Camptothesome-based combination nanotherapeutic regimen for improved colorectal cancer immunochemotherapy.

Camptothesome is a sphingomyelin-conjugated camptothecin (SM-CSS-CPT) nanovesicle that fortified the therapeutic delivery of CPT in diverse cancer types. To mitigate the Camptothesome-induced IDO1 negative feedback mechanism, we had co-encapsulated, indoximod (IND, IDO1 inhibitor) into Camptothesome using doxorubicin-derived IND (DOX-IND). To maximize the therapeutic potential of DOX-IND/Camptothesome, herein, we first dissected the synergistic drug ratio (DOX-IND/SM-CSS-CPT) via systematical in vitro screening. DOX-IND/Camptothesome with optimal drug ratio synchronized in vivo drug delivery with significantly higher tumor uptake compared to free drugs. This optimum DOX-IND/Camptothesome outperformed the combination of Camptothesome, Doxil and IND or other IDO1 inhibitors (BMS-986205 or epacadostat) in treating mice bearing late-stage MC38 tumors, and combination with immune checkpoint blockade (ICB) enabled it to eradicate 60 % of large tumors. Further, this optimized co-delivery Camptothesome beat Folfox and Folfiri, two first-line combination chemotherapies for colorectal cancer in antitumor efficacy and exhibited no side effects as compared to the severe systemic toxicities associated with Folfox and Folfiri. Finally, we demonstrated that the synergistic DOX-IND/Camptothesome was superior to the combined use of Onivyde + Doxil + IND in curbing the advanced orthotopic CT26-Luc tumors and eliminated 40 % tumors with complete metastasis remission when cooperated with ICB, eliciting stronger anti-CRC immune responses and greater reversal of immunosuppression. These results corroborated that with precise optimal synergistic drug ratio, the therapeutic potential of DOX-IND/Camptothesome can be fully unleased, which warrants further clinical investigation to benefit the cancer patients.

Sphingomyelin-derived nanovesicles for the delivery of the IDO1 inhibitor epacadostat enhance metastatic and post-surgical melanoma immunotherapy.

Epacadostat (EPA), the most advanced IDO1 inhibitor, in combination with PD-1 checkpoint inhibitor, has failed in a recent Phase III clinical trial for treating metastatic melanoma. Here we report an EPA nanovesicle therapeutic platform (Epacasome) based on chemically attaching EPA to sphingomyelin via an oxime-ester bond highly responsive to hydrolase cleavage. Via clathrin-mediated endocytosis, Epacasome displays higher cellular uptake and enhances IDO1 inhibition and T cell proliferation compared to free EPA. Epacasome shows improved pharmacokinetics and tumour accumulation with efficient intratumoural drug release and deep tumour penetration. Additionally, it outperforms free EPA for anticancer efficacy, potentiating PD-1 blockade with boosted cytotoxic T lymphocytes (CTLs) and reduced regulatory T cells and myeloid-derived suppressor cells responses in a B16-F10 melanoma model in female mice. By co-encapsulating immunogenic dacarbazine, Epacasome further enhances anti-tumor effects and immune responses through the upregulation of NKG2D-mediated CTLs and natural killer cells responses particularly when combined with the PD-1 inhibitor in the late-stage metastatic B16-F10-Luc2 model in female mice. Furthermore, this combination prevents tumour recurrence and prolongs mouse survival in a clinically relevant, post-surgical melanoma model in female mice. Epacasome demonstrates potential to synergize with PD-1 blockade for improved response to melanoma immunotherapy.