CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: Chronic lymphocytic leukemia (CLL) is considered the one of most prevalent hematological diseases in the Western world, with an incidence of 4.2/100 000/year that increases to more than 30/100 000/year at an age of greater than 80 years. The Bruton tyrosine kinase inhibitor ibrutinib has been considered the treatment of choice in treatment naïve and relapsed/refractory settings (R/R). Venetoclax, along with navitoclax, are the selected BCL2 inhibitors in first and second-line settings for chronic lymphocytic leukemia. A degree of acquired resistance for this agents has been observed in clinical settings, and is also determined by scientific rationale. METHODS: A PubMed literature search and Google Scholar search were conducted using the terms "chronic lymphocytic leukemia" AND "novel therapies", "BTK degraders", and "acquired resistance", and "bispecific antibodies", and "chimeric antigen T cell therapy." " recent phase III trials" and "CLL" AND "MURANO trial" AND "BRUIN trial" AND "CLL14 trial" AND "TRANSCEND trial" AND "updates." RESULTS: Acquired resistance has been extensively documented in treatment of CLL, mainly due to the mutation Gly101Val that leads to displacement of pro-apoptotic proteins. Newer agents identified include pirtobrutinib and nemtabrutinib, non-covalent, reversible BTK inhibitors, the anti-CD20 monoclonal antibodies employing CD20 target antigen mechanisms ofatumumab, obinutuzumab, lisocabtagene maraleucel, a CD19 chimeric antigen T cell receptor therapy, teclistamab, a BsAb that targets the B cell maturation antigen or BCMA and Siglec-6 monoclonal antibodies. CONCLUSION: CLL has demonstrated acquired resistance to BTK inhibitors and BCL2 inhibitors, necessitating the development and evaluating of treatment options beyond their use. Cancer immunotherapies such as bispecific antibodies and chimeric T cell therapies present with viable therapies for CLL. Novel agents have also been developed that enhance the cytotoxic effect of T cells. Future studies may focus on the developing treatments that overcome the acquired resistance that results when treatment with standard of care targeted therapies ibrutinib and venetoclax.