Despite the therapeutic potential of VISTA inhibition demonstrated in preclinical studies2, clinical development of anti-VISTA antibodies has been challenging due to: 1) uncertainty about the critical counter-receptor responsible for T-cell suppression; 2) high drug clearance via target-mediated drug disposition (TMDD) by VISTA+ neutrophils and monocytes at physiologic pH, and; 3) cellular activation and cytokine release syndrome (CRS) at sub-therapeutic doses due to engagement of VISTA in the blood, reducing the likelihood of reaching efficacious target occupancy levels in tumors. The gene discussed is VSIR; the disease is congenital rubella syndrome.