Acute lymphoblastic leukemia with t(4;11) in children 1 year and older: The 'big sister' of the infant disease?

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Gene Therapy-Mediated Reprogramming Tumor Infiltrating T Cells Using IL-2 and Inhibiting NF-κB Signaling Improves the Efficacy of Immunotherapy in a Brain Cancer Model

Immune-mediated gene therapy using adenovirus expressing Flt3 ligand and thymidine kinase followed by ganciclovir administration (Flt3/TK) effectively elicits tumor regression in preclinical glioma models. Herein, we assessed new strategies to optimize Flt3L/TK therapeutic efficacy in a refractory RG2 orthotopic glioblastoma model. Specifically, we aimed to optimize the therapeutic efficacy of Flt3L/TK treatment in the RG2 model by overexpressing the following genes within the brain tumor microenvironment: 1) a TK mutant with enhanced cytotoxicity (SR39 mutant TK), 2) Flt3L-IgG fusion protein that has a longer half-life, 3) CD40L to stimulate DC maturation, 4) T helper cell type 1 polarizing dendritic cell cytokines interleukin-12 or C-X-C motif ligand 10 chemokine (CXCL)-10, 5) C-C motif ligand 2 chemokine (CCL2) or C-C motif ligand 3 chemokine (CCL3) to enhance dendritic cell recruitment into the tumor microenvironment, 6) T helper cell type 1 cytokines interferon-γ or interleukin-2 to enhance effector T-cell functions, and 7) IκBα or p65RHD (nuclear factor kappa-B [NF-κB] inhibitors) to suppress the function of Foxp3+ Tregs and enhanced effector T-cell functions. Anti-tumor immunity and tumor specific effector T-cell functions were assessed by cytotoxic T lymphocyte assay and intracellular IFN-γ staining. Our data showed that overexpression of interferon-γ or interleukin-2, or inhibition of the nuclear factor kappa-B within the tumor microenvironment, enhanced cytotoxic T lymphocyte-mediated immune responses and successfully extended the median survival of rats bearing intracranial RG2 when combined with Flt3L/TK. These findings indicate that enhancement of T-cell functions constitutes a critical therapeutic target to overcome immune evasion and enhance therapeutic efficacy for brain cancer. In addition, our study provides novel targets to be used in combination with immune-therapeutic strategies for glioblastoma, which are currently being tested in the clinic.Fil: Mineharu, Yohei. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Muhammad, AKM Ghulam. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Yagiz, Kader. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Candolfi, Marianela. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kroeger, Kurt M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Xiong, Weidong. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Puntel, Mariana. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Liu, Chunyan. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Levy, Eva. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Lugo, Claudia. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Kocharian, Adrina. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados UnidosFil: Allison, James P.. Howard Hughes Medical Institute; Estados UnidosFil: Curran, Michael A.. Howard Hughes Medical Institute; Estados UnidosFil: Lowenstein, Pedro R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos. University of Michigan; Estados UnidosFil: Castro, Maria G.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos. University of Michigan; Estados Unido

Human tankyrases are aberrantly expressed in colon tumors and contain multiple epitopes that induce humoral and cellular immune responses in cancer patients

PURPOSE: Tankyrases 1 and 2 are telomere-associated poly(ADP-ribose) polymerases (PARP) that can positively regulate telomere elongation and interact with multiple cellular proteins. Recent reports implicated tankyrases as tumor antigens and potential targets of anticancer treatment. We examined expression of tankyrases in colon tumors and immune response to these enzymes in patients with different types of cancer. METHODS: mRNA and protein expression was evaluated by quantitative real-time RT-PCR and Western blotting, respectively. Humoral immune response to recombinant tankyrases was investigated by modified enzyme-linked immunoassays. Cellular immune response was analysed by ELISPOT and (51)Cr release assays. RESULTS: We found that both mRNA and protein levels of tankyrase 2 (TNKL) are upregulated in colon tumors. In contrast, protein level of tankyrase 1 (TNKS) is downregulated, while mRNA level shows variable changes. More than a quarter of colon cancer patients develop humoral immune response to at least one of the two tankyrases. In this study we mapped common and unique B-cell epitopes located in different domains of the two proteins. Additionally, we present evidence for T-cell responses both to epitopes that are unique for TNKL and to those shared between TNKL and TNKS. CONCLUSION: Our study favors a biomarker usage of antibody response to tankyrases. Spontaneous CD8(+) T-cell responses to these enzymes are rare and further investigation is needed to evaluate tankyrases as potential targets for cancer immunotherapy