21 / 2022
Cancer immunotherapy with CAR-T cells is an important therapeutic strategy for lymphoma and leukaemia, but it can cause serious adverse reactions. Experts at the Paul-Ehrlich-Institut investigated whether the regulatory measures currently in force, such as amended treatment guidelines in the investigator's brochure in clinical trials, contribute to making the use of the therapy safer. The extensive analysis showed that the current measures can lead to benefits such as a reduction of severe immune system disruptions. Transfusion Medicine and Hemotherapy reports on the results in its online edition from 29 November 2022.
By the end of 2021, three CAR-T cell products had received marketing authorisation for the European Union. CAR-T cells are genetically modified immune cells (T cells) from diseased patients. A certain type of immune cells (T cells) are removed from the patient for the production of CAR-T cells. These cells are genetically engineered outside the body with a chimeric (synthetic) antigen receptor (CAR), expanded and returned to the same patient. The antigen receptor is an exact fit to certain surface structures on the cancer cells. In the case of the above-mentioned authorised CAR-T cell therapies the receptor is directed to the CD19 antigen. Since the immune cells are equipped with the chimeric antigen receptor, it is now possible to recognise and kill the cancer cells.
In the EU, all three CAR-T cell therapies have undergone an accelerated assessment (priority medicines procedure, PRIME) to facilitate the development and clinical use of advanced therapy medicinal products that address unmet medical needs.
In the clinical trials, CAR-T cells showed remarkable therapeutic effects in patients suffering from recurrent or refractory B-cell tumours. However, CAR-T cells are associated with a number of serious adverse reactions, including cytokine release syndrome (CRS) with fever and low blood pressure and central nervous system impairment. Severe cases of cytokine release syndrome can lead to multi-organ failure and thus become life-threatening. The occurrence of neurotoxicity is also common. Clinical appearance of neurotoxicity varies and can range from headaches and lack of concentration to the development of brain edema.
It is therefore important to detect these toxicities, which may occur suddenly during treatment, at an early stage and to mitigate adverse reactions with prompt intervention. Timely treatment can also increase the chance of a therapeutic benefit. This is already relevant during clinical development, as unexpected adverse events can lead to the interruption or termination of clinical trials. Strict monitoring and adaptation of treatment protocols is important, even after marketing authorisation has been issued.
Are the currently prescribed treatment protocols effective in reducing the frequency of particularly serious adverse reactions? In order to answer this question, regulatory experts from the Safety of Medicinal Products and Medical Devices Division at the Paul-Ehrlich-Institut re-evaluated clinical study data, analysed reports in the European database for adverse drug reactions, and conducted a survey of treating physicians.
The experts found that after a revision of the investigator's brochure treatment guidelines for patients treated with CAR-T cells there were fewer severe cases of cytokine release syndrome (proportion of CRS ≥ grade 3: 2.4% vs. 5.1%) and a lower neurotoxicity rate (5.6% vs. 9.6%).
The evaluation of the reports in the European database, which records adverse drug reactions after market introduction, showed that essential information was lacking in many cases. Only 38.3% of CRS cases had complete information on the treatment indication, the occurrence of CRS, the outcome, and the severity grading. It is therefore useful to systematically monitor novel therapeutics even after they have been introduced to the market via approaches such as register studies.
Finally, the treatment centre survey showed that the majority of practitioners consider the legal requirements to be sensible. The analysis also showed, however, that it would be useful to harmonise the regulatory requirements for the various CAR-T cell therapeutics.
Based on this data analysis, the Paul-Ehrlich-Institut experts conclude that clearly defined regulatory measures make an important contribution to the safe and effective use of new therapeutics. In addition, it is important to regularly re-evaluate any new measures in order to continuously improve the regulatory requirements. Improved regulation leads to effective and safe therapy for diseases, which have hitherto been difficult to treat.
Updated: 19.12.2022
