Advances in patent applications related to cancer vaccine using CpG-ODN and OX40 association.

Introduction: This review aims to assess the available technologies, advances, and trends from technological readiness level 4 to level 8 for cancer immunologic therapeutics using the association of OX40 and CPG-ODN, usually known as cancer vaccine.Areas covered: Patent documents and clinic studies referring to the use of CpG-ODN and of OX40 association for cancer therapeutics. Patent data were obtained within the worldwide basis of the European Patent Office (EPO). The 138 patents of 36 patent families found were analyzed focusing on word distribution of technology developers and potential markets, legal status, annual evolution of first priority, technological domains, applicants and co-applicants and detailed analysis of each technology. Two clinical studies are in progress.Expert opinion: Traditional methods in post cancer diagnosis are being replaced by immunological association therapies. It is expected that the development of cancer vaccines will expand the scope of cancer-specific immunotherapy, especially if associated with alternative systems for expression and delivery with future potential. It is expected that genetic and controlled and/or specific nano delivery are improved. Furthermore, these new developments will likely address the problem of long-term treatments, reducing cancer mortality and reducing patient numbers worldwide.

Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy.

BACKGROUND: Our understanding of phenotypic and functional signatures of CD8+ T cell dysfunction in acute myeloid leukemia (AML) is limited. Deciphering these deranged T cell functional states and how they are impacted by induction chemotherapy is essential for incorporation of novel immune-based strategies to restore and maintain antileukemia immunity. METHODS: We utilized high-dimensional immunophenotyping, gene expression, and functional studies to characterize peripheral blood and bone marrow CD8+ T cells in 72 AML patients at diagnosis and after induction chemotherapy. RESULTS: Our data suggest that multiple aspects of deranged T cell function are operative in AML at diagnosis, with exhaustion and senescence being the dominant processes. Following treatment, the phenotypic and transcriptional profile of CD8+ T cells diverged between responders and nonresponders. Response to therapy correlated with upregulation of costimulatory, and downregulation of apoptotic and inhibitory, T cell signaling pathways, indicative of restoration of T cell function. In functional studies, AML blasts directly altered CD8+ T cell viability, expansion, co-signaling and senescence marker expression. This CD8+ T cell dysfunction was in part reversible upon PD-1 blockade or OX40 costimulation in vitro. CONCLUSION: Our findings highlight the uniqueness of AML in sculpting CD8+ T cell responses and the plasticity of their signatures upon chemotherapy response, providing a compelling rationale for integration of novel immunotherapies to augment antileukemia immunity. FUNDING: This work was supported by the Leukemia & Lymphoma Society grant no. 6449-13; NIH grants UM1-CA186691 and R01-HL110907-01; the American Society for Blood and Marrow Transplantation New Investigator Award/Gabrielle's Angel Foundation; the Vienna Fund for Innovative Cancer Research; and by fellowships from the Wenner-Gren Foundation and the Swedish Society for Medical Research.

The In Vitro Impact of Glycyrrhizic Acid on CD4+ T Lymphocytes through OX40 Receptor in the Patients with Allergic Rhinitis.

Glycyrrhizic acid (GA), the major bioactive component of glycyrrhiza, possesses anti-inflammatory, anti-allergic, and immunomodulatory activities. This study aimed to investigate the in vitro anti-allergic effect of GA through the OX40 receptor in patients with allergic rhinitis. Purified naive CD4+ T cells of patients with allergic rhinitis (n = 12) were activated with anti-CD3/anti-CD28 with and without anti-OX40 agonist mAbs and then treated with 50, 100, and 200 µM GA and 0.1 µM dexamethasone. Cells were incubated (72 h) to measure cell proliferation. Expression of OX40 in anti-OX40 mAb stimulated CD4+ T cells was evaluated by flow cytometry. mRNA expression of the OX40 receptor and T-bet, GATA-3, and forkhead box P3 (FoxP3) transcriptional factors were measured by a quantitative polymerase chain reaction. The levels of interleukin (IL)-4, IL-10, and interferon-γ (IFN-γ) were also measured. GA inhibited significantly the augmented T cell proliferation induced with anti-OX40 mAb. Protein and gene expression of OX40 was also decreased significantly. Dexamethasone and GA inhibited T-bet and GATA-3 genes expression, but this inhibition was only significant for GATA-3. In contrast, enhanced gene expression of FoxP3 was seen using 200 µM GA and dexamethasone. The levels of IL-4, IL-10, and IFN-γ decreased after treatment with both dexamethasone and GA, but the ratio of IFN-γ/IL-4 (Th1/Th2 balance) increased significantly due to 200 µM GA treatment. This study suggests that GA may have a therapeutic effect on allergic rhinitis, partly by modulation of the Th1/Th2 balance through suppression of OX40 and increasing the activity of regulatory T cells.

Expression and function of the OX40/OX40L costimulatory pair during herpes stromal keratitis.

Herpes stromal keratitis (HSK) is an immunopathological disease regulated by Th1 CD4 T cells, which require APC and costimulation within the infected cornea to mediate disease. Recent studies suggest the OX40:OX40 ligand (OX40L) interaction enhances effector cell cytokine secretion at inflammatory sites. OX40(+) cells were detected in HSV-1-infected mouse corneas as early as 3 days postinfection (dpi), prior to the onset of HSK, and their frequency increased through 15 dpi, when all mice exhibited severe HSK. OX40L(+) cells were first detected at 7 dpi, coincident with the initiation of HSK. It is interesting that the OX40L(+) cells did not coexpress MHC Class II or the dendritic cell (DC) marker CD11c. Our findings demonstrate rapid infiltration of activated (OX40(+)) CD4(+) T cells into HSV-1-infected corneas and expression of OX40L on MHC Class II-negative cells but surprisingly, not on MHC Class II(+) CD11c(+) DC, which are present in the infected corneas and required for HSK. Moreover, neither local nor systemic treatment of mice with a blocking antibody to OX40L or with a blocking fusion protein altered the course of HSK significantly, possibly as a result of a lack of OX40L expression on functional APC.