Restoration and Enhancement of Immunogenic Cell Death of Cisplatin by Coadministration with Digoxin and Conjugation to HPMA Copolymer

Complete tumor eradication is the ultimate goal of cancer therapy. However, the majority of anticancer drugs cause nonimmunogenic cell death and only exert on-site anticancer activities. The intrinsic genomic instability of cancer allows for the persistence and later expansion of treatment-resistant clones after surviving a sort of Darwinian selection of chemotherapy. Additional incorporation of immunotherapy, which is robust and individualized could be game-changing. Herein, we report a combination strategy that delivers nonimmunogenic cell death inducer Cisplatin to treat primary tumors and converts the tumor cells into vaccines that spurs a long-lasting immune response against residual tumors to prevent tumor recurrence and metastasis. Cisplatin(IV) prodrug was linked to the N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer (P-Cis) and coadministered with digoxin (Dig), which eventually launched two attacks to cancer cells. First, P-Cis exhibited superior tumor retention and cytotoxicity over free Cisplatin (to inhibit the primary tumor growth). Then, Dig reversed the inability of Cisplatin to trigger calreticulin exposure, and HPMA copolymer-amplified Cisplatin-induced ATP release. These complementary mechanisms induced potent immunogenic cell death that promotes dendritic cell maturation and activates CD8+ T cell responses. In established tumor models, P-Cis + Dig combination completely eradicate tumors with no residual cancer cells remaining. Cancer cells succumbing to P-Cis + Dig could protect syngeneic mice against the subsequent challenge with living cells of the same type and stimulated robust abscopal and antimetastatic effects. Such a strategy might be promising to restore the immunogenicity of nonimmunogenic drugs and generate vaccine-like functions for improved immunochemotherapy.