Browsing by Author "Li, Zhiguo"

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    Alphavirus Replicon Particle Vaccine Breaks B Cell Tolerance and Rapidly Induces IgG to Murine Hematolymphoid Tumor Associated Antigens.
    (Frontiers in immunology, 2022-01) Su, Hsuan; Imai, Kazuhiro; Jia, Wei; Li, Zhiguo; DiCioccio, Rachel A; Serody, Jonathan S; Poe, Jonathan C; Chen, Benny J; Doan, Phuong L; Sarantopoulos, Stefanie
    De novo immune responses to myeloid and other blood-borne tumors are notably limited and ineffective, making our ability to promote immune responses with vaccines a major challenge. While focus has been largely on cytotoxic cell-mediated tumor eradication, B-cells and the antibodies they produce also have roles in anti-tumor responses. Indeed, therapeutic antibody-mediated tumor cell killing is routinely employed in patients with hematolymphoid cancers, but whether endogenous antibody responses can be incited to blood-born tumors remains poorly studied. A major limitation of immunoglobulin therapies is that cell surface expression of tumor-associated antigen (TAA) targets is dynamic and varied, making promotion of polyclonal, endogenous B cell responses appealing. Since many TAAs are self-antigens, developing tumor vaccines that enable production of antibodies to non-polymorphic antigen targets remains a challenge. As B cell responses to RNA vaccines are known to occur, we employed the Viral Replicon Particles (VRP) which was constructed to encode mouse FLT3. The VRP-FLT3 vaccine provoked a rapid IgG B-cell response to this self-antigen in leukemia and lymphoma mouse models. In addition, IgGs to other TAAs were also produced. Our data suggest that vaccination with RNA viral particle vectors incites a loss of B-cell tolerance that enables production of anti-tumor antibodies. This proof of principle work provides impetus to employ such strategies that lead to a break in B-cell tolerance and enable production of broadly reactive anti-TAA antibodies as potential future therapeutic agents for patients with hematolymphoid cancers.
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    Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions.
    (Blood advances, 2024-02) Bracken, Sonali J; Suthers, Amy N; DiCioccio, Rachel A; Su, Hsuan; Anand, Sarah; Poe, Jonathan C; Jia, Wei; Visentin, Jonathan; Basher, Fahmin; Jordan, Collin Z; McManigle, William C; Li, Zhiguo; Hakim, Frances T; Pavletic, Steven Z; Bhuiya, Nazmim S; Ho, Vincent T; Horwitz, Mitchell E; Chao, Nelson J; Sarantopoulos, Stefanie

