Bacterial ghosts as adjuvant to oxaliplatin chemotherapy in colorectal carcinomatosis

Abstract

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality worldwide. At late stage of the disease CRC often shows (multiple) metastatic lesions in the peritoneal cavity which cannot be efficiently targeted by systemic chemotherapy. This is one major factor contributing to poor prognosis. Oxaliplatin is one of the most commonly used systemic treatment options for advanced CRC. However, drug resistanceoften due to insufficient drug deliveryis still hampering successful treatment. The anticancer activity of oxaliplatin includes besides DNA damage also a strong immunogenic component. Consequently, the aim of this study was to investigate the effect of bacterial ghosts (BGs) as adjuvant immunostimulant on oxaliplatin efficacy. BGs are empty envelopes of gramnegative bacteria with a distinct immune-stimulatory potential. Indeed, we were able to show that the combination of BGs with oxaliplatin treatment had strong synergistic anticancer activity against the CT26 allograft, resulting in prolonged survival and even a complete remission in this murine model of CRC carcinomatosis. This synergistic effect was based on an enhanced induction of immunogenic cell death and activation of an efficient T-cell response leading to long-term anti-tumor memory effects. Taken together, co-application of BGs strengthens the immunogenic component of the oxaliplatin anticancer response and thus represents a promising natural immune-adjuvant to chemotherapy in advanced CRC.

Resolving the Paradox of Colon Cancer Through the Integration of Genetics, Immunology, and the Microbiota

“…Interestingly, OXA alone could promote the release of ATP and HMGB1, two hallmarks of ICD, that were not mandatory for the immunizing capacities of dying IEC, in contrast to live bacteria or pathogen associated molecular patterns (26). This is in contrast with a report utilizing gram negative bacteria ghosts injected intraperitoneally with OXA that could turn on ICD in the peritoneal cavity and elicit potent NKT and CD8 + T cell responses associated with regression of peritoneal carcinogenesis (247). These observations emphasize that the tumor macroenvironment and organ may critically influence the requirements for efficient priming of a T cell response.…”

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

“…empty envelopes of Gram-negative bacteria) with oxaliplatin to elicit therapeutically relevant T cell responses against CT26 mouse colorectal tumors coupled to the establishment of long-term immunological memory. 363 Gao and collaborators (University of Science and Technology of China, Hefei, China) found that, as compared to the either agent delivered as standalone therapy, the co-administration of doxorubicin and a small molecule IDO1 inhibitor (NLG919) profoundly inhibits the growth of 4T1 mouse mammary tumors in vivo. 364 Gebremeskel and colleagues (Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada) combined cyclophosphamide, gemcitabine and α-galactosylceramide (α-GalCer)-loaded DCs (which potently activate NKT cells), achieving disease eradication and long-term immunological protection in mice bearing 4T1 tumors, as demonstrated by their ability to reject a subsequent challenge with the same cancer cells.…”

CD47-targeted cancer immunogene therapy: Secreted SIRPα-Fc fusion protein eradicates tumors by macrophage and NK cell activation

“…Its use within a systemically applied, targeted gene delivery system would be the next logical step, where specificity of delivery (e.g., using cell-targeting ligands) and/or specificity of expression (using tumor-specific promoters or miRNA-based de-targeting approaches) is further pursued. 16 , 18 , 45 For preclinical studies, syngeneic tumor models need to be evaluated (e.g., CT26 colon cancer in BALB/c mice 14 , 46 ). This is important as the adaptive immune system, especially CD8+ cytotoxic T cells, is also involved in tumor eradication after CD47 blockage.…”