A new study published on Nature shows that a trispecific antibody to HER2, CD3 and CD28 could enhance immune-cell activation and contribute to the regression of breast cancer in a murine model by a CD-4 dependent inhibition of tumor cell cycle progression.
Among successful immunotherapies, approved bispecific antibodies such as blinatumomab have stimulated interest in other multispecific antibody therapies; since some cancers, such as triple-negative breast cancer, express physiological levels of HER2 and are resistant to HER2-targeted monoclonal antibody therapy, the authors tried to develop improved therapies against such malignancies by generating a trispecific antibody composed of HER2, CD3 and CD28 arms that, respectively, target, activate and prolong survival of T cells that lyse these tumors. Tested in a humanized mouse model of breast cancer, the trispecific antibody stimulated regression of tumors through a mechanism involving CD4-dependent inhibition of tumor cell cycle progression. Although CD8 T cells directly mediated tumor lysis in vitro, CD4 T cells exerted antiproliferative effects by blocking cancer cell cycle progression. Furthermore, when Tcell subsets were adoptively transferred into a humanized breast cancer tumor mouse model, CD4 T cells alone inhibited HER2+ breast cancer growth in vivo. RNA microarray analysis revealed that CD4 T cells markedly decreased tumor cell cycle progressionandproliferation, and also increased pro-inflammatory signaling pathways. «CD4 T cells exerted antiproliferative effects that contribute toregression of breast cancers in humanized mice; thus the trispecific antibody to HER2 induced T cell-dependent tumor regression through direct antitumor and indirect pro-inflammatory/immune effects driven by CD4 T cells», authors conclude.