Browsing by Author "Rizzieri, David A"

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    Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells.
    (Proc Natl Acad Sci U S A, 2013-02-05) Kurokawa, Manabu; Ito, Takahiro; Yang, Chih-Sheng; Zhao, Chen; Macintyre, Andrew N; Rizzieri, David A; Rathmell, Jeffrey C; Deininger, Michael W; Reya, Tannishtha; Kornbluth, Sally
    Increased understanding of the precise molecular mechanisms involved in cell survival and cell death signaling pathways offers the promise of harnessing these molecules to eliminate cancer cells without damaging normal cells. Tyrosine kinase oncoproteins promote the genesis of leukemias through both increased cell proliferation and inhibition of apoptotic cell death. Although tyrosine kinase inhibitors, such as the BCR-ABL inhibitor imatinib, have demonstrated remarkable efficacy in the clinic, drug-resistant leukemias emerge in some patients because of either the acquisition of point mutations or amplification of the tyrosine kinase, resulting in a poor long-term prognosis. Here, we exploit the molecular mechanisms of caspase activation and tyrosine kinase/adaptor protein signaling to forge a unique approach for selectively killing leukemic cells through the forcible induction of apoptosis. We have engineered caspase variants that can directly be activated in response to BCR-ABL. Because we harness, rather than inhibit, the activity of leukemogenic kinases to kill transformed cells, this approach selectively eliminates leukemic cells regardless of drug-resistant mutations.
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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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    Myeloablative conditioning with total body irradiation for AML: Balancing survival and pulmonary toxicity.
    (Adv Radiat Oncol, 2016-10) Stephens, Sarah J; Thomas, Samantha; Rizzieri, David A; Horwitz, Mitchell E; Chao, Nelson J; Engemann, Ashley M; Lassiter, Martha; Kelsey, Chris R
    PURPOSE: The purpose of this study was to compare leukemia-free survival (LFS) and other clinical outcomes in patients with acute myelogenous leukemia who underwent a myeloablative allogeneic stem cell transplant with and without total body irradiation (TBI). METHODS AND MATERIALS: Adult patients with acute myelogenous leukemia undergoing myeloablative allogeneic stem cell transplant at Duke University Medical Center between 1995 and 2012 were included. The primary endpoint was LFS. Secondary outcomes included overall survival (OS), nonrelapse mortality, and the risk of pulmonary toxicity. Kaplan-Meier survival estimates and Cox proportional hazards multivariate analyses were performed. RESULTS: A total of 206 patients were evaluated: 90 received TBI-based conditioning regimens and 116 received chemotherapy alone. Median follow-up was 36 months. For all patients, 2-year LFS and OS were 36% (95% confidence interval [CI], 29-43) and 39% (95% CI, 32-46), respectively. After adjusting for known prognostic factors using a multivariate analysis, TBI was associated with improved LFS (hazard ratio: 0.63; 95% CI: 0.44-0.91) and OS (hazard ratio: 0.63; 95% CI, 0.43-0.91). There was no difference in nonrelapse mortality between cohorts, but pulmonary toxicity was significantly more common with TBI (2-year incidence 42% vs 12%,P< .001). High-grade pulmonary toxicity predominated with both conditioning strategies (70% and 93% of cases were grade 3-5 with TBI and chemotherapy alone, respectively). CONCLUSIONS: TBI-based regimens were associated with superior LFS and OS but at the cost of increased pulmonary toxicity.
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    Single-cell landscape analysis unravels molecular programming of the human B cell compartment in chronic GVHD.
    (JCI insight, 2023-06) Poe, Jonathan C; Fang, Jiyuan; Zhang, Dadong; Lee, Marissa R; DiCioccio, Rachel A; Su, Hsuan; Qin, Xiaodi; Zhang, Jennifer Y; Visentin, Jonathan; Bracken, Sonali J; Ho, Vincent T; Wang, Kathy S; Rose, Jeremy J; Pavletic, Steven Z; Hakim, Frances T; Jia, Wei; Suthers, Amy N; Curry-Chisolm, Itaevia M; Horwitz, Mitchell E; Rizzieri, David A; McManigle, William C; Chao, Nelson J; Cardones, Adela R; Xie, Jichun; Owzar, Kouros; Sarantopoulos, Stefanie
    Alloreactivity can drive autoimmune syndromes. After allogeneic hematopoietic stem cell transplantation (allo-HCT), chronic graft-versus-host disease (cGVHD), a B cell-associated autoimmune-like syndrome, commonly occurs. Because donor-derived B cells continually develop under selective pressure from host alloantigens, aberrant B cell receptor (BCR) activation and IgG production can emerge and contribute to cGVHD pathobiology. To better understand molecular programing of B cells in allo-HCT, we performed scRNA-Seq analysis on high numbers of purified B cells from patients. An unsupervised analysis revealed 10 clusters, distinguishable by signature genes for maturation, activation, and memory. Within the memory B cell compartment, we found striking transcriptional differences in allo-HCT patients compared with healthy or infected individuals, including potentially pathogenic atypical B cells (ABCs) that were expanded in active cGVHD. To identify intrinsic alterations in potentially pathological B cells, we interrogated all clusters for differentially expressed genes (DEGs) in active cGVHD versus patients who never had signs of immune tolerance loss (no cGVHD). Active cGVHD DEGs occurred in both naive and BCR-activated B cell clusters. Remarkably, some DEGs occurred across most clusters, suggesting common molecular programs that may promote B cell plasticity. Our study of human allo-HCT and cGVHD provides understanding of altered B cell memory during chronic alloantigen stimulation.
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    Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment.
    (The Journal of clinical investigation, 2014-07) Horwitz, Mitchell E; Chao, Nelson J; Rizzieri, David A; Long, Gwynn D; Sullivan, Keith M; Gasparetto, Cristina; Chute, John P; Morris, Ashley; McDonald, Carolyn; Waters-Pick, Barbara; Stiff, Patrick; Wease, Steven; Peled, Amnon; Snyder, David; Cohen, Einat Galamidi; Shoham, Hadas; Landau, Efrat; Friend, Etty; Peleg, Iddo; Aschengrau, Dorit; Yackoubov, Dima; Kurtzberg, Joanne; Peled, Tony

    Background

    Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo-expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment.

    Methods

    In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls.

    Results

    No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively.

    Conclusion

    UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell-containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation.

    Trial registration

    Clinicaltrials.gov NCT01221857.

    Funding

    Gamida Cell Ltd.