Genetically engineered immune cells watched in real-time as they kill cancer
One of the main problems with cancer cells is that the body's immune system generally doesn’t recognize them as enemies. By using a crippled HIV-like virus as a vehicle to arm lymphocytes with T-cell receptors, researchers have been able to genetically engineer a well-armed battalion of tumor-seeking immune system cells. By also inserting a reporter gene, which glows “hot” during positron emission tomography (PET) scanning, the researchers were able to watch in real time as these "special forces" traveled throughout the body to locate and attack dangerous melanomas.
The gene therapy work carried out by researchers at UCLA’s Jonsson Comprehensive Cancer Center, was done with melanomas grown in mice. After the genetically engineered lymphocytes were injected into the bloodstream, the researchers tracked them as they made their way to the lungs and lymph nodes, and then specifically homed in on the tumors wherever they were located in the body.
By imaging the genetically engineered T-cells as they seek out and attack the cancer, the scientists can closely examine the processes of the immune system as it fights malignancies, which could result in better monitoring responses to therapy in melanoma patients.
"We're trying to genetically engineer the immune system to become a cancer killer and then image how the immune system operates at the same time," said senior study author Dr. Antoni Ribas, an associate professor of hematology–oncology and a researcher at UCLA's Jonsson Comprehensive Cancer Center. "We knew this approach of arming the lymphocytes with T-cell receptors showed significant anti-tumor activity based on studies in humans. Now, by tracking the immune system's reaction to cancer and imaging it in real time, we can project how the same process that succeeded in mice might behave in people."
"The novelty of our work is that we were able to pack together the cancer-specific T-cell receptor and the PET reporter genes in a single vector and use it in mice with an intact immune system that closely resembles what we would see in real patients," said Dr. Richard Koya, an assistant professor of surgical oncology at the David Geffen School of Medicine at UCLA and first author of the study. "We were also gladly surprised to see the targeted tumors literally melt away and disappear, underscoring the power of the combined approach of immune and gene therapy to control cancer."
In this study, the cells were injected into the bloodstreams of mice; within two to three days, they had found and begun to fight the melanoma. The mice were imaged periodically for ten days to ensure the lymphocytes were indeed killing the cancer. The process to find and kill the malignant cells could take longer in people, Ribas said.
If a patient's tumor did not respond well to the administration of the genetically engineered T cells, scientists could determine by PET scanning whether the cells had not successfully made it to the tumor site or, if they did arrive, whether or not they functioned as expected, the researchers said. Monitoring the immune response also could provide clues on ways to better engineer the lymphocytes to more effectively enter and attack the tumors.
For the study, about one million genetically engineered lymphocytes were created and injected into a mouse. In humans, the number of tumor-seeking cells needed to fight the cancer is about one billion, Ribas said.
Ribas and his team are working now on creating a vector, or vehicle, to insert the T-cell receptors and reporter gene into the lymphocytes in a way that is safe to use in humans. If all goes well, human studies of the process could begin in about a year, Ribas said.
The study appears in the early online edition of the journal Proceedings of the National Academy of Sciences.