Chronic lymphocytic leukemia (CLL) is one of the most commonly occurring hematologic malignances with no known cure and is defined by the clonal expansion and accumulation of CD5+ B cells in the blood and bone marrow. Standard treatments to manage disease include chemotherapy and rituximab (anti-CD20 monoclonal antibody). Newer therapies that are less prone to resistance or treatment failure are currently being examined, such as Bruton tyrosine kinase (BTK) inhibitors and anti-CD20 biosimilars,.
T cells play a critical role in anti-tumor responses, but CLL patients typically have CD4+ and CD8+ T cells with functional and phenotypic changes consistent with exhaustion that is likely to limit their efficacy. Untreated CLL patients commonly have elevated levels of regulatory T cells (Tregs) in peripheral blood, and this increase in Tregs can cause immune suppression and allow malignant CLL blasts to proliferate as anti-tumor immune responses are suppressed. Phenotypic characterization of T cells provides critical insights into the potential efficacy of different immuno-oncology treatments, as recently described in a study that identified T cell signatures associated with the efficacy of chimeric antigen receptor (CAR) T cell-based treatment of CLL.
Champions Internal data collected from the CLL VitroScreen evaluating Venetoclax treatment ex vivo
Newly developed immuno-oncology therapies can reverse immune suppression and restore T cell functions. Treatment with BTK inhibitors such as ibrutinib have been shown to improve cytotoxic T cell functions, suppress Tregs, decrease immune checkpoint molecule expression and restore cytokine responses,,. Ibrutinib also appears to attenuate the inflammatory environment in the bone marrow that allows CLL B cells to suppress antitumor responses. Together these effects can restore T cell function and improve antitumor responses to CLL, especially relapsed or refractory (R/R) CLL. Venetoclax is another recently licensed R/R CLL treatment that inhibits the function of the antiapoptotic protein B cell lymphoma 2 (Bcl2), which is constitutively expressed in CLL cells and causes resistance to apoptotic cell death. Venetoclax is a highly selective inhibitor that can induce apoptosis in CLL and reduce immunosuppression and can be combined with other immune-oncology treatments. Pevonedistat is a first-in-class Nedd8-activating enzyme inhibitor that can sensitize CLL cells to death-receptor mediated apoptosis and has been given a Breakthrough Therapy Designation for the treatment of higher-risk myelodysplastic syndromes, like CLL, in combination with other chemotherapeutics.
These recent breakthroughs in immuno-oncology development highlight the importance of functional T cell responses and the flexibility of the immune system that allows for such responses to be restored, even under chronic immunosuppression.
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