activated via CD40-ligation caused by ISF35 to make another protein that is closely related to P53, called P73. P73 can step in for P53 and sensitize leukemic cells, making them once again susceptible to commonly used CLL treatments.
This has resulted in a clinical study for patients who have leukemia cells with the 17p- defect in P53 or that are resistant to anti-cancer drugs. Patients can have their leukemia cells modified with Ad-ISF35. Following infusions of their own leukemia cells with ISF35, they are then given chemoimmunotherapy. Some patients already have been treated with such an approach and have achieved a complete remission following treatment, a rarity in this group of patients. This study is currently enrolling patients at UCSD in a study co-sponsored by Memgen, and the Leukemia and Lymphoma Society, and support from the BCRF.
Another strategy that is being explored at the Moores Cancer Center is direct injection of Ad-ISF35 into the enlarged lymph nodes of patients with CLL. A study led by Dr. Januario Castro has shown that a 1-time injection of Ad-ISF35 into an enlarged lymph node was well tolerated and appeared effective in reducing the leukemia blood counts and in decreasing the size of enlarged lymph nodes and spleen. This is quite exciting! It appears that the injection of one lymph node apparently can cause a reduction in all of the enlarged lymph nodes. A follow-up study will soon be available to give patients multiple injections, which we hope stimulates a vigorous anti-leukemia immune response. Studies in experimental animals have shown this treatment to be effective in eliminating lymphoma cells and in stimulating protective anti-lymphoma immunity that can protect against recurrent disease.