ADOPTIVE T-CELL IMMUNOTHERAPY LAB FOCUSES ON BREAST AND OVARIAN CANCERS

"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.

Think of adoptive T-cell immunotherapy as a kind of immune system "upgrade." This promising new strategy to fight various infections and cancers–which is still in the investigative stages—involves 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.

Keith Knutson, Ph.D., finds the possibilities of this approach so exciting that he is leading a research program focused on adoptive T-cell therapy for cancer patients at Mayo Clinic. His goal: to bring an effective adoptive T cell therapy for breast and ovarian cancers to clinical trial by 2008. "This is a fascinating new approach, and there's plenty of evidence that it will work in human clinical trials," Dr. Knutson explains, noting that it's a logical extension of recent research that has been done in his laboratory and other laboratories.

Background Biology

Certain key proteins are over-expressed in many kinds of cancers. Among them is HER-2/neu. It is a cancer-causing protein that prompts cells to grow uncontrollably and is associated with poor outcome in patients with breast and ovarian cancers. Researchers have successfully generated T-cell immunity to this protein using vaccines. That's the good news. The bad news is that 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 want to get around this limiting feature. They hope to take the work done thus far on vaccines to the next level 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, ready for a fight.

Targeting Breast and Ovarian Cancers

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. This is important because 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. Notes Dr. Knutson: "Because these cancers share some fundamental biology that I have extensive experience with, conceivably we can have a single strategy to treat them both."

In order to expand his repertoire of approaches, Dr Knutson is also focusing attention on another candidate tumor-associated antigen. It is known as 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 from our efforts," Dr. Knutson notes.

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, Dr. Knutson will collaborate with medical oncology specialists to identify suitable patients for immunotherapy.

Mayo Foci of Excellence

A multi-step process is involved in adoptive T-cell therapy—with many challenges at each stage yet to be surmounted. Dr. Knutson and Mayo Clinic colleagues have identified several key foci for improving 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

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. Says Dr. Knutson: "We need to find the best way to encourage a variety of bodily systems, ranging from the immune system to the cardiovascular system to accept T-cells once they are grown outside the body."

Imaging T-cell activity in the body. To help researchers follow the progress and travels of T-cells once they're back in the body, they need to develop ways to image them. "We've come up with some novel ways to follow T-cell trafficking using magnetic resonance imaging, positron emission tomography and computed tomography and that's really exciting," says Dr. Knutson. "The purpose of the image is to learn crucial details about T-cell behavior once they are reintroduced into the patient."

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. "In addition it's not obvious what constitutes a sufficient cell dose to control cancer cells," Dr. Knutson says. "Without knowing how many cells to infuse, it's hard to know how aggressive we need to be in our efforts in expanding the T-cells in the laboratory—a technically challenging process." Another advantage that improved tracking of T-cell whereabouts will give researchers is help in predicting which patients will benefit from the adoptive T-cell therapy.

A Collaboration Ethic

Dr. Knutson and colleagues will overcome some of the limitations to adoptive T-cell therapy by collaborating with other investigators within the Departments of Immunology, Medical Oncology and Hematology.

Collaboration is the key. Cancer is such a multi-faceted biological foe that no single discipline can hope to manage or cure it. Throughout Mayo Clinic research, investigators with different expertise have always shared their knowledge and ideas to leverage creative and intellectual capital in the race to develop novel therapeutic approaches that can make a safe and effective difference in patients' lives. Under the Mayo model of patient-oriented research, patients who participate in Mayo Clinic immunotherapy clinical trials can be sure that they are receiving treatment options that have been thoroughly studied in animal model systems before they've been approved for human use.