Booster for immunotherapy
Researchers from the University of Texas have shown that treatment with ipilimumab, which triggers an immune response by blocking the activity of the CTLA-4 receptor protein on T-lymphocytes, is accompanied by an increase in the synthesis of EZH2 – an enzyme from the group of methyltransferases. Normally, EZH2 regulates regeneration processes, and in excess enhances the transformation of healthy cells into cancer cells. There was a need to develop a combination therapy using ipilimumab and a drug that would inhibit EZH2.
The researchers studied samples of bladder, prostate and melanoma cancers taken from patients before and after treatment to analyze changes in immune activity. The level of EZH2 in T-lymphocytes of patients after treatment with ipilimumab was increased, and this increase correlated with the progression of prostate cancer.
It is known that EZH2 works epigenetically: it suppresses genes, regulates histone synthesis, and stabilizes the expression of transcription factor in regulatory T-lymphocytes, thus reducing the immune response.
Researchers have shown that inhibition of EZH2 enhances the function of effector T cells (CD8+ and CD4+ T lymphocytes). A series of tests with four different inhibitors demonstrated the greatest effect of the CPI-1205 methyltransferase inhibitor. It suppressed the differentiation of T-lymphocytes into regulatory ones. Subsequent experiments showed that inhibition of EZH2 led to the loss of regulatory T-lymphocytes of their suppressive action, they became effector-like T-cells.
Genetically modified mice with the absence of EZH2 in regulatory T lymphocytes showed significant tumor regression compared to control mice after inoculation of the bladder cancer cell line. They also had elevated levels of CD8+ T cells in and around the tumor.
T cells are activated by the co-stimulating CD28 molecule after binding to the antigen. CD28 also includes CTLA-4, an immune checkpoint that prevents an overreaction of the immune system. Scientists have suggested that blocking CTLA-4 with ipilimumab leads to increased CD28 signaling and an increase in EZH2 levels in T cells.
Treatment with a combination of ipilimumab and CPI-1205 led to a significant slowdown in tumor growth, increased the survival rate of mice. In mice with melanoma and bladder cancer, the number of regulatory T cells in the tumor decreased, there were more effector lymphocytes.
The administration of ipilimumab to mice with the disabled EZH2 gene led to the complete destruction of the tumor by the immune system.
No side effects from the immune system were observed in mice receiving the combined treatment.
Phase I of clinical trials of combined immunotherapy, designed to assess the safety of the method and select the optimal dose of drugs, began in the spring of 2018. Patients with various types of advanced stage tumors (melanoma, non-small cell lung cancer, renal cell carcinoma and urothelial carcinoma) will be treated with a combination of CPI-1205 and ipilimumab or CPI-1205 and pembrolizumab.
Article by S. Goswami et al. Modulation of EZH2 expression in T cells improves the efficacy of anti–CTLA-4 therapy published in the Journal of Clinical Investigation.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of The University of Texas MD Anderson Cancer Center: Researchers find combination can enhance ipilimumab immunotherapy.