Vaccines With Interleukin-12–Transduced Acute Myeloid Leukemia Cells Elicit Very Potent Therapeutic and Long-Lasting Protective Immunity

Abstract

Interleukin-12 (IL-12) is a heterodimeric cytokine mediating a dynamic interplay between T cells and antigen-presenting cells (APCs). Preclinical studies have demonstrated that recombinant murine IL-12 (rmIL-12) promotes specific antitumor immunity mediated by T cells in several types of tumors. However, the in vivo antitumor properties of IL-12 in acute myeloid leukemia (AML) have not been previously reported. We show here in a murine AML model that systemic administration of rmIL-12 significantly delays tumor growth but is incapable of rescuing mice from lethal leukemia. In contrast, AML cells genetically modified to express IL-12 (IL12-AML) using murine stem cell virus (MSCV) p40 + p35 elicit very potent antileukemic activity. Vaccines with lethally irradiated IL12-AML cells protect naive mice against challenge with wild-type AML cells and, more importantly, can cure mice bearing a considerable leukemic burden. Immunized mice show no signs of systemic IL-12 toxicity and their spleen histology is comparable with naive mice spleen. In vivo depletion of IL-12, interferon-γ (IFN-γ), or CD8+ T cells after injections with live IL12-AML cells abrogates completely the antileukemia immune responses. Studies on the in vitro effects of IFN-γ on AML cells demonstrate enhanced expression of major histocompatibility complex (MHC) and accessory molecules and induction of the costimulatory molecules B7.1 and B7.2, but no significant direct antiproliferative effect. 51Cr release assays show that rejection of live IL12-AML cells supports the development of long-lasting leukemia-specific cytotoxic T lymphocyte (CTL) activity. In conclusion, our results demonstrate that IL12-AML vaccination is a safe and potent immunotherapeutic approach that has a great potential to eliminate minimal residual disease in patients with AML.

Dendritic cells and immunotherapy for malignant disease

“…In the case of myeloma, retroviral gene transfer successfully induced expression of the B7‐1 molecule on tumour cells resulting in CTL induction, although this was not possible with cytokines or CD40L (Tarte et al , 1999). Alternatively, cells may be transduced with genes encoding cytokines, as recently described for GM‐CSF in human melanoma (Soiffer et al , 1998) or IL‐12 in murine leukaemia (Dunussi‐Joannoppoulos et al , 1999). In these cases, effective responses may result either from activation of DCs or though directing effector helper T cells along the Th1 pathway.…”

“…There is also now evidence that leukaemic blasts in AML may have an analogous potential for antigen presentation. This has been observed in vitro following transfection of blasts with the CD80 accessory molecule (Mutis et al , 1998) and in a murine leukaemia model using cells transfected with the IL‐12 gene (Dunussi‐Joannoppoulos et al , 1999). In the latter case, protection and regression of established leukaemia was achieved which could not be replicated by systemic IL‐12 administration.…”

Immunological weapons against acute myeloid leukaemia

“…In contrast to systemic IL-12 administration, vaccines with irradiated IL-12 AML cells can cure mice bearing a considerable leukaemic burden and can protect naïve mice against challenge with wild-type AML cells. 40 Another strategy to enhance anti-leukaemia immunity has been to introduce the B7.1 gene into the leukaemia cells as a means of expressing one of the major co-stimulatory molecules required for T-cell activation upon its interaction with CD28 on the T-cell surface. Details of the B7 family of ligands and its receptors could be found in the latest annual reviews of immunology.…”

“…45 Later, the same group published other studies on an even more potent anti-leukaemia protective and therapeutic immunity using either GM-CSF-or IL-12-modified leukaemia cells. 40,46 The first report for human B7 . 1-modified AML blasts showed encouraging T-cell responses, albeit in an allogeneic setting.…”

Μελέτη Της Ανοσολογικής Απόκρισης Ποντικών Ανοσοποιημένων Με Εμβόλια Γενετικού Υλικού Που Στοχεύουν Επιλεγμένα Καρκινικά Αντιγόνα

“…Στο υποξικό περιβάλλον του όγκου ο HIF-1 ενεργοποιεί τη μεταγραφή του VEGF για την επίτευξη επαρκούς αγγείωσης και οξυγόνωσης (Semenza, 2013 (Locke et al, 2015). Επίσης η μείωση των επιπέδων έκφρασης των καρκινικών αντιγόνων στους όγκους εμβολιασμένων πειραματοζώων σχετίζεται με μεγαλύτερο προσδόκιμο επιβίωσης, καλύτερη απόκριση στη θεραπεία και βελτιωμένους δείκτες παθογονικότητας (Chen et al, 2013;Farsaci et al, 2014;Dunussi-Joannopoulos et al, 1999).…”