Adoptive T cell ‘clones’ advancing immunotherapy
As immunotherapy gains traction in the fight against cancer, researchers continue to probe the benefits of adoptive T cells.
In 2015, a team of scientists from Johns Hopkins School of Medicine infused specific cytotoxic T cells into cancer patients with the goal of recognizing, targeting, and destroying tumor cells. 
Now, researchers at the Fred Hutchinson Cancer Research Center have tracked rare T cells to ensure the correct ones can be selected for treatment from a patient's immune system. 
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T cells are harvested either from tumor (tumor-infiltrating lymphocytes, TILs) or peripheral blood (peripheral blood lymphocytes, PBLs). TILs can be expanded non-specifically since they are preferentially tumor-specific prior to culture. In contrast, tumor specificity must be induced in PBLs, either through antigen-specific expansion or genetic engineering. After several weeks of expansion in culture, tumor-specific T cells can be reinfused into the cancer patient.
“We found that the cells in each patient's immune system that will ultimately have a clinical effect are incredibly rare,” said Dr. Aude Chapuis, lead author of the paper and a member of the Clinical Research Division at Fred Hutchinson. “Knowing what we've found, we can now refine the selection of the cells that we will ultimately use for adoptive T cell transfer so that the cells persist and keep the tumors at bay longer in our patients.”
In adoptive T cell transfer, T cells from the patient's own blood are primed to seek and destroy cancerous cells by multiplying them in a lab and then returning the cells to the patient. In some treatment settings, the cancer-targeting T cells are instead obtained from a healthy donor's blood.
However, each infusion contains a variety of T cells each with varying cancer-killing capabilities. Researchers have not known which T cells offer the most effective anti-cancer punch. Also, the cells' anti-cancer properties change as they grow in the lab and the “clones” differ from the original T cells.
Dr. Chapuis and the team have discovered an important step in identifying specific T cells best suited to fight cancer. The method distinguishes T cells from each other according to the nature of their receptor, which is T cells' weapon against cancer. Adaptive Biotechnologies Corp, a spinout of Fred Hutchinson, has developed high-throughput receptor sequencing for immune cells. The technology gives each T cell receptor a “bar code,” allowing researchers to track T cells.
“High throughput T cell receptor sequencing allows us to distinguish the cells and figure out where they came from, which ones grow in culture and which ones persist after being transferred to the patient,” Dr. Chapuis said. “We can finally track in detail what's going on when doing adoptive T cell transfers.”
Following the bar codes of the T cell receptors, scientists are now tracking how the cells in 10 metastatic melanoma patients. Two patients went into complete remission after T cell infusion, and the researchers note the specific T cells that dominated the patient's cancer-fighting army after infusion were rare in their bodies originally.
The method also allowed the researchers to observe the T cells likely having the most powerful effect tend to be younger. This suggests that the T cells had better capabilities to multiply and survive, which is essential for long-term tumor control.
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- Perica K, Varela JC, Oelke M, Schneck J. Adoptive T Cell Immunotherapy for Cancer. Rambam Maimonides Med J 2015;6 (1):e0004. doi:10.5041/RMMJ.10179
- Science Immunology 24 Feb 2017: Vol. 2, Issue 8, DOI: 10.1126/sciimmunol.aal2568