Despite the significant therapeutic advances provided by the immune-checkpoint blockade and chimeric antigen receptor T cell treatments, many malignancies remain unresponsive to immunotherapy. Bispecific antibodies targeting tumor antigens and activating T cell receptor signaling have shown some clinical efficacy; however, providing co-stimulatory signals may improve T cell responses against tumors. Here, we developed a trispecific antibody that interacts with CD38, CD3 and CD28 to enhance both T cell activation and tumor targeting. The engagement of both CD3 and CD28 affords efficient T cell stimulation, whereas the anti-CD38 domain directs T cells to myeloma cells, as well as to certain lymphomas and leukemias. In vivo administration of this antibody suppressed myeloma growth in a humanized mouse model and also stimulated memory/effector T cell proliferation and reduced regulatory T cells in non-human primates at well-tolerated doses.
Lan Wu, Edward Seung et al. Nature Cancer 18 Nov 2019 https://doi.org/10.1038/s43018-019-0004-z.
Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. After a successful phase 2 trial involving patients heterozygous for Phe508del CFTR mutation and a minimal function mutation (Phe508del–minimal function genotype), showed the combination of elaxacaftor, tezacaftor, and ivacaftor improved the Phe508del CFTR function and clinical outcomes. In a multicenter (115 sites in 13 countries) phase 3 trial, involving 200 patients on the triple-drug and 203 placebo patients, an improved clinical and functional outcome was shown as it was confirmed by a concurrent phase 3 trial (Heijerman HG et al. Lancet 2019 Oct 31) of the same combination regimen. The drug combination had an acceptable side-effect profile and was generally safe. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor–tezacaftor–ivacaftor group. The FDA approved the drug combination, called Trikafta made by Vertex Pharmaceuticals, Boston MA, on 21 Oct 2019.
Middelton PG et al. NEngJM Oct 31 10.1056/NEJMoa1908639