Team BORIES

Pathophysiology of Multiple Myeloma and Next-Generation Immunotherapies

Over the past decade, long non-coding RNAs (lncRNAs) have emerged as important modulators of epigenetic state and chromatin structure. LncRNAs play essential regulatory roles during normal development and differentiation processes, and the deregulation of their expression is implicated in the onset and etiology of many malignant diseases, including MM.

We use high-throughput functional screening, transcriptomic and epigenetic approaches to study the contribution of lncRNAs to various aspects of MM pathophysiology, with the goal of identifying novel prognostic markers and therapeutic targets. Our recent work has focused on a lncRNA called CRNDE, whose expression is elevated in tumor plasma cells from MM patients, and which contributes to MM cell proliferation and survival. To understand its mechanism of action, we recently performed a high-throughput molecular screen to identify partner proteins interacting with CRNDE. This study revealed that in MM cells, CRNDE interacts with and stabilizes the deacetylase protein SIRT1, leading to downstream effects on Hedgehog signaling, a pathway important for the survival and self-renewal properties of MM tumor cells. In our ongoing work, we are combining transcriptomic profiling of patient samples with CRISPR-based high-throughput functional screens of differentially expressed lncRNAs, in order to identify novel lncRNAs influencing the tumorigenic properties of MM cells as well as the development of resistance to immunotherapies.

CAR T cells expressing a chimeric antigen receptor targeting BCMA (B Cell Maturation Antigen), currently used to treat MM patients, have shown impressive initial response rates, but many patients relapse and develop resistance. Our research, supported by clinical trials, aims to identify the molecular mechanisms associated with resistance of tumor plasma cells to CAR T therapy and to develop improved CAR strategies, initially for MM and then for other lymphoid malignancies.

Identification of mechanisms of tumor plasma cell resistance to anti-BCMA CAR T cell activity.

Analysis of clinical data from patients treated with anti-BCMA CAR T cells (Ide-cel) reveals good initial response rates but a relatively short progression-free survival (< 13 months). By combining genomic strategies (RNAseq) on patient plasma cells with in vitro functional screening methods (CRISPR/Cas9), we are currently seeking to identify genes associated with MM cell resistance to CAR T cells. Our results will allow better prediction of patient survival and improvement of therapeutic cell activity in vivo.

Characterization of mechanisms regulating in vivo CAR T cell persistence.

Our results indicate that CAR T cells derived from heavily pretreated patients show reduced efficacy in vitro and in mouse models, compared to CAR T cells derived from patients at diagnosis or from healthy donors. These data, together with other studies in the literature, suggest that the short-lived clinical remissions observed in MM patients after CAR T therapy are most often attributed to exhaustion processes, leading to limited persistence and dysfunction of therapeutic T lymphocytes. We are developing genome-wide functional screening strategies (CRISPR/Cas9) to characterize genes whose inactivation improves anti-BCMA CAR T cell persistence in a murine MM model. This program will provide new insights into the mechanisms associated with CAR T cell persistence in MM and may yield data applicable to other cancers.

Development of new CAR T cells.

Despite the impressive clinical results obtained with CAR T cells targeting BCMA, many patients relapse, and MM remains an incurable disease. The majority of clinical trials have evaluated CARs containing signaling domains derived from CD3z and 4-1BB (or CD28) molecules, without knowing whether these combinations are optimal. Recent work by team members has suggested new approaches: (i) novel targets on MM cells (CCR10/ITGB7); (ii) different signaling domains; (iii) dual CAR T cells targeting CD38 and CS1 antigens. We are currently combining and testing these modifications in order to improve the efficacy of dual CAR T cells in MM and other hematological malignancies.