Successes and challenges of leukaemia treatment using CAR-T cells – where are we now?
Treatment of leukaemia and lymphomas using genetically modified immune cells of the patient (CAR-T cells) has produced impressive results in clinical trials, especially for the treatment of B-cell malignancies. However, serious adverse events were reported as well, partly with fatal outcome. A detailed summary of previously published results and a discussion of the reasons why less than ten percent of the clinical trials are conducted in Europe have been published by researchers under the supervision of the Paul-Ehrlich-Insitute in EMBO Molecular Medicine (August 1, 2017, online early view).
For many decades, cancer therapy consisted of surgery, chemotherapy and radiotherapy as well as blood stem cell transplantations. A novel and very promising therapy concept is the stimulation of the patient’s immune system. This stimulation enables the immune system to recognise and kill cancer cells. In this so-called adoptive immunotherapy, particular immune cells (T cells) are removed from the patient and are genetically modified to express a cancer cell specific antigen receptor on their surface. These CAR-T cells are then reinfused into the patient. Upon recognition of a specific surface antigen on the cancer cell, the CAR-T cell gets stimulated, starts to replicate and subsequently kills the cancer cell.
CAR-T cells are a very complex medicinal product. Consisting of patient's own body cells, the product can replicate and persist in the patient over longer periods – up to several years. Thus, translation of these new therapies from pre-clinical development to the application in humans is particularly challenging for the pharmaceutical industry, academia, as well as regulatory authorities.
Experts of the Paul-Ehrlich-Institut under the supervision of Professor Christian Buchholz, project leader of the Horizon2020-funded EU-research project 'CARAT', have analysed all data available from clinical trials with CAR-T cells world-wide, which are either still ongoing or already completed. This work was supported by the CARAT consortium. The aim of the analysis, among other things, was to identify essential obstacles for clinical development of this new group of active substances. On the basis of this analysis, the researchers developed suggestions about how the process of translation, i.e. the process from research to clinical use of CAR-T cells could be pushed ahead, especially in Europe.
At the current state of development, CAR-T cell therapy seems to be particularly effective in the treatment of malignant CD19-positive B-cell disorders. This type of cancer disease is caused by malignantly altered blood cells (B-lymphocytes) carrying the CD19 surface antigen. Despite the partly unexpectedly high – therapeutic efficacy, there is the risk of serious adverse effects. Especially cytokine storms can be life-threatening, due to the release of high amounts of cytokines by the activated immune cells. Another possible serious adverse reaction is neurotoxicity, a usually transient impairment of the brain and its functions.
The complete press release with more information is available here.
Hartmann J, Schüßler-Lenz M, Bondanza A, Buchholz CJ (2017):
Clinical development of CAR-T cells – challenges and opportunities in translating innovative treatment concepts.
EMBO Mol Med Aug 01 [Epub ahead of print].