The activated conformation of integrin β7 is a novel multiple myeloma–specific target for CAR T cell therapy

Abstract

Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin β molecules. The MMG49 epitope, in the N-terminal region of the β chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin β conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin β lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target.

Chimeric antigen receptor T-cell therapy for multiple myeloma

“…Clinical trials will be performed soon. Importantly, these results provide the first clear evidence that that a conformation of a receptor protein can be a specific immunotherapeutic target [20] (Fig. 2).…”

Chimeric Antigen Receptor T-Cell Therapy for Multiple Myeloma

“…Smith et al in Memorial Sloan Kettering Center recently reported GPRC5 as a promising target for CAR T cells against MM [37]. Not reported yet - [38] We also developed a new CAR T cell for MM. Since genes and proteins that are specifically expressed in MM cells have been thoroughly searched for using transcriptome or proteome analyses, no MM-specific transcripts or proteins seems to remain unidentified anymore.…”

CCL5-armed oncolytic virus augments CCR5-engineered NK cell infiltration and antitumor efficiency

“…Although xenograft models cannot completely model the situation in a human body, immunodeficient mice are frequently used to evaluate the in vivo antitumor effects of human T and NK cells. [36][37][38][39] Hence, we employed immunodeficient mice in the present study to test the combination of OV with human NK cells. As expected, OVs expressing CCL5 increased the intratumorous expression of this chemokine and so could be used to enhance NK cell recruitment in vivo ( figure 6), indicating the combination strategy may be applicable to humans.…”