PDCD1 and non-small cell lung carcinoma: ALT-803, in which IL-15 and IL-15Rα subunits are precomplexed to mimic the in vivo form of APC-dependent dimerization, yielded a potent anti-tumor response (ORR: 29%, DCR: 76%) with nivolumab in anti-PD-1 r/r NSCLC patients,540 and similarly in a patient cohort with different ICI r/r solid tumors.541 Novel structure designs such as introducing tumor-targeted542,543 and/or conditionally activated (within the TME)544,545 moieties into cytokine-based agents can avoid systemic toxicity and achieve preferential tumor control and cell-biased binding properties (Fig. 5b).