Investigating the causes of the varied response to CAR-T treatment
What is CAR-T therapy?
CAR-T therapy involves the modification of a patient's T lymphocytes so that they are equipped with a specially designed receptor, the so-called chimeric antigen receptor (CAR). This receptor allows the CAR-T lymphocyte to specifically bind to the cancer cell and eliminate it. Numerous studies have proven the effectiveness of CAR-T therapy. Its use is associated with high rates of complete response (e.g., up to 54% for large B-cell lymphoma, up to 93% for B-cell acute lymphoblastic leukemia). Among patients achieving disease remission, long-term response is observed in tens of percent. It is worth noting that CAR-T lymphocytes have been administered to patients in the Department of Hematology, Transplantation and Internal Medicine MUW for more than two years - both as part of drug programs and a non-commercial clinical trial in which Prof. Grzegorz Basak, supervisor of my project entitled “Identification and characterization of omics profiles in the serum of patients undergoing anti-CD19 CAR-T therapy,” is the principal investigator. Thanks to the commitment of the department's team, patients receive treatment according to the highest world standards.
Why it is important to study the mechanisms of the diverse response to CAR-T treatment
Currently, CAR-T lymphocyte research is focused on several areas. One is the development of CAR-T lymphocytes with improved constructs, including allogeneic (taken, for example, from a healthy donor) or “transient” (mRNA-based), their testing in preclinical studies and then in the department. Another field concerns strictly clinical trials, which evaluate the efficacy of therapies in earlier lines of treatment, in combination with other therapeutics or in new indications. Another field is basic research, which focuses on understanding, among other things, the mechanisms and pathophysiology of observed events. It is in this area that we focus our interest. This is due, among other things, to the fact that despite the high efficacy of CAR-T therapy, there is still a relatively high percentage of patients who do not achieve a response to treatment. Moreover, CAR-T therapy is associated with serious side effects, such as cytokine release syndrome (CRS), neurotoxicity and persistent blood count abnormalities. To date, the reasons behind the variability in response to treatment and patients' propensity for adverse events have not been determined.
The pathogenesis of the above phenomena is most likely very complex, and its explanation requires a holistic approach, taking into account processes occurring at the level of the whole organism, as well as locally. Thousands of different proteins and small-molecule compounds (metabolites) are present in the human body at any given time, and are involved in processes occurring at different levels of the body. The totality of proteins and metabolites is called the proteome and metabolome, respectively, and the study of them is called proteomics and metabolomics (collectively called omics). The type and level of proteins and metabolites provide a fingerprint, so to speak, from which it is possible to determine what reactions take place in the body, what substances are produced in excess and what substances are lacking. This makes it possible to determine the molecular basis of the phenomena observed in the department and to design targeted therapeutic interventions.
How the study by MUW scientists will proceed
At the Medical University of Warsaw, we have omic analysis capabilities at the Regenerative Medicine Laboratory MUW headed by Prof. Magdalena Kucia, with expertise in basic research in hematology. As part of this collaboration, omics analysis of samples is performed using mass spectrometry. The resulting data are analyzed using bioinformatics techniques and linked to clinical data. To date, we have already piloted the validation of the methodology, during which we detected, among other things, an overrepresentation of non-specific immune response elements in patients developing CRS. It is worth noting that obtaining the material for our study is a minimally invasive process for the patient - it involves additional collection of a small amount of blood. We collect the material at several time points, before and during CAR-T lymphocyte therapy. This allows us to capture changes in proteomic and metabolomic profiles occurring over time. In addition, the use of readily available material increases the chances of later applicability of the result.
In conclusion, there is currently a lack of well-established knowledge of how the patient's proteome and metabolome are linked to the course of CAR-T therapy. The lack of understanding of the molecular basis has a limiting effect on the efficacy of CAR-T therapy. The purpose of our study is to identify the proteomic and metabolomic profiles present in patients undergoing CAR-T therapy and to relate them to treatment response and the presence of adverse events. The information thus obtained will allow us to better understand the details of the pathogenesis of adverse events and to characterize potential predictors of response to CAR-T therapy. In the long run, we hope that the data obtained will allow us to optimize the care of patients undergoing CAR-T therapy.