Search

Surgical resection, chemotherapy and radiotherapy were, for many years, the only available cancer treatments. Recently, the use of immune checkpoint inhibitors and adoptive cell therapies has emerged as promising alternative. These cancer immunotherapies are aimed to support or harness the patient's immune system to recognize and destroy cancer cells. Preclinical and clinical studies, based on the use of T cells and more recently NK cells genetically modified with chimeric antigen receptors retargeting the adoptive cell therapy towards tumor cells, have already shown remarkable results. In this review, we outline the latest highlights and progress in immunotherapies for the treatment of Diffuse Large B-cell Lymphoma (DLBCL) patients, focusing on CD19-targeted immunotherapies. We also discuss current clinical trials and opportunities of using immunotherapies to treat DLBCL patients. [ABSTRACT FROM AUTHOR]

We assessed WT1 expression (expressed as messenger copies/104 ABL1) from marrow cells of 122 patients with acute myeloid leukaemia ( AML), before and after an unmanipulated allogeneic haemopoietic stem cell transplant ( HSCT). The median age was 44 years (15-69), 59% were in first remission, 74% received a myeloablative conditioning regimen and the median follow up was 865 d (34-2833). Relapse was higher in 67 patients with WT1 expression, at any time post- HSCT, exceeding 100 copies (54%), as compared to 16%, for 55 patients with post- HSCT WT1 expression <100 copies ( P < 0·0001). Similarly, actuarial 5-year survival ( OS) was 40% vs. 63%, respectively ( P = 0·03). In multivariate Cox analysis, WT1 expression post- HSCT was the strongest predictor of relapse ( Hazard Ratio [ HR] 4·5, P = 0·0001), independent of disease phase ( HR 2·3, P = 0·002). Donor lymphocyte infusions ( DLI) were given to 17 patients because of increasing WT1 levels: their OS was 44%, vs. 14% for 21 patients with increasing WT1 expression who did not receive DLI ( P = 0·004). In conclusion, WT1 expression post- HSCT is a strong predictor of leukaemia relapse and survival in AML; WT1 may be used as a marker for early interventional therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: It has been well-demonstrated that EZH1/2 enzymes are involved not only in tumor development and progression, but also in the regulation of normal hematopoiesis from CD34+-HSPC. Given the crucial role of NK cells in tumor immune surveillance, in this study, we investigated whether EZH1/2 inhibitors can interfere with NK cell differentiation and functional maturation. Our results suggest that EZH1/2 inhibitors push CD56+ precursor proliferation, skewing precursor cell lineage commitment towards ILC3. In recent years, several clinical trials on the use of EZH1/2 inhibitors against solid tumors have been carried out. Since these in vitro observations revealed possible epigenetic mechanisms involved in NK/ILC development, it is important to evaluate patient monitoring of competent NK cells repertoire in order to design appropriate therapeutic protocols. The dysregulation of epigenetic modifications has a well-established role in the development and progression of hematological malignancies and of solid tumors. In this context, EZH1/2 inhibitors have been designed to interfere with EZH1/2 enzymes involved in histone methylation (e.g., H3K27me3), leading to tumor growth arrest or the restoration of tumor suppressor gene transcription. However, these compounds also affect normal hematopoiesis, interfering with self-renewal and differentiation of CD34+-Hematopoietic Stem/Progenitor Cells (HSPC), and, in turn, could modulate the generation of potential anti-tumor effector lymphocytes. Given the important role of NK cells in the immune surveillance of tumors, it would be useful to understand whether epigenetic drugs can modulate NK cell differentiation and functional maturation. CD34+-HSPC were cultured in the absence or in the presence of the EZH1/2 inhibitor UNC1999 and EZH2 inhibitor GSK126. Our results show that UNC1999 and GSK126 increased CD56+ cell proliferation compared to the control condition. However, UNC1999 and GSK 126 favored the proliferation of no-cytotoxic CD56+ILC3, according to the early expression of the AHR and ROR-γt transcription factors. Our results describe novel epigenetic mechanisms involved in the modulation of NK cell maturation that may provide new tools for designing NK cell-based immunotherapy. [ABSTRACT FROM AUTHOR]