As with antibodies, T-cell-based immunotherapy has to address the “needle-in-the-haystack” challenge of getting the right kind of T-cell, with the right receptor, to the tumor. Most approaches fall under the umbrella of adoptive cell therapy (ACT)—a technique pioneered by Philip Greenberg, MD, and a team at the Hutchinson Center in the early 1990s.
In this treatment, a patient’s white blood cells are collected in a process called leukapheresis. In the laboratory, doctors attempt to isolate the specific T-cells with the most cancer-fighting potency. These cells are grown into the billions in vitro and then reinfused into the patient to work against the cancer.
At Seattle Cancer Care Alliance (SCCA), ACT has been used effectively against advanced melanoma. More recently, Paul Nghiem, MD, PhD, has been studying the technique’s effectiveness in Merkel cell carcinoma, and Seth Pollack, MD, is running a clinical trial of ACT for treating sarcoma.
A newer version of cellular immunotherapy uses tumor-infiltrating lymphocytes (TIL) as the specific type of T-cell that will be expanded in vitro. The idea here is that the T-cells present within a tumor are responding against tumor antigens. This approach eliminates the step of selecting individual T-cells from the patient’s blood. Sylvia Lee, MD, and her colleagues are currently studying the effectiveness of TIL therapy in patients with advanced melanoma.
Stanley R. Riddell, MD, is also a key player—along with Cameron J. Turtle, MD, PhD, and Michael Jensen, MD—in a study of an exciting new T-cell transfer technology using chimeric antigen receptors (CARs). The trial uses a special, genetically engineered T-cell with a receptor that is “half monoclonal antibody and half T-cell receptor.”
“What we are doing,” explains Dr. Riddell, “is coupling the exquisite specificity of the antibody to the potent effector function of the T-cell. We target the tumor with the antibody and kill it with the T-cell. Moreover, since this is a living therapy, the engineered cells can grow in the patient until the tumor is eradicated.”
In addition to better targeting, the CAR approach addresses a major limitation faced by all previous T-cell therapies. As with bone marrow transplants, in T-cell therapy, tumor-associated target antigens are associated with MHC molecules. So each individual antigen is present in only a small fraction of cancer patients. But with CAR, the antibody component bypasses the MHC-dependence of T-cell receptor signaling requirements. This means CAR could allow doctors to treat a much larger percentage of potential cancer patients.
A clinical trial using the CAR approach is underway at Seattle Children’s for treating childhood leukemia. Rebecca Gardner, MD, uses a hollowed-out virus as a “vector” for inserting a new gene into the patient’s T-cells. The DNA infusion causes the cells to develop a receptor capable of recognizing—and fighting—the disease. Dr. Gardner says this technique has the potential to be a much easier-to-tolerate alternative to the current standard of care, which is a bone marrow transplant.
What to Expect
Patients receive T-cell treatment through an intravenous infusion. The active ingredient is the patient’s own white blood cells, so there is generally little or no toxicity.
Other than the prostate cancer vaccine Provenge, there are currently no FDA-approved treatments based on T-cell therapy. A wide variety of promising clinical trials, however, are investigating these promising approaches. In many cases these are combination treatments that may start with chemotherapy and then deliver T-cells along with Interleukin-2 as a growth factor to sustain the transferred cells. The side effects of these other drugs are significant and challenging for many patients.
Because SCCA is a nexus for research and treatment, our medical oncologists are familiar with a wide range of clinical studies that might help their patients. Our doctors have broad experience in selecting the right trial, coordinating communications with the lead investigator, and helping patients prepare for the treatments.