Inhibition of hyperprogressive cancer disease induced by immune-checkpoint blockade upon co-treatment with meta-tyrosine and p38 pathway inhibitor

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BackgroundAlthough immune-checkpoint inhibitors (ICI) are overall promissory for cancer treatment, they entail, in some cases, an undesired side-effect called hyperprogressive-cancer disease (HPD) associated with acceleration of tumor growth and shortened survival.MethodsTo understand the mechanisms of HPD we assayed the ICI therapy on two murine tumors widely different regarding immunogenicity and, subsequently, on models of local recurrences and metastases of these tumors. To potentiate the immune response (IR), we combined ICI with meta-tyrosine—that counteracts immune-suppressive signals—and a selective inhibitor of p38 pathway that proved to counteract the phenomenon of tumor-immunostimulation.ResultsICI were therapeutically effective against both tumor models (proportionally to their immunogenicity) but only when they faced incipient tumors. In contrast, ICI produced acceleration of large and residual tumors. The combined treatment strongly inhibited the growth of large tumors and it managed to cure 80% of mice with local recurrences and 60% of mice bearing residual metastases.ConclusionsTumor enhancement was paradoxically correlated to a weak increase of the antitumor IR suggesting that a weak IR – different from a strong tumor-inhibitory one—may produce stimulation of tumor growth, mimicking the HPD observed in some clinical settings.