Introduction:
The Food and Drug Administration (FDA) has approved immunotherapy for some patients with mantle cell lymphoma, a rapidly growing blood cancer that has proven difficult to treat effectively. Brexucabtagene Autoleucel (Tecartus), a CAR T-cell therapy, has been approved for patients with mantle cell lymphoma that has not responded to other treatments or have returned.
B cells, a subset of white blood cells, are where mantle cell lymphoma develops. Mantle cell lymphoma is typically diagnosed in its most advanced, aggressive form when it has already spread. Brexucabtagene was tested in 60 patients with mantle cell lymphoma who had received up to five prior treatments in a clinical trial called ZUMA-2, the foundation for the FDA's approval.
In the trial, Brexucabtagene effectively treated 87% of the patients, and 62 % of those patients experienced a complete response, which meant they temporarily lost all signs of the disease.
What Is Mantle Cell Lymphoma?
Mantle cell lymphoma (MCL) is a relatively uncommon subtype of B-cell lymphoma with a wildly varying clinical course. MCL is an abnormal expression of CD5, mature B-cell antigens (CD19, CD20, and CD22), IgM and IgD surface immunoglobulins, and other immunoglobulins. In the majority of cases, cyclin D1 (CCND1/PRAD-1 gene) is overexpressed due to the signature chromosomal translocation t(11;14)(q13: q32).
Cyclin D1, a cell cycle regulator, is a biomarker for pathologies with malignant B lymphocytes, which include MCL, because normal B lymphocytes do not express it. Although this overproduction of oncogenes causes the cell cycle to be dysregulated, it is not the only reason for the development of MCL. MCL development depends on secondary oncogenic pathways, such as mutations resulting in dampened DNA damage response mechanisms.
The median age at diagnosis for MCL is 67, and there is a 2:1 clinical male predominance. High serum lactate dehydrogenase (LDH) levels, advanced age, male sex, blastoid variant, advanced stage, extensive nodal involvement, and prognostic biomarkers like high Ki-67 expression index and presence of TP53 mutation are all indicators of poor outcome. MCL is still an incurable lymphoma, despite improvements in our knowledge of its pathogenesis and management strategies. Despite being effective, new medications like Bruton tyrosine kinase (BTK) inhibitors, Lenalidomide, and Venetoclax have a short duration of action and eventually cause relapse in patients. Novel drugs are required to treat high-risk patients with TP53 aberrations, high Ki-67 levels, or progressed after BTK inhibition.
What Is the Management of Mantle Cell Lymphoma?
Age and comorbidities have an impact on MCL management. Patients in the younger, physically fitter population receive chemotherapy regimens with high-dose Cytarabine as an induction treatment, then autologous stem cell transplantation as a consolidation treatment (ASCT). For older patients and people with poor functional status, maintenance Rituximab therapy and less intensive chemotherapy are options.
CAR T-cell therapies that target B-cell antigens are highly effective in treating B-cell leukemia and lymphomas, including MCL. Targeting cell surface B-cell antigens in relapsed and refractory MCL is a viable strategy, given the significant responses in other B-cell malignancies. The data that are currently available for CAR T-cell therapy for MCL will then be examined, with a focus on Brexucabtagene Autoleucel (Brexu-cel, formerly KTE-X19), which is accepted for use in patients with relapsed and refractory MCL.
Non-intensive Therapy:
Older patients or those with comorbid conditions cannot tolerate intensive induction with high-dose Cytarabine. Regimens such as Bendamustine and Rituximab or Bortezomib, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (VR-CAP) are preferred treatments. Lenalidomide and Rituximab can also be considered in untreated patients who are not eligible for intensive induction.
Intensive Therapy:
The duration of response is improved by consolidation with ASCT. For younger MCL patients, several highly effective induction regimens include high-dose Cytarabine. These regimens include the Nordic regimen, which consists of augmented-strength Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (maxi-CHOP) alternated with high-dose Cytarabine and Rituximab, R-CHOPand also alternated with Rituximab, Dexamethasone, Cytarabine, and a platinum-derivative (R (RC). Explains these regimens in detail. Following ASCT, Rituximab maintenance has also been shown to improve overall survival. Even though most young patients have excellent outcomes, some high-risk populations do not benefit much from intensive therapy. Shorter OS rates and progression-free survival are linked to a high Ki-67 proliferation index above 30%.
CAR T Cell Therapy:
Brexu-cel is a second-generation CAR with an intracellular CD28 costimulatory domain, an external single-chain variable fragment (scFv) domain, and a T-cell receptor CD3 signaling domain. In conjunction with the intracellular CD3 signaling domain, the outer domain of the CAR-T cell enables it to identify and attach to the CD19 antigen on B-cells. This activates T-cell signaling and sets off a series of cytokine events that promote tumor eradication. By directly releasing cytotoxic granules containing the anti-apoptotic agent's granzyme B and perforin, CAR induces apoptosis in tumor cells. CAR-T cell expansion, persistence, and antitumor activity are all enhanced by co-stimulation with CD28.
Brexu-cel and Axi-cel have the same CAR design, but the manufacturing techniques differ significantly. Leukapheresis is used in both products to gather autologous peripheral-blood mononuclear cells, which are subsequently delivered to the production facility. Brexu-cel requires a T-cell-enrichment step because the autologous product contains leukemic blasts or lymphoma cells from patients with acute lymphoblastic lymphoma and MCL.
Magnetic beads coated with anti-CD4 and anti-CD8 antibodies perform T-cell enrichment. The CAR gene is then transferred using a lentiviral vector after the product has been cultured in IL-2. The CAR-T product is collected and put through quality control testing before release. No specific T-cell subsets are chosen for the finished product with either Brexu-cel or Axi-cel.
Conclusion:
Despite multiple advancements, MCL remains an incurable disease. Future directions in the treatment of MCL are moving toward utilizing combinations of different targeted agents, such as the concurrent inhibition of BTK, BCL2, and targeting of CD19. As CAR-T therapies become standard in treating relapsed and refractory lymphomas, Brexu-cel and Liso-cel are also proving efficacious in relapsed and refractory MCL.
