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3 minute read
Mantle cell lymphoma (MCL) is a rare and aggressive non-Hodgkin’s lymphoma (NHL) that originates in B cells and occurs in secondary follicles of the lymph nodes.1 MCL accounts for roughly 6% of all lymphomas diagnosed annually, and despite its relatively low incidence, the aggressive course of MCL means it can quickly become a life-threatening disease. Understanding the origin and progression of MCL is crucial to identify new targets for drug development studies.
Understanding Mantle Cell Lymphoma Pathology
Over the last decade, our understanding of MCL pathogenesis has evolved from a single definition to a consensus that MCL development and progression is related to a range of molecular events. Early on MCL was defined as a pathognomonic chromosomal translocation t(11;14)(q13;q32) causing a mutation in the CCND1 gene, resulting in the over-expression of Cyclin D1.1, 2
Under normal conditions, Cyclin D1 is heavily regulated and modulates cell cycle transition from G1 phase to S phase.1 However, overexpression of Cyclin D1 activates cyclin-dependent kinases (CDK) 4 and 6 which later deactivate the retinoblastoma protein (Rb), a cell cycle inhibitor. This series of events accelerates cell cycle progression from G1 to S phase in many cell types, including B-cells.3 The progression of this process induces uncontrolled B-cell proliferation causing an enlargement of lymph nodes and immune system dysfunction that eventually spreads to critical organs.
Fewer Mutations Raise More Questions
Interestingly, Cyclin D1 mutations are not found in all MCL cells, suggesting other molecular actors, such as transcription factors, are involved. In 90% of MCL patients, transcription factor SOX11 is over-expressed in MCL cells with and without mutated CCND1. While SOX11’s role in MCL is not well understood, studies suggest that PAX-5, a transcription factor that regulates B-cell development and differentiation, is activated by SOX11.4 The overexpression of SOX11 that is commonly seen in MCL patients can therefore lead to reduced B-cell differentiation and increased B-cell antigen signaling.3, 5
Identifying Treatment Targets in Mantle Cell Lymphoma
B-cell proliferation and differentiation rely on B-cell receptor (BCR) signaling and are activated in response to antigen binding.6 Using the framework for CLL pathogenesis, preliminary MCL-BCR research has found that BCR signaling is highly active in MCL patients and intentional BCR activation resulted in an increase of BCR signaling in MCL cells.7 Additionally, murine studies have found SOX11-overexpressing B-cells have high levels of BTK, a key enzyme involved with BCR signaling, resulting in proliferation which suggests SOX11’s deeper role in MCL.7
Initial MCL treatment includes R-CHOP therapy, however, many MCL patients are refractory or become resistant creating a need for additional therapies. As with CLL, BCR signaling plays a critical role in MCL progression shifting treatment protocols towards BTK inhibitors (BTKi) like ibrutinib, approved in 2013.1, 3 Ibrutinib is metabolized in the liver via CYP3A and CYPRD6 and irreversibly binds to cysteine residue 481 found on the active site of BTK.
While this targeting strategy effectively blocks BTK signaling limiting MCL cell development, ibrutinib has significant off-target consequences, namely IL-2 inducible kinase (ITK), which sparked the development of zanubrutinib.8 Zanubrutinib was approved for use in MCL patients and though it has a similar mechanism of action to ibrutinib, its reduced affinity for ITK, a major T-cell and natural killer (NK) cell regulator,9 makes it a highly selective and potent BTKi with improved overall response rate relative to ibrutinib.8
Resistant Mantle Cell Lymphoma and Future Therapeutic Strategies
Unfortunately, 32% of MCL patients become resistant to BTKi due to BTK mutations.10, 11 As a result, combination therapies such as ibrutinib combined with cirmtuzumab (a novel anti-ROR1 monoclonal antibody) or with obinutuzumab and venetoclax have been used to treat resistant MCL patients. 11 These therapeutic combinations have shown excellent remission results paving the way for other combination therapies, such as acalabrutinib, rituximab, and bendamustine. 11, 12 Notably, a phase 1 study investigating acalabrutinib, rituximab, and bendamustine achieved an 85% overall response rate which has led to a larger, ongoing Phase 2 study (NCT04115631). Additionally, novel MCL-1 inhibitors are under development in preclinical studies.13
Recently, the FDA has approved the first CAR T cell therapy for relapsed/refractory MCL, brexucabtagene autoleucel (Tecartus).14 Tecartus has shown durable response at the 3-year follow-up even in high-risk patients (NCT02601313), with sustained survival and a 67% complete response rate.15
Understanding the pathophysiology of naïve and BTKi resistant MCL is crucial to developing curative MCL therapies. While standard of care treatments like ibrutinib and zanubrutinib have had some success, additional studies investigating strategic combination therapies are underway providing hope for patients battling this disease.
Champions supports your in vivo preclinical studies with low passaged MCL PDX models available for subcutaneous modeling and fully characterized with NGS data in 4 models CTG-3771, CTG-3772, CTG-3776 (shown to be rituximab and ibrutinib resistant) and CTG-3808. Preclinical hematological scientists need to evaluate their pipeline of therapeutic candidates in robust hematological screening platforms; Champions' VitroScreen platform can advance potential next-generation therapies into the clinic, generating additional options for MCL patients.
