| First Author | Tichet M | Year | 2023 |
| Journal | Immunity | Volume | 56 |
| Issue | 1 | Pages | 162-179.e6 |
| PubMed ID | 36630914 | Mgi Jnum | J:332640 |
| Mgi Id | MGI:7428283 | Doi | 10.1016/j.immuni.2022.12.006 |
| Citation | Tichet M, et al. (2023) Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8(+) T cells and reprogramming macrophages. Immunity 56(1):162-179.e6 |
| abstractText | Immunotherapies have shown remarkable, albeit tumor-selective, therapeutic benefits in the clinic. Most patients respond transiently at best, highlighting the importance of understanding mechanisms underlying resistance. Herein, we evaluated the effects of the engineered immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer that is resistant to checkpoint and other immunotherapies. PD1-IL2v utilizes anti-PD-1 as a targeting moiety fused to an immuno-stimulatory IL-2 cytokine variant (IL2v) to precisely deliver IL2v to PD-1(+) T cells in the tumor microenvironment. PD1-IL2v elicited substantial infiltration by stem-like CD8(+) T cells, resulting in tumor regression and enhanced survival in mice. Combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogramming immunosuppressive tumor-associated macrophages and enhancing T cell receptor (TCR) immune repertoire diversity. These data provide a rationale for clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, particularly in immunotherapy-resistant tumors infiltrated with PD-1(+) stem-like T cells. |
