Research we fund

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by resistance to standard treatments and short survival. For the 2023 LLS MCLII Synergistic Team Award, we have assembled a team of leaders in basic, translational, and clinical research in MCL to tackle the current significant obstacles in understanding and treating MCL. In the last decade, we investigated the therapy resistance mechanism of MCL, and pioneered clinical trials for targeted therapies (ibrutinib, lenalidomide) and chimeric antigen receptor T-cell (CAR-T) therapy. However, despite these dramatic advancements, resistance to these newer therapies, including targeted therapy and CAR-T cells, is seen in over 50% of patients. Thus, it remains an unmet need to better define the mechanisms of resistance and then develop rationally designed strategies to overcome resistance. The overall goal of this Synergistic Team Award is to develop improved curative therapies for patients with MCL at relapse. The goals will be addressed in three highly focused, independent but highly integrated projects that utilize state-of-the-art genomic technologies, patient-derived xenograft models, clinical data and primary MCL samples. With the joint effort of our laboratories, highly interactive and accomplished scientists, and physician researchers from multiple institutions with expertise in MCL and therapy, we are uniquely poised to develop improved next-generation of combination therapy for relapsed MCL patients.

The MULTIPLY is a large multi-institutional project aimed at characterization of a variety of clinical predictors, both baseline and at relapse through three interconnected Work Packages (WP) with the following objectives: I) Identification of clinical factors affecting prognosis and characterization of relapses; II) Identification of lymph node biomarkers III) characterization of liquid tissue associated biomarkers. All parameters will be integrated through biostatistical and artificial intelligence tools to establish a comprehensive model of relapse prediction and optimal salvage treatment. The proposal is conducted by the Eu-MCL-Network which is the largest group conducting clinical and translational research worldwide in MCL including the largest phase III trials ever conducted. MULTIPLY will exploit the extensive dataset and tissue bank of the TRIANGLE trial that will be presented as abstract #1 at the ASH plenary session. This study will establish a novel standard by the addition of ibrutinib to first-line treatment, but will also raise relevant issues for prediction and management of disease relapse in first-line BTK-era. The expected results will be the generation of comprehensive integrated models for relapse prediction MCL and development of an effective platform to develop rational chemotherapy-free strategies based on genetic alterations of the malignant cell and innovative biomarker-driven strategies.

Most patients respond well to drugs that inhibit an important MCL target named BTK. However, almost all of them will eventually relapse and then do very poorly. Inhibition of MALT1, a target which is biochemically downstream of BTK, may rescue many of these patients, and inhibiting both BTK and MALT1 may be better still. Developing a drug that inhibits both targets at the same time, from the beginning of treatment, will avoid some complications and likely be best of all; we will find out.