The mechanisms of action of Plasmodium infection against cancer

Abstract

Our murine cancer model studies have demonstrated that Plasmodium infection activates the immune system that has been inhibited by cancer cells, counteracts tumor immunosuppressive microenvironment, inhibits tumor angiogenesis, inhibits tumor growth and metastasis, and prolongs the survival time of tumor-bearing mice. Based on these studies, three clinical trials of Plasmodium immunotherapy for advanced cancers have been approved and are ongoing in China. After comparing the mechanisms of action of Plasmodium immunotherapy with those of immune checkpoint blockade therapy, we propose the notion that cancer is an ecological disease and that Plasmodium immunotherapy is a systemic ecological counterattack therapy for this ecological disease, with limited side effects and without danger to public health based on the use of artesunate and other measures. Recent reports of tolerance to treatment and limitations in majority of patients associated with the use of checkpoint blockers further support this notion. We advocate further studies on the mechanisms of action of Plasmodium infection against cancer and investigations on Plasmodium-based combination therapy in the coming future.

Anti-Tumor Effect of Parasitic Protozoans

“…Thus, several doses of attenuated parasites are necessary to achieve anticancer efficacy in clinical use. Another solution is to give a single low dose of a drug, such as artesunate for Plasmodium [ 41 ], to control the parasite density to a safe level. This may raise the concerns of the drug resistance of artesunate.…”

“…This may raise the concerns of the drug resistance of artesunate. According to their reports [ 41 ], up to now there are no signs of drug resistance in the treatment of over 100 cancer patients, therefore the clinical safety of Plasmodium immunotherapy is guaranteed.…”

“…Possibly, the toxic activation of NK cells via IFN-γ expression is induced by the infection of Plasmodium through the up-regulated expression of CD69 and CD25 [ 40 ]. As reported by Chen, et al [ 41 ], three clinical trials based on Plasmodium immunotherapy against advanced cancers have been approved and are underway with clinical safety guaranteed. In addition, the infection of N. caninum [ 7 ], Leishmania amazonensis [ 42 ], and T. gondii [ 43 ] increased the levels of NK cells mainly through an IFN-γ-dependent pathway.…”

“…According to many reports, VEGF is known as a major proangiogenic molecular released by tumor-associated macrophages (TAMs) and is correlated with many human cancers [ 85 ]. Later, they discovered the diminished angiogenic responses in Plasmodium -infected tumor-bearing mice probably by decreasing the expression of angiogenesis-related enzyme MMP9 via the insulin-like growth factor (IGF) axis through the PI3-K and MAPK signaling pathways [ 41 , 84 ]. In addition, the parasite-derived antigens have an effort on inhibiting vascularization in tumors as well.…”

Microneedle arrays integrated with living organisms for smart biomedical applications

“…Moreover, certain living creatures that possess immunogenicity could be applied to “train” the innate immune system to prevent various diseases. For instance, studies demonstrate that malaria infection can counteract tumor immunosuppressive microenvironment and inhibit the angiogenesis, growth and metastasis of tumors, which has been preliminarily validated by experiments on mice and human beings 105 , 106 . It indicates the potential of delivering plasmodium by MNA as a non-invasive manner to combat certain cancers.…”