Furthermore, PD-1 disruption can be used in combination with other immune checkpoint knock-outs, such as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) as blocking PD-1 can induce compensatory TIM-3 up-regulation; genes that promote T-cell death, such as FAS could also be knocked out in combination with other immune checkpoint receptors, in order to achieve optimal anti-tumour effect by cytotoxic T cells. This evidence concerns the gene PDCD1 and neoplasm.