This new tumour model allows researchers to more easily study the big questions and bottlenecks that now frustrate the wide clinical application of immunotherapy. For example: why does one patient respond well to immunotherapy and another not at all? How do cancer cells bypass the immune system and how do immune cells react to that? And finally: how can we intervene in all these mechanisms?
The organoids were cultured from tumor tissue from 13 patients with a specific form of colorectal cancer (mismatch repair deficient colorectal cancer) and 6 patients with non-small cell lung cancer. These subtypes of cancer are partly sensitive to immunotherapy, because the amount of DNA damage is so substantial that the immune system recognizes the cancer cells as 'foreign'. However, only a minority of patients with metastatic cancer responds well to immunotherapy. Using organoids, immune cells from the blood of about one in three patients were successfully 'trained' to recognize tumor cells.
The immune cells in question are T cells. T cells (for the expert: type CD8+) are white blood cells with a dual function: they recognize foreign elements and kill them as well, hence the nickname killer T cells. From the bloodstream, they infiltrate and attack the tumor. In the forms of immunotherapy that are now used - as standard treatment or experimentally - these T cells take the front stage. However, in the micro-environment of the tumor, all kinds of mechanisms are at work that make it impossible, or no longer possible, for T cells to recognize or kill the cancer cells. These mechanisms can now be studied better.
Immunotherapy is aimed at strengthening and/or expanding T cells in the tumor microenvironment. Immunotherapy was first applied to cutaneous melanoma, an aggressive form of skin cancer, and only afterwards to several other cancers. 'With melanoma, it is relatively easy to grow T cells from the tumor itself,' says Voest. 'That has proved much more difficult with epithelial cancers such as colorectal cancer and lung cancer.' That is why he is so happy that his group has succeeded in obtaining T cells from the bloodstream. 'T cells from the bloodstream are also likely to be 'fresher' than T cells that have already become exhausted during their stay in the tumor microenvironment.'
The new discovery also opens the way to develop cellular therapy in which T cells are 'trained' outside the body to recognize the tumor and then returned to the patient. The organoids can likewise be used to test combinations of immunotherapy and other therapies.
Krijn Dijkstra & Chiara Cattaneo et al., 'Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids'. Cell (2018), 9 August 2018.
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