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

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.

Meta-tyrosine modulates the immune response induced by bacterial endotoxins.

Sepsis is characterized by an early pro-inflammatory phase followed by compensatory anti-inflammatory mechanisms that lead to a late generalized immunosuppression, period where most deaths occur. Immunotherapy approaches to recover the immunocompetence in sepsis are similar to those used in cancer. Meta-tyrosine (m-Tyr) is a product of oxidative stress present in circulation during the sepsis and cancer-associated pro-inflammatory stages. In this work, considering its potential participation in pro-inflammatory processes, we evaluate the effect of m-Tyr during LPS induced immunosuppression phase in a murine model. In addition, we examine the effect of m-Tyr in a vaccination strategy using a weakly immunogenic tumor model. Our results showed that m-Tyr could prevent the establishment of immunosuppression and rescue the host from an installed immunosuppression induced by LPS. These effects were parallel to the ability of m-Tyr to improve the pro-inflammatory effects induced by LPS and inhibit the anti-inflammatory action of dexamethasone. Also, m-Tyr treatment prevents both the reduction of splenic lymphocytes and the increase of the expression of programmed death ligand-1 in splenic myeloid cells associated with immunosuppression. Besides, treatment with m-Tyr increased the protective effect of an anti-tumor vaccine, suggesting that m-Tyr could improve the immune response. In summary, we suggest that m-Tyr can modulate critical immunological indicators through the inflammatory context, which could improve the management of diseases, such as sepsis and cancer, in which immunosuppression is a significant clinical problem.

Meta-tyrosine. A powerful anti-metastatic factor with undetectable toxic-side effects.

Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. While former studies have indicated that T-cell dependent processes mediate CR in hosts bearing immunogenic small tumors, the most universal manifestation of CR induced by immunogenic and non-immunogenic large tumors had been associated with an antitumor serum factor that remained an enigma for many years. In a recent paper, we identified that elusive factor(s) as an equi-molar mixture of meta-tyrosine and ortho-tyrosine, two isomers of tyrosine that are not present in normal proteins and that proved to be responsible for 90% and 10%, respectively, of the total serum anti-tumor activity. In this work, we have extended our previous findings demonstrating that a periodic intravenous administration of meta-tyrosine induced a dramatic reduction of lung and hepatic metastases generated in mice bearing two different metastatic murine tumors and decreased the rate of death from 100% up to 25% in tumor-excised mice that already exhibited established metastases at the time of surgery. These anti-metastatic effects were achieved even at very low concentrations and without displaying any detectable toxic-side effects, suggesting that the use of meta-tyrosine may help to develop new and less harmful means of managing malignant diseases, especially those aimed to control the growth of metastases that is the most serious problem in cancer pathology.

Meta-tyrosine: A powerful anti-metastatic factor with undetectable toxic-side effects

Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. While former studies have indicated that T-cell dependent processes mediate CR in hosts bearing immunogenic small tumors, the most universal manifestation of CR induced by immunogenic and non-immunogenic large tumors had been associated with an antitumor serum factor that remained an enigma for many years. In a recent paper, we identified that elusive factor(s) as an equi-molar mixture of meta-tyrosine and ortho-tyrosine, two isomers of tyrosine that are not present in normal proteins and that proved to be responsible for 90% and 10%, respectively, of the total serum anti-tumor activity. In this work, we have extended our previous findings demonstrating that a periodic intravenous administration of meta-tyrosine induced a dramatic reduction of lung and hepatic metastases generated in mice bearing two different metastatic murine tumors and decreased the rate of death from 100% up to 25% in tumor-excised mice that already exhibited established metastases at the time of surgery. These anti-metastatic effects were achieved even at very low concentrations and without displaying any detectable toxic-side effects, suggesting that the use of meta-tyrosine may help to develop new and less harmful means of managing malignant diseases, especially those aimed to control the growth of metastases that is the most serious problem in cancer pathology.(AU)

