A strong force against lymphoma: CAR T-cell therapy
CAR T-cell therapy is an immunotherapy that is used against certain types of leukaemia and lymphoma. The side effects often include inflammation. Certain genetic changes in blood cells - "clonal haematopoiesis of undetermined potential" - have also been linked to inflammation. Researchers have investigated whether they influence the success of CAR T-cell therapy and its side effects.
In CAR T-cell therapy, T-cells from lymphoma or leukaemia patients are genetically modified outside the body and then re-administered to the patients. These T cells carry an artificial receptor ("chimeric antigen receptor", CAR), which enables them to specifically attack tumour cells. The side effects of this innovative treatment method often include inflammation. Researchers at the University Hospital Dresden, the University of Dresden, the National Centre for Tumour Diseases (NCT) Dresden, the German Cancer Research Centre (DKFZ) Heidelberg and Dresden and the German Centre for Translational Cancer Research (DKTK) have investigated whether the outcome of CAR T-cell therapy and its possible side effects are influenced by the presence of "clonal hematopoiesis of indeterminate potential" (CHIP). This is because CHIP can be detected in many patients undergoing CAR T-cell therapy. In addition, CHIP, which occurs mainly in older age, is also often associated with inflammation.
Outcome and side effects: No influence of CHIP
The scientists in Dresden and Heidelberg analysed biosamples from 32 patients suffering from aggressive lymphoma before and after treatment with CAR T-cells. Before starting therapy, they detected CHIP in eleven of the 32 patients. "The analyses after CAR T-cell treatment showed that the patients with CHIP responded comparably well to the therapy," says Dr. Raphael Teipel from the University Hospital Dresden. "And we also found no significant difference in the occurrence of side effects of the CAR T-cell therapy. First of all, that is a good sign for patients."
Deep sequencing as a method
The researchers analysed the samples using the state-of-the-art deep sequencing method. Scientists use sequencing to determine the order of nucleotides in DNA. The comparison of healthy and mutated DNA sequences enables, for example, the diagnosis of various diseases, including different types of cancer. Deep sequencing involves the targeted sequencing of specific gene loci.
MNCs/PBMCs: Isolation of special cells by BioBank Dresden
To be able to use this method, the researchers needed white blood cells (leukocytes). Employees of BioBank Dresden isolated these cells from the blood and bone marrow samples and made them available in cryopreserved form. "The isolation of such mononuclear cells as well as mononuclear cells of the peripheral blood - called MNCs and PBMCs - is a very sensitive processing step that is not only extremely time-consuming but can also have a decisive influence on the quality of the samples," says Dr. Heidi Altmann, scientific coordinator of the Dresden Integrated Liquid Biobank at BioBank Dresden. "Our biobank has great expertise in this area. That is why we are particularly pleased that we were able to provide high-quality samples for this study, on the basis of which our colleagues gained important insights.“
Further research needed
Further studies are needed to shed light on the possible influence of CHIP on CAR T-cell therapy. "Although we were unable to establish a connection between the presence of CHIP and increased inflammation as side effects of immunotherapy or an inferior outcome, one reason for this could be the small size of the group of patients who were included," says senior author PD Dr. Malte von Bonin from the German Cancer Research Center (DKFZ) Dresden and German Center for Translational Cancer Research (DKTK). "An important question for the future is whether CHIP can progress in conjunction with CAR T-cell therapy and increase the risk of other diseases in the longer term."
Photo credit: University Hospital Carl Gustav Carus Dresden/BioBank Dresden
Raphael Teipel, Frank P Kroschinsky, Michael Kramer, Theresa Kretschmann, Katharina Egger-Heidrich, Thomas Krüger, Leo Ruhnke, Sylvia Herold, Sebastian Stasik, Katja Sockel, Jan M Middeke, Karolin Trautmann-Grill, Martin Bornhauser, Christian Thiede, Malte von Bonin; Prevalence and variation of CHIP in patients with aggressive lymphomas undergoing CD19-directed CAR-T-cell treatment. Blood Adv 2022; bloodadvances.2021005747. doi: doi.org/10.1182/bloodadvances.2021005747
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