ABSTRACT
Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds to CEACAM6, a cell-surface protein that is highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Using chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) to measure the tumor extracellular pH (pHe), we confirmed that L-DOS47 raises the tumor pHe from 4 h to 96 h post injection in acidic tumors (average increase of 0.13 units). Additional studies showed that combining L-DOS47 with anti-PD1 significantly increases the efficacy of the anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.
ABSTRACT
The worldwide burden of cancers is increasing at a very high rate, including the aggressive and resistant forms of cancers. Certain levels of breakthrough have been achieved with the conventional treatment methods being used to treat different forms of cancers, but with some limitations. These limitations include hazardous side effects, destruction of non-tumor healthy cells that are rapidly dividing and developing, tumor resistance to anti-cancer drugs, damage to tissues and organs, and so on. However, oncolytic viruses have emerged as a worthwhile immunotherapeutic option for the treatment of different types of cancers. In this treatment approach, oncolytic viruses are being modeled to target cancer cells with optimum cytotoxicity and spare normal cells with optimal safety, without the oncolytic viruses themselves being killed by the host immune defense system. Oncolytic viral infection of the cancer cells are also being genetically manipulated (either by removal or addition of certain genes into the oncolytic virus genome) to make the tumor more visible and available for attack by the host immune cells. Hence, different variants of these viruses are being developed to optimize their antitumor effects. In this review, we examined how grave the burden of cancer is on a global level, particularly in sub-Saharan Africa, major conventional therapeutic approaches to the treatment of cancer and their individual drawbacks. We discussed the mechanisms of action employed by these oncolytic viruses and different viruses that have found their relevance in the fight against various forms of cancers. Some pre-clinical and clinical trials that involve oncolytic viruses in cancer management were reported. This review also examined the toxicity and safety concerns surrounding the adoption of oncolytic viro-immunotherapy for the treatment of cancers and the likely future directions for researchers and general audience who wants updated information.
