Inhibition of hyperprogressive cancer disease induced by immune-checkpoint blockade upon co-treatment with meta-tyrosine and p38 pathway inhibitor
Abstract Background Although 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. Methods To understand th...
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-022-09941-2 |
| _version_ | 1798037911967367168 |
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| author | Daniela R. Montagna Alejandra Duarte Paula Chiarella Bárbara Rearte Oscar D. Bustuoabad Mónica Vermeulen Raúl A. Ruggiero |
| author_facet | Daniela R. Montagna Alejandra Duarte Paula Chiarella Bárbara Rearte Oscar D. Bustuoabad Mónica Vermeulen Raúl A. Ruggiero |
| author_sort | Daniela R. Montagna |
| collection | DOAJ |
| description | Abstract Background Although 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. Methods To 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. Results ICI 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. Conclusions Tumor 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. |
| first_indexed | 2024-04-11T21:33:02Z |
| format | Article |
| id | doaj.art-7014d5b3eecf46a6801398cccc3db71b |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-11T21:33:02Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-7014d5b3eecf46a6801398cccc3db71b2022-12-22T04:01:50ZengBMCBMC Cancer1471-24072022-08-0122111710.1186/s12885-022-09941-2Inhibition of hyperprogressive cancer disease induced by immune-checkpoint blockade upon co-treatment with meta-tyrosine and p38 pathway inhibitorDaniela R. Montagna0Alejandra Duarte1Paula Chiarella2Bárbara Rearte3Oscar D. Bustuoabad4Mónica Vermeulen5Raúl A. Ruggiero6Laboratory of Experimental Oncology, Instituto de Medicina Experimental (IMEX-CONICET), Academia Nacional de Medicina de Buenos AiresLaboratory of Experimental Immunology, IMEX-CONICET, Academia Nacional de Medicina de Buenos AiresLaboratory of Experimental Oncology, Instituto de Medicina Experimental (IMEX-CONICET), Academia Nacional de Medicina de Buenos AiresLaboratory of Physiology of Inflammatory Processes, IMEX-CONICET, Academia Nacional de Medicina de Buenos AiresLaboratory of Experimental Oncology, Instituto de Medicina Experimental (IMEX-CONICET), Academia Nacional de Medicina de Buenos AiresLaboratory of Antigen Presenting Cells and Inflammatory Response, IMEX-CONICET, Academia Nacional de Medicina de Buenos AiresLaboratory of Experimental Oncology, Instituto de Medicina Experimental (IMEX-CONICET), Academia Nacional de Medicina de Buenos AiresAbstract Background Although 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. Methods To 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. Results ICI 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. Conclusions Tumor 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.https://doi.org/10.1186/s12885-022-09941-2Hyperprogressive cancer diseaseImmune checkpoints inhibitorsMeta-tyrosineMetastasesMurine tumors |
| spellingShingle | Daniela R. Montagna Alejandra Duarte Paula Chiarella Bárbara Rearte Oscar D. Bustuoabad Mónica Vermeulen Raúl A. Ruggiero Inhibition of hyperprogressive cancer disease induced by immune-checkpoint blockade upon co-treatment with meta-tyrosine and p38 pathway inhibitor BMC Cancer Hyperprogressive cancer disease Immune checkpoints inhibitors Meta-tyrosine Metastases Murine tumors |
| title | Inhibition of hyperprogressive cancer disease induced by immune-checkpoint blockade upon co-treatment with meta-tyrosine and p38 pathway inhibitor |
| title_full | Inhibition of hyperprogressive cancer disease induced by immune-checkpoint blockade upon co-treatment with meta-tyrosine and p38 pathway inhibitor |
| title_fullStr | Inhibition of hyperprogressive cancer disease induced by immune-checkpoint blockade upon co-treatment with meta-tyrosine and p38 pathway inhibitor |
| title_full_unstemmed | Inhibition of hyperprogressive cancer disease induced by immune-checkpoint blockade upon co-treatment with meta-tyrosine and p38 pathway inhibitor |
| title_short | Inhibition of hyperprogressive cancer disease induced by immune-checkpoint blockade upon co-treatment with meta-tyrosine and p38 pathway inhibitor |
| title_sort | inhibition of hyperprogressive cancer disease induced by immune checkpoint blockade upon co treatment with meta tyrosine and p38 pathway inhibitor |
| topic | Hyperprogressive cancer disease Immune checkpoints inhibitors Meta-tyrosine Metastases Murine tumors |
| url | https://doi.org/10.1186/s12885-022-09941-2 |
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