In an increasingly powerful and general approach to cancer immunotherapy for solid tumors, Honda, et al. have reported success in the journal, Molecular Therapy, with an iPS cell-based T cell therapy for cervical cancer.
T cells are a component of the adaptive immune system and are able to recognize non-self (foreign) protein molecules on cells. When T cells recognize such foreign proteins on cells, they can expand their population and mount an attack on cells appearing to be foreign and destroy them. In the example of this report, a person who has been infected by the human papilloma virus (HPV) will have proteins, made by the virus, not normally present in the body, displayed on the surface of the cells of their tissues. T cells have the ability to change the genes encoding their cell surface receptors and some of those changes may result in creation of a T cell with a genetic memory to specifically recognize cells with a unique foreign protein displayed on its surface. In this way, T cells play an important role in detecting and destroying infected cells and the tumors some viruses can cause.
In the last two decades, researchers have worked to harness this anti-tumor activity of the body’s own T cells by isolating T cells that have the genetic memory to recognize and attack tumors. Once isolated, the anti-tumor T cells can be driven by signals to expand their population in a dish, while still carrying the same genetic memory that allows them to specifically target the tumor, and then deliver the cells back to the patient to attack the tumor. Unfortunately, in the body many tumors are very slow to develop and T cells, while maybe retaining the genetic memory of a tumor, lose their capacity to divide over time and can fail to eliminate cancers.
A challenge for researchers was to find a way to isolate the anti-tumor T cells and somehow rejuvenate them and give them the ability to greatly expand again and also to have a potentially unlimited supply of the same cells to continually treat patients with enough cells to effectively eliminate a tumor.
A key step forward was previously shown when T cells with a genetic memory of tumor-specific proteins could be reprogrammed as iPS cells and then differentiated back to T cells. These rejuvenated T cells did indeed retain their anti-tumor activity and could destroy tumors more effectively than T cells without reprogramming. Indeed, it was found that when T cells become pluripotent they undergo changes to their chromosomes that reset their ability to divide more once converted back into anti-tumor T cells.
To isolate T cells that can recognize cervical cancer cells, researchers took blood cells from patients previously infected by HPV and presented those cells with protein fragments identical to those made by the virus. This induced the T cells to be activated and divide and thus be isolated and reprogrammed. When rejuvenated HPV-recognizing T cells were transplanted into mice with human cervical cancer tumors, the cell therapy effectively attacked and eliminated the tumors.
While not the first example of this approach, the report by Honda, et al. shows another success of rejuvenating anti-tumor T cells with iPS technology for cell-based therapy against solid tumors. This approach, often combining genetic engineering and isolation of immune cells with natural anti-tumor activity to make an iPS cell intermediate, has allowed researchers to produce so-called off-the-shelf immune cell therapies against specific cancers and is clearly becoming an effective and rapidly expanding area of clinical research.
