Platinum Twin and Triplet Drugs Improve Chemoimmunotherapy

Several chemoimmunotherapy regimens
have been approved
by the U.S.
FDA, verifying the great clinical value and potential of the strategy.
However, the immunomodulatory function of chemotherapy was insufficient,
which did not provide extra overall survival benefits, especially
in a head-to-head comparison of chemoimmunotherapy versus immunotherapy.
Here, we engineered twin and triplet drugs derived from an immunogenic
chemotherapeutic drug (oxaliplatin) and small-molecule inhibitors
of negative immunoregulation pathways (COX2 and IDO) in tumors as
an improved chemotherapeutic component within chemoimmunotherapy.
The twin and triplet drugs exhibited significantly improved synergy
with anti-PD-1 in a CT26 colorectal mouse tumor model. Mechanistic
analyses revealed that the drug induced immunogenic cell death and
restored tumor immune microenvironment toward tumor clearance in vivo,
resulting in a great decrease in tumor-infiltrating Tregs and an increase
in the CD8+ T/Treg ratio when combined with anti-PD-1.
Our work expands the application of platinum twin drugs in combination
with an immune checkpoint blockade.