La resistencia concomitante antitumoral (RC) es el fenómeno según el cual un individuo portador de tumor inhibe el crecimiento de implantes tumorales secundarios y metástasis. Si bien desde hace tiempo se sabe que la RC inducida por tumores inmunogénicos de pequeño tamaño es generada por mecanismos inmunológicos dependientes de células T, por otro lado, la manifestación más universal de la RC, generada tanto por tumores inmunogénicos como no-inmunogénicos de gran tamaño, había sido asociada con un (unos) factor sérico antitumoral cuya naturaleza permaneció elusiva por años. En un trabajo reciente, nuestro grupo de trabajo identificó este factor como la mezcla equi-molar de meta-tirosina y orto-tirosina, dos isómeros de tirosina que no están presentes en proteínas normales y que demostraron ser responsables del 90% y 10%, respectivamente, de la actividad antitumoral total del suero. En este trabajo, continuamos nuestras investigaciones demostrando que la administración periódica de meta-tirosina reducía drásticamente el número de metástasis pulmonares y hepáticas en ratones portadores de dos tumores murinos altamente metastásicos y disminuía dramáticamente la mortandad (de 100% a 25%) de ratones con metástasis ya establecidas al momento de la extirpación quirúrgica del tumor. Estos efectos anti-metastásicos se lograron aun con muy bajas concentraciones de meta-tirosina y sin efectos tóxicos perceptibles, lo que sugiere que su uso puede ayudar a diseñar nuevas y menos nocivas estrategias para el tratamiento del cáncer, especialmente aquellas destinadas a controlar el crecimiento metastásico, que es el problema más grave en la enfermedad oncológica.(AU)

Meta-tyrosine: A powerful anti-metastatic factor with undetectable toxic-side effects

Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. While former studies have indicated that T-cell dependent processes mediate CR in hosts bearing immunogenic small tumors, the most universal manifestation of CR induced by immunogenic and non-immunogenic large tumors had been associated with an antitumor serum factor that remained an enigma for many years. In a recent paper, we identified that elusive factor(s) as an equi-molar mixture of meta-tyrosine and ortho-tyrosine, two isomers of tyrosine that are not present in normal proteins and that proved to be responsible for 90% and 10%, respectively, of the total serum anti-tumor activity. In this work, we have extended our previous findings demonstrating that a periodic intravenous administration of meta-tyrosine induced a dramatic reduction of lung and hepatic metastases generated in mice bearing two different metastatic murine tumors and decreased the rate of death from 100% up to 25% in tumor-excised mice that already exhibited established metastases at the time of surgery. These anti-metastatic effects were achieved even at very low concentrations and without displaying any detectable toxic-side effects, suggesting that the use of meta-tyrosine may help to develop new and less harmful means of managing malignant diseases, especially those aimed to control the growth of metastases that is the most serious problem in cancer pathology.

La resistencia concomitante antitumoral (RC) es el fenómeno según el cual un individuo portador de tumor inhibe el crecimiento de implantes tumorales secundarios y metástasis. Si bien desde hace tiempo se sabe que la RC inducida por tumores inmunogénicos de pequeño tamaño es generada por mecanismos inmunológicos dependientes de células T, por otro lado, la manifestación más universal de la RC, generada tanto por tumores inmunogénicos como no-inmunogénicos de gran tamaño, había sido asociada con un (unos) factor sérico antitumoral cuya naturaleza permaneció elusiva por años. En un trabajo reciente, nuestro grupo de trabajo identificó este factor como la mezcla equi-molar de meta-tirosina y orto-tirosina, dos isómeros de tirosina que no están presentes en proteínas normales y que demostraron ser responsables del 90% y 10%, respectivamente, de la actividad antitumoral total del suero. En este trabajo, continuamos nuestras investigaciones demostrando que la administración periódica de meta-tirosina reducía drásticamente el número de metástasis pulmonares y hepáticas en ratones portadores de dos tumores murinos altamente metastásicos y disminuía dramáticamente la mortandad (de 100% a 25%) de ratones con metástasis ya establecidas al momento de la extirpación quirúrgica del tumor. Estos efectos anti-metastásicos se lograron aun con muy bajas concentraciones de meta-tirosina y sin efectos tóxicos perceptibles, lo que sugiere que su uso puede ayudar a diseñar nuevas y menos nocivas estrategias para el tratamiento del cáncer, especialmente aquellas destinadas a controlar el crecimiento metastásico, que es el problema más grave en la enfermedad oncológica.