In this study we focussed mostly on idecabtagene vicleucel which was the first FDA approved BCMA-directed CAR T-cell therapy for patients who had received four or more prior lines of therapy, this was back in March 2021. We had seen some toxicities, particularly severe toxicities like grade 3 or higher CRS and ICANS, occurring in about 5.52% of patients. But what we wanted to really analyse in the study is what factors predispose a patient to experience these severe toxicities and then what factors may associate with durable responses. So really the main purpose of our study was to identify and analyse pre-treatment characteristics and key biomarkers that are associated with the toxicity and durable responses in patients receiving commercial idecabtagene vicleucel and consented to a biospecimen protocol at our institution.
What was the study design?
This was essentially a retrospective sample study. We had about 108 patients that were included in this study. As I mentioned, all of them received standard of care idecabtagene vicleucel. In this protocol we analysed serum cytokines at different timepoints within a patient’s treatment course utilising a type of immunoassay called ELISA immunoassay. We isolated peripheral blood mononuclear cells and that’s to capture peak CAR T expansion at several timepoints. Then we also looked at bone marrow biopsies that were done before the initiation of CAR T-cell therapy and that’s to analyse immune cell subsets and part of the bone marrow environment that may predict for these toxicities and durable responses.
What were the results of this study?
In this study, as I mentioned, we had about 108 patients. We found that about a third of the patients had very high risk features, particularly patients with extramedullary disease, those who had penta-class refractoriness, high plasma cell burden and high risk cytogenetics. We also identified that patients who were more likely to experience severe CRS, so grade 2 or higher CRS, these patients received a higher median CAR T-cell dose and in those who were more likely to experience neurotoxicity these patients had a higher plasma cell burden, more advanced disease, triple class refractoriness and a higher baseline inflammatory state. There’s evidence by clinical biomarkers that ferritin is a very active protein. We also found some cytokine associations with CRS as well as ICANS and we identified certain immune subsets that also associated with CAR expansion as well as durable response. Particularly we identified that monocytic myeloid-derived suppressor cells reduced CAR expansion. We found that peak cytokines associated with peak CAR expansion and ultimately a durable response. Also, durable responders were more likely to have higher CD4/CD8 ratios as well as stem central memory CD8+ T-cells in their pre-CAR-T bone marrow biopsy. We did also identify that in patients who have high disease burden they’re more likely to experience T-cell exhaustion, or markers of T-cell exhaustion were found in the bone marrow biopsy, essentially leading to impaired activation proliferation, increased expression of inhibitory immune receptors favouring tumoral immune tolerance.
What do you think is the significance of these results?
I think the significance here is that we were able to identify that patients who have a high disease burden and a high inflammatory state were able to identify an association with toxicity and durable response as well as an association with cytokines, immune subsets with CAR expansion and durable [??] responses in patients receiving this product. But really what’s important about this study is that it hopefully provides some insight into potential avenues for toxicity mitigation as well as therapeutic optimisation in patients who are deemed to be high risk for experiencing either a non-durable response or increased risk for toxicities. This is not just restricted to ide-cel, it could be for any novel immunotherapies.
