An ultra-long-acting L-asparaginase synergizes with an immune checkpoint inhibitor in starvation-immunotherapy of metastatic solid tumors.

Metastasis stands as the primary contributor to mortality associated with tumors. Chemotherapy and immunotherapy are frequently utilized in the management of metastatic solid tumors. Nevertheless, these therapeutic modalities are linked to serious adverse effects and limited effectiveness in preventing metastasis. Here, we report a novel therapeutic strategy named starvation-immunotherapy, wherein an immune checkpoint inhibitor is combined with an ultra-long-acting L-asparaginase that is a fusion protein comprising L-asparaginase (ASNase) and an elastin-like polypeptide (ELP), termed ASNase-ELP. ASNase-ELP's thermosensitivity enables it to generate an in-situ depot following an intratumoral injection, yielding increased dose tolerance, improved pharmacokinetics, sustained release, optimized biodistribution, and augmented tumor retention compared to free ASNase. As a result, in murine models of oral cancer, melanoma, and cervical cancer, the antitumor efficacy of ASNase-ELP by selectively and sustainably depleting L-asparagine essential for tumor cell survival was substantially superior to that of ASNase or Cisplatin, a first-line anti-solid tumor medicine, without any observable adverse effects. Furthermore, the combination of ASNase-ELP and an immune checkpoint inhibitor was more effective than either therapy alone in impeding melanoma metastasis. Overall, the synergistic strategy of starvation-immunotherapy holds excellent promise in reshaping the therapeutic landscape of refractory metastatic tumors and offering a new alternative for next-generation oncology treatments. The reversible thermosensitivity of L-asparaginase (ASNase) fused to an elastin-like polypeptide (ASNase-ELP) allows for forming a pharmaceutical depot that exhibits zero-order release kinetics following a single intra-tumoral administration. This depot effectively and selectively sustains L-asparagine (Asn) catabolism, thereby inducing tumor cells to enter a state of starvation. Simultaneously, anti-programmed cell death protein-1 antibody (aPD-1) inhibits the binding of PD-1 to its corresponding receptor, PD-L1, and enhances the recognition of major histocompatibility complex class I (MHC-I) molecules by the T-cell receptor (TCR). Consequently, aPD-1 elicits a robust immune response against the tumor cells, synergistically enhancing the anti-metastatic efficacy in conjunction with the starvation mechanism. [Display omitted] [ABSTRACT FROM AUTHOR]