Breast Cancer Chemo-immunotherapy through Liposomal Delivery of an Immunogenic Cell Death Stimulus Plus Interference in the IDO-1 Pathway

Abstract

Immunotherapy provides the best approach to reduce the high mortality of metastatic breast cancer (BC). We demonstrate a chemo-immunotherapy approach, which utilizes a liposomal carrier to simultaneously trigger immunogenic cell death (ICD) as well as interfere in the regionally overexpressed immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO-1) at the BC tumor site. The liposome was constructed by self-assembly of a phospholipid-conjugated prodrug, indoximod (IND), which inhibits the IDO-1 pathway, followed by the remote loading of the ICD-inducing chemo drug, doxorubicin (DOX). Intravenous injection of the encapsulated two-drug combination dramatically improved the pharmacokinetics and tumor drug concentrations of DOX and IND in an orthotopic 4T1 tumor model in syngeneic mice. Delivery of a threshold ICD stimulus resulted in the uptake of dying BC cells by dendritic cells, tumor antigen presentation and the activation/recruitment of naïve T-cells. The subsequent activation of perforin- and IFN-γ releasing cytotoxic T-cells induced robust tumor cell killing at the primary as well as metastatic tumor sites. Immune phenotyping of the tumor tissues confirmed the recruitment of CD8+ cytotoxic T lymphocytes (CTLs), disappearance of Tregs, and an increase in CD8+/FOXP3+ T-cell ratios. Not only does the DOX/IND-Liposome provide a synergistic antitumor response that is superior to a DOX-only liposome, but it also demonstrated that the carrier could be effectively combined with PD-1 blocking antibodies to eradicate lung metastases. All considered, an innovative nano-enabled approach has been established to allow deliberate use of ICD to switch an immune deplete to an immune replete BC microenvironment, allowing further boosting of the response by coadministered IDO inhibitors or immune checkpoint blocking antibodies.

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…19,[111][112][113] Second, cancer cells undergoing ICD must provide tumor-naïve, syngeneic hosts with immunemediated prophylactic protection against a subsequent challenge with living cancer cells of the same (but not different) type. 4,12,19,[114][115][116][117][118][119] Here, it is important to note that the first approach, while relatively straightforward, cannot be employed to discriminate ICD inducers (i.e. agents that kill cancer cells in an immunogenic manner) from immunostimulatory chemotherapies (i.e.…”

Overview of recent advances in liposomal nanoparticle-based cancer immunotherapy

“…Therefore, Lu et al designed a chemoimmunotherapy approach to codeliver DOX and IDO-1 inhibitor. Doxorubicin can effectively induce ICD, while indoximod can interfere with immunosuppression; thus, binary immunotherapy significantly enhances the antitumor immune response [31].…”

Doxorubicin pretreatment enhances FAPα/survivin co-targeting DNA vaccine anti-tumor activity primarily through decreasing peripheral MDSCs in the 4T1 murine breast cancer model

“…This may be due to the short half-life (t 1/2 ) of free Dox (5 mg/kg) in vivo, which limits the uptake of Dox by tumors. 48 Notably, both the vaccine and combination treatments increased the proportion of M1 TAMs. However, the proportion of M2 TAMs in the combination group increased compared with that in the vaccine group, which might explain the inability of the combination of two rounds of Dox to completely eliminate the tumors.…”