Adoptive T-Cell Immunotherapy: Breast and Ovarian Cancers

Investigator: Keith Knutson, Ph.D.

"Combining advanced technologies with a collaborative research environment committed to excellence is what really guides the development of novel treatment procedures that will help cancer patients overcome their disease."
Keith Knutson, Ph.D.

Mayo scientists are combining advanced technologies with a collaborative research environment committed to develop novel treatment procedures that will help cancer patients overcome their disease in three basic steps:

• Harvesting specific T-cells from the immune system of the patient
• Activating these T-cells outside the body in the laboratory to recognize tumor cells and destroy them
• Infusing these "boosted" T-cells back into the patient. There they are "adopted" by the body to enhance its natural immune system.

Dr. Knutson is leading a research program focused on adoptive T-cell therapy for cancer patients at Mayo Clinic. His goal is to bring an effective adoptive T-cell therapy for breast and ovarian cancers to clinical trial, a logical extension of recent research that has been done in his laboratory and other laboratories. Researchers have successfully generated T-cell immunity to this protein using vaccines. Unfortunately, tumors suppress the natural expansion of HER-2/neu-specific T-cells--thus limiting their numbers and potential strength as a vaccine. Dr. Knutson and his colleagues are bypassing this limiting feature by removing these T-cells from the body, boosting their numbers and function in the cell culture dish--and then infusing the "bulked up" T-cells back in the body to fight disease.

Dr. Knutson's lab is focusing on breast and ovarian cancers because these are diseases in which a number of tumor-associated proteins (i.e. antigens) are known. Evidence is accumulating that antigen-specific adoptive T-cell therapy strategies may work better than other approaches. In addition, Dr. Knutson's extensive experience studying HER-2/neu in breast and ovarian cancers gives him a strategic advantage in applying knowledge of how the immune system components can be activated and directed to the tumor sites. These cancers share some fundamental biology suggesting that a single strategy could treat them both. His research team is also focusing attention on another candidate tumor-associated antigen called the high affinity folate receptor. Eighty percent of ovarian cancers over-express this antigen, so that's a sizeable patient population that may possible benefit.

The Next Step

The next step toward making adoptive T-cell therapy available to patients is establishing an appropriate laboratory setting in which to generate tumor antigen-specific T-cells from patients. This has to be done under closely-regulated, clean-room conditions to assure the highest quality T-cell generation. Once the T-cell therapy can be manufactured to exacting standards, the researchers will collaborate with clinical colleagues to identify suitable patients for immunotherapy.

Areas of Focus for Research Excellence

Understanding T-cells in their natural biological context is central to the success of adoptive T-cell immunotherapy because currently testing the functioning of T-cells in a lab culture dish doesn't translate into the body. A multi-step process is involved in adoptive T-cell therapy has many challenges at each stage. Improved tracking of T-cell whereabouts also helps researchers predict which patients will benefit from the adoptive T-cell therapy.

Dr. Knutson and his colleagues have identified several key areas on which they are focusing to improve the art and science of adoptive T-cell therapy. Among them are:

Vaccination
Cancer vaccines have been used for several years to prevent tumor relapse. But vaccines can be used another way, too. In the context of adoptive T-cell therapy, vaccination can be used as a booster prior to harvesting the patient's T-cells, thus increasing the T-cell expansion.

Ex vivo Expansion
Researchers are looking for technologies to rapidly expand the T- cell population outside the body, and then get it quickly back in the body where, when activated, it can recognize and destroy tumor cells.

Conditioning the Patient to Prevent Rejection of Adopted T-cells
As with organ transplants, T-cells that have been reconstituted, conditioned and expanded in the lab need to be accepted by the body when infused back into the host--or else the infused cells will not have therapeutic effects.