A new study by Kyoto University scientists has demonstrated the ability to produce some of the most potent anti-cancer immune cells for adoptive cell therapy (ACT) using induced pluripotent stem cell (iPSC) technology.
In recent decades, methods of treating cancer have been rapidly developing. Radiotherapy and chemotherapy have saved countless lives. However, one of the most promising and intensively studied methods at present is adoptive cell therapy. For ACT, T cells (T lymphocytes) from the patient blood are modified in vitro, enhancing their anti-cancer immune effect, and reintroduced to the patient.
Despite the conspicuous advantages, this method, based on the ability of immune cells to kill cancer, has limitations in its use in some patients.
The laboratory of Professor Shin Kaneko from the Center for iPS Cell Research and Application (CiRA) at Kyoto University explores the technology of induced pluripotent stem cells as a solution to this problem.
“We have to process the T cells before injecting them into the patient. This processing affects the quality. If we first process the cells as iPS cells and then differentiate them into T cells, we can avoid many of these problems”, – he said.
As promising as this strategy is, the process of generating T cells from iPSCs is complex. Kaneko’s group reported numerous studies in which iPSCs were differentiated into T-lymphocyte-like cells. Namely, the resulting cells displayed properties that suggest they are chimeras of T lymphocytes and other immune cells.
“The innate immune properties may cause the cells to kill non-cancer cells in the patient or graft versus host disease”, – explained Kaneko.
To differentiate into functional T lymphocytes, iPS cells must be cultured with various cytokines, which are factors naturally secreted by immune cells.
“IL-2 and IL-15 are commonly used to generate T cells, but we found they promoted innate immunity characteristics”, – explained Dr. Yohei Kawai, the first author of the study, the results of which were published in Molecular Therapy. “To get adaptive immunity characteristics, we replaced IL-2 and IL-15 with IL-21.”
IL-21 is a pleiotropic (polyfunctional) cytokine secreted by T helper cells, the effect of which is not fully understood.
“I was constantly searching cytokines to suppress the innate phenotype”, – added Kawai.
The immune system is subdivided into innate and adaptive immunity. As the names suggest, the cells of the first group attack everything that is considered foreign to the body, while the cells of the second group, which include T lymphocytes, are sensitized to specific pathogens, including cancer.
T lymphocytes are classified into phenotypes that include effector cells and memory cells. Effector T cells are more vigilant and can be seen as an advanced defense. On the other hand, memory T cells are involved in training but remain inactive. If necessary, they can be promoted to effector T cells and move to the front line, but the memory T cells themselves are kept off the battlefield.
Besides activity, another critical difference between phenotypes is the ability to proliferate. Memory cells can multiply much faster than effector cells. Thus, somewhat paradoxically, therapy with memory T cells is preferred, as they can rapidly mature to an effector phenotype if necessary. In addition, they can also proliferate while waiting, increasing the number of cells ready to attack.
In the new study, memory T cells derived from iPS cells did indeed show a better anti-cancer effect in the ACT and increased proliferation than primary T cells.
“Our culture system could produce unlimited numbers of memory and effector T cells from iPS cells. This advance will help us develop iPS cell technology into powerful cancer immunotherapies”, – said Kaneko.