The gene therapy research, conducted with melanomas grown in mice, utilized an inactive HIV-like virus to serve as a vehicle to arm the lymphocytes with T cell receptors, which caused the lymphocytes to become specific killers of cancerous cells. A reporter gene, which glows "hot” during PET scanning, also was inserted into the cells so researchers could track the genetically engineered lymphocytes after they were injected into the blood stream, made their way to the lungs and lymph nodes, and then specifically homed in on the tumors wherever they were located within the body.
"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 Dr. Antoni Ribas, an associate professor of hematology/oncology, a researcher at the University of California, Los Angeles' (UCLA) Jonsson Comprehensive Cancer Center (USA) and the senior author of the study. "We knew this approach of arming the lymphocytes with T cell receptors showed significant antitumor 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 study was published July 12, 2010, in the early online issue of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS). "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,” stated Dr. Richard Koya, an assistant professor of surgical oncology at UCLA's David Geffen School of Medicine, 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.”
The immune system typically does not recognize cancer cells in the body as enemies. The insertion of the antigen-specific T cell receptors--modified to seek out a tumor antigen on the surface of the melanoma cells--in effect uncovers the malignant cells, revealing them as lethal invaders that must be sought out and destroyed. By imaging the genetically modified 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 then result in better monitoring response to therapy in melanoma patients.
In this study, the cells were injected into the bloodstreams of the mice, which were found to begin to fight the melanoma within two to three days. The mice were imaged periodically for 10 days to ensure the lymphocytes were indeed killing the cancer. The process to find and kill the malignant cells could take longer in people, according to Dr. Ribas.
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. Monitoring the immune response also could provide insights into ways to better engineer the lymphocytes to more effectively enter and attack the tumors.
In this 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 approximately one billion, according to Dr. Ribas. He 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 approximately one year, Dr. Ribas noted.
Related Links:
University of California, Los Angeles' Jonsson Comprehensive Cancer Center
