krn-7000 and Lymphoma

Topics: Animals; Antigens, Neoplasm; Brain Neoplasms; Cancer Vaccines; Cell Line, Tumor; Disease Models, Animal; Galactosylceramides; Humans; Immunization; Lymphocyte Activation; Lymphoma; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Natural Killer T-Cells; Peptides; T-Lymphocytes

Messenger RNA encoding tumor antigens has the potential to evoke effective antitumor immunity. This study reports on a nanoparticle platform, named mRNA Galsomes, that successfully co-delivers nucleoside-modified antigen-encoding mRNA and the glycolipid antigen and immunopotentiator α-galactosylceramide (α-GC) to antigen-presenting cells after intravenous administration. By co-formulating low doses of α-GC, mRNA Galsomes induce a pluripotent innate and adaptive tumor-specific immune response in mice, with invariant natural killer T cells (iNKT) as a driving force. In comparison, mRNA Galsomes exhibit advantages over the state-of-the-art cancer vaccines using unmodified ovalbumin (OVA)-encoding mRNA, as we observed up to seven times more tumor-infiltrating antigen-specific cytotoxic T cells, combined with a strong iNKT cell and NK cell activation. In addition, the presence of suppressive myeloid cells (myeloid-derived suppressor cells and tumor-associated macrophages) in the tumor microenvironment was significantly lowered. Owing to these antitumor effects, OVA mRNA Galsomes significantly reduced tumor growth in established E.G7-OVA lymphoma, with a complete tumor rejection in 40% of the animals. Moreover, therapeutic vaccination with mRNA Galsomes enhanced the responsiveness to treatment with a PD-L1 checkpoint inhibitor in B16-OVA melanoma, as evidenced by a synergistic reduction of tumor outgrowth and a significantly prolonged median survival. Taken together, these data show that intravenously administered mRNA Galsomes can provide controllable, multifaceted, and effective antitumor immunity, especially when combined with checkpoint inhibition.

Topics: Animals; Antigens, Neoplasm; Cancer Vaccines; Female; Galactosylceramides; Immunity, Cellular; Kaplan-Meier Estimate; Killer Cells, Natural; Liposomes; Lymphocyte Activation; Lymphoma; Melanoma; Melanoma, Experimental; Mice; Natural Killer T-Cells; Ovalbumin; RNA, Messenger; T-Lymphocytes

Valpha24(+) natural killer T (NKT) cell is a human counterpart of mice Valpha14(+) NKT cell that has a regulatory role for innate and acquired potential antitumor activity. The efficient expansion of NKT cells is an obstacle to the clinical application of Valpha24(+) NKT cells for immunotherapy.. We used mononuclear cells (MNC) obtained from the peripheral blood (PB) of normal healthy donor (HD) and malignant lymphoma (ML) patients before and after granulocyte colony-stimulating factor (G-CSF) treatment. MNC were cultured for 12 days with alpha-galactosylceramide (100 ng/mL) and interleukin-2 (IL-2; 100 U/mL).. The fold expansion of Valpha24(+) NKT cells was higher in HD than in ML patients (208 versus 0.00), despite comparable numbers of Valpha24(+) NKT cells before culture. G-CSF administration enhanced the predominance of Valpha24(+) NKT cell fold expansion in HD compared with ML patients (1935 versus 1.95). After treatment with G-CSF, the expression of CD1d molecules was up-regulated in CD14(+) cells from HD but not ML patients. The fold expansion of Valpha24(+) NKT cells and CD1d expression on CD14(+) cells was strongly correlated in both HD and ML patients (r(2)=0.84). However, replacement of a patient's CD14(+) cells with HD cells did not increase the efficacy of Valpha24(+) NKT cell expansion.. G-CSF-mobilized PB from ML patients has inhibitory characteristics for Valpha24(+) NKT cell expansion as a result of both monocytes and Valpha24(+) NKT cells. Multiple procedures would be needed for the expansion of patients' Valpha24(+) NKT cells.

Topics: Adult; Antigens, CD1; Cell Proliferation; Cells, Cultured; Female; Galactosylceramides; Gene Expression Regulation, Neoplastic; Granulocyte Colony-Stimulating Factor; Humans; Immunity, Innate; Immunophenotyping; Immunotherapy, Adoptive; Injections, Subcutaneous; Interleukin-2; Killer Cells, Natural; Leukocytes, Mononuclear; Lipopolysaccharide Receptors; Lymphoma; Male; Receptors, Antigen, T-Cell; Recombinant Proteins; Tumor Escape