by Mark Wheeler
Zaid Al-Kadhimi is a molecular traffic cop — his aim is to direct genetically engineered T-cells to attack lymphoma and infection. And to get them where they need to go, his delivery vehicles are T-cells that normally fight a well known foe: the common flu bug.
Bone marrow transplants (BMT) and chemotherapeutic drugs are powerful weapons against cancer, but following treatment, sometimes a few cancer cells linger in the body — and may potentially re-seed. Patients, their immune systems weakened, are also threatened by viral infections that usually pose little risk to healthy adults.
Al-Kadhimi, M.D., from the Department of Hematology & Hematopoietic Cell Transplantation, plans on genetically engineering T-cells — key components of the immune system — to mop up any remaining cancer cells and stop viral infections following a BMT. The Lymphoma Research Foundation recently awarded him a two-year, $100,000 grant to eliminate these two threats.
His current work continues research published last year in the journal Blood, in which he demonstrated that genetically engineered T-cells completely destroyed well-established tumors in a rodent model when injected directly alongside the tumor. In the course of that research, Al-Kadhimi found something intriguing: In working with a variety of T-cells (T-cells only recognize a specific antigen, or substance, that is foreign to the body), he noticed that the anti-influenza T-cells he used carried a unique receptor, called CCR7, which caused them to travel, or “traffic,” to the lymph nodes at a quantity that was several-folds better than other T-cells.
Trafficking to the lymph nodes is significant, for two reasons: They are a common hideout for the few cancer cells that may remain behind after therapy, and they have a good environment for T-cell growth.
“The lymph nodes are where T-cells are nurtured, divide and expand, before they go out to find the bad guys and kill them,” Al-Kadhimi said.
In his current research, Al-Kadhimi is exclusively using flu-specific T-cells as his “base,” then genetically engineering them in the hope of achieving several goals. First he will add a gene called CD19 receptor that should make the T-cells attack and destroy lymphoma tumor cells, while the CCR7 receptor will maintain the cell’s ability to still traffic to the lymph nodes, where they will be continuously refreshed.
To bolster the immune system even more, Al-Kadhimi will engineer an influenza vaccine. It, too, will traffic to the lymph nodes and meet up with, and activate, the dual lymphoma/flu-specific T-cells. This should ratchet-up the body’s immune system even more to continually hunt down and destroy any remaining lymphoma cells. “That will give these cells a double whammy,” said Al-Kadhimi. “By recognizing both the flu and the cancer receptors, the activation level of the immune system will go sky high, and the ability of the T-cells to kill cancer cells becomes much more effective.”
Last, instead of injecting his engineered T-cells directly near the tumor, he will add them to the blood to see if they naturally traffic to the lymph nodes and cancerous cells. By adding a luciferase gene to the T-cells (that is the gene that enables fireflies to light up), he will be able to track them as they travel through the rodent’s body.
Because he and his colleagues have already completed the bulk of the groundwork, Al-Kadhimi is optimistic about this research. “We already have a lot of knowledge about the baseline platform of how to engineer T-cells, how to grow them, and how to assay the activity in the lab, and we know what questions to ask about the T-cell’s activity in the animal model.” If successful, Al-Kadhimi is hopeful that clinical trials can begin in the not-too-distant future.