PNAS: PET monitors response to immune, gene therapy to control cancer

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By molecular imaging of genetically engineered T cells with PET reporter genes as they seek out and attack the cancer cells, 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, according to a study published July 12 in the early online edition of the journal Proceedings of the National Academy of Sciences.

The gene therapy work, done with melanomas grown in mice, employed a viral vector 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 PET reporter gene, sr39tk, also was inserted into the cells so that the 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 the study's senior author Antoni Ribas, MD, an associate professor of hematology/oncology at University of California, Los Angeles (UCLA) 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.”

In the study, the genetically engineered lymphocytes were injected into the bloodstreams of the mice and they had found and begun 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, Ribas said.

“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 the study's lead author Richard C. Koya, MD, PhD, an assistant professor of surgical oncology at UCLA’s David Geffen School of Medicine. “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.”

Monitoring the immune response also could provide clues on ways to better engineer the lymphocytes to more effectively enter and attack the tumors. 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.