Theoretical premises of a "three in one" therapeutic approach to treat immunogenic and nonimmunogenic cancers: a narrative review.

OBJECTIVE

We describe experimental and theoretical premises of a powerful cancer therapy based on the combination of three approaches. These include (I) vaccination (intratumoral injections of CpG oligonucleotides and anti-OX40 antibody); (II) chronometric or metronomic low-dose cyclophosphamide (CMLD CP)-based chemotherapy; (III) cancer stem cell-eradicating therapy referred to as (from the Sanskrit ["source"] + ["to kill"]).

BACKGROUND

In murine models, the first two approaches are particularly potent in targeting immunogenic tumors for destruction. vaccination activates a fully fledged anticancer immune response via an intricate network of ligand-receptor-cytokine interactions. CMLD CP-based chemotherapy primarily targets the suppressive tumor microenvironment and activates tumor-infiltrating effectors. In contrast, technology, being aimed at replicative machinery of tumor cells (both stem-like and committed), does not depend on tumor immunogenicity. With this technology, mice engrafted with ascites and/or solid tumors can be successfully cured. There is a significant degree of mechanistic and therapeutic overlap between these three approaches. For instance, the similarities shared between vaccination and technology include the therapeutic procedure, the cell target [antigen-presenting cells (APC) and dendritic cells (DC)], and the use of DNA-based preparations (CpG and DNAmix). Features shared between CMLD CP-based chemotherapy and technology are the timing and the dose of the cytostatic drug administration, which lead to tumor regression.

METHODS

The following keywords were used to search PubMed for the latest research reporting successful eradication of transplantable cancers in animal models that relied on approaches distinct from those used in the technology: and others.

CONCLUSION

We hypothesize, therefore, that very potent anticancer activity can be achieved once these three therapeutic modalities are combined into a single approach. This multimodal approach is theoretically curative for any type of cancer that depends on the presence of tumor-inducing cancer stem cells, provided that the active therapeutic components are efficiently delivered into the tumor and the specific biological features of a given patient's tumor are properly addressed. We expect this multimodal approach to be primarily applicable to late-stage or terminal cancer patients who have exhausted all treatment options as well as patients with inoperable tumors.