    Abstract

    Chronic graft-versus-host disease (cGVHD) is a debilitating, autoimmune-like syndrome that can occur after allogeneic hematopoietic stem cell transplantation. Constitutively activated B cells contribute to ongoing alloreactivity and autoreactivity in patients with cGVHD. Excessive tissue damage that occurs after transplantation exposes B cells to nucleic acids in the extracellular environment. Recognition of endogenous nucleic acids within B cells can promote pathogenic B-cell activation. Therefore, we hypothesized that cGVHD B cells aberrantly signal through RNA and DNA sensors such as Toll-like receptor 7 (TLR7) and TLR9. We found that B cells from patients and mice with cGVHD had higher expression of TLR7 than non-cGVHD B cells. Using ex vivo assays, we found that B cells from patients with cGVHD also demonstrated increased interleukin-6 production after TLR7 stimulation with R848. Low-dose B-cell receptor (BCR) stimulation augmented B-cell responses to TLR7 activation. TLR7 hyperresponsiveness in cGVHD B cells correlated with increased expression and activation of the downstream transcription factor interferon regulatory factor 5. Because RNA-containing immune complexes can activate B cells through TLR7, we used a protein microarray to identify RNA-containing antigen targets of potential pathological relevance in cGVHD. We found that many of the unique targets of active cGVHD immunoglobulin G (IgG) were nucleic acid-binding proteins. This unbiased assay identified the autoantigen and known cGVHD target Ro-52, and we found that RNA was required for IgG binding to Ro-52. Herein, we find that BCR-activated B cells have aberrant TLR7 signaling responses that promote potential effector responses in cGVHD.
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    Morphologic leukemia-free state in acute myeloid leukemia is sufficient for successful allogeneic hematopoietic stem cell transplant.
    (Blood cancer journal, 2021-05-16) Pabon, Cindy M; Li, Zhiguo; Hennig, Therese; de Castro, Carlos; Neff, Jadee L; Horwitz, Mitchell E; LeBlanc, Thomas W; Long, Gwynn D; Lopez, Richard D; Sung, Anthony D; Chao, Nelson; Gasparetto, Cristina; Sarantopoulos, Stefanie; Adams, Donna B; Erba, Harry; Rizzieri, David A
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    Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.
    (J Hematol Oncol, 2018-03-04) Green, Michael MB; Chao, Nelson; Chhabra, Saurabh; Corbet, Kelly; Gasparetto, Cristina; Horwitz, Ari; Li, Zhiguo; Venkata, Jagadish Kummetha; Long, Gwynn; Mims, Alice; Rizzieri, David; Sarantopoulos, Stefanie; Stuart, Robert; Sung, Anthony D; Sullivan, Keith M; Costa, Luciano; Horwitz, Mitchell; Kang, Yubin
    BACKGROUND: The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation. METHODS: We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis. RESULTS: Thirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls. CONCLUSIONS: Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01280955.
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    Rad18 confers hematopoietic progenitor cell DNA damage tolerance independently of the Fanconi Anemia pathway in vivo.
    (Nucleic Acids Res, 2016-05-19) Yang, Yang; Poe, Jonathan C; Yang, Lisong; Fedoriw, Andrew; Desai, Siddhi; Magnuson, Terry; Li, Zhiguo; Fedoriw, Yuri; Araki, Kimi; Gao, Yanzhe; Tateishi, Satoshi; Sarantopoulos, Stefanie; Vaziri, Cyrus
    In cultured cancer cells the E3 ubiquitin ligase Rad18 activates Trans-Lesion Synthesis (TLS) and the Fanconi Anemia (FA) pathway. However, physiological roles of Rad18 in DNA damage tolerance and carcinogenesis are unknown and were investigated here. Primary hematopoietic stem and progenitor cells (HSPC) co-expressed RAD18 and FANCD2 proteins, potentially consistent with a role for Rad18 in FA pathway function during hematopoiesis. However, hematopoietic defects typically associated with fanc-deficiency (decreased HSPC numbers, reduced engraftment potential of HSPC, and Mitomycin C (MMC) -sensitive hematopoiesis), were absent in Rad18(-/-) mice. Moreover, primary Rad18(-/-) mouse embryonic fibroblasts (MEF) retained robust Fancd2 mono-ubiquitination following MMC treatment. Therefore, Rad18 is dispensable for FA pathway activation in untransformed cells and the Rad18 and FA pathways are separable in hematopoietic cells. In contrast with responses to crosslinking agents, Rad18(-/-) HSPC were sensitive to in vivo treatment with the myelosuppressive agent 7,12 Dimethylbenz[a]anthracene (DMBA). Rad18-deficient fibroblasts aberrantly accumulated DNA damage markers after DMBA treatment. Moreover, in vivo DMBA treatment led to increased incidence of B cell malignancy in Rad18(-/-) mice. These results identify novel hematopoietic functions for Rad18 and provide the first demonstration that Rad18 confers DNA damage tolerance and tumor-suppression in a physiological setting.
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    Sample size calculation for studies with grouped survival data.
    (Statistics in medicine, 2018-06-10) Li, Zhiguo; Wang, Xiaofei; Wu, Yuan; Owzar, Kouros
    Grouped survival data arise often in studies where the disease status is assessed at regular visits to clinic. The time to the event of interest can only be determined to be between two adjacent visits or is right censored at one visit. In data analysis, replacing the survival time with the endpoint or midpoint of the grouping interval leads to biased estimators of the effect size in group comparisons. Prentice and Gloeckler developed a maximum likelihood estimator for the proportional hazards model with grouped survival data and the method has been widely applied. Previous work on sample size calculation for designing studies with grouped data is based on either the exponential distribution assumption or the approximation of variance under the alternative with variance under the null. Motivated by studies in HIV trials, cancer trials and in vitro experiments to study drug toxicity, we develop a sample size formula for studies with grouped survival endpoints that use the method of Prentice and Gloeckler for comparing two arms under the proportional hazards assumption. We do not impose any distributional assumptions, nor do we use any approximation of variance of the test statistic. The sample size formula only requires estimates of the hazard ratio and survival probabilities of the event time of interest and the censoring time at the endpoints of the grouping intervals for one of the two arms. The formula is shown to perform well in a simulation study and its application is illustrated in the three motivating examples.