Christine M. Ho

Recent Advances in Glycomics and Glycogenetics

As the human genome sequence is nearly deciphered, it is important to turn the attention to the physiological functions of the genes. Thus, the study of the gene products, the proteins, is the next big challenge. The proteins, however, are not the final gene products in many cases. It has been shown that carbohydrates participate in post-translational modifications and in many other functional regulations, hence the study of the glycome, the entire collection of carbohydrates is essential in order to determine the functions of all genes, and will greatly enhance the field of chemical genetics. Known biological function / targets of carbohydrates and combinatorial synthesis & structural analysis of natural / non-natural carbohydrates are surveyed in this review. Methods to search for new biological targets that include carbohydrate mimetics and carbohydrate scaffolds along with chip technology, are also presented.

Microbiome-Host Interactions in Hematopoietic Stem-Cell Transplant Recipients

Author: Tessa Andermann, Jonathan Peled, Christine Ho, Pavan Reddy, Marcie Riches, Rainer Storb, Takanori Teshima, Marcel van den Brink, Amin Alousi, Sophia Balderman, Patrizia Chiusolo, William Clark, Ernst Holler, Alan Howard, Leslie Kean, Andrew Koh, Philip McCarthy, John McCarty, Mohamad Mohty, Ryotaro Nakamura, Katy Rezvani, Brahm Segal, Bronwen Shaw, Elizabeth Shpall, Anthony Sung, Daniela Weber, Jennifer Whangbo, John Wingard, William Wood, Miguel-Angel Perales, Robert Jenq, Ami Bhatt

BPX-501 T cells interfere with minimal residual disease evaluation of B-cell acute lymphoblastic leukemia

Cellular therapies are increasingly used to treat hematologic malignancies requiring providers to recognize and learn to treat newly prominent complications of therapy such as cytokine release syndrome as well as adapting their practice to incorporate the special requirements for working with cellular therapies. Here we present an unusual complication of BPX-501 T cells affecting the clinical workflow and emphasizing the need for good communication between providers and the laboratory. The patient is a 24-year-old female with Philadelphia chromosome positive precursor B-cell acute lymphoblastic leukemia (pre-B-ALL) in first complete remission who received an alpha beta T-cell depleted, CD34+ selected haploidentical peripheral blood hematopoietic stem cell transplant (HSCT) after myeloablative conditioning with fludarabine, cyclophosphamide, anti-thymocyte globulin, rituximab, and total body irradiation. The patient received a planned infusion of BPX-501 T cells on day 13 as a part of clinical trial (ClinicalTrials.gov identifier: NCT0174423). BPX-501 T cells are allogeneic donor T cells that have been modified with an inducible apoptosis safety switch based on the fusion of human caspase 9 to human FK506-binding protein (FKBP12). Upon binding of remiducid (AP1903), a bioinert agent with high affinity to FKBP12, caspase 9 dimerizes and is activated, inducing apoptosis. The development of acute graft versus host disease can be abrogated in recipients of haploidentical transplants who have received infusions of BPX-501 T cells upon exposure to remiducid [1]. Neutrophil and platelet engraftment occurred 11 days after transplant. The patient was discharged to her home on day 22, and received follow up in clinic twice weekly. Her post-transplant course was complicated by relative eosinophilia and transplant-related microangiopathy, which was resolved by discontinuing tacrolimus. The patient developed mild grade 1 acute graft versus host disease of the skin (stage 1), which was treated with topical corticosteroids. Bone marrow biopsies at 30, 60, and 180 days following HSCT did not reveal any evidence of residual leukemia by morphology, cytogenetics, or standard flow cytometry. As a part of validation study for the detection of minimal residual disease (MRD) in B-ALL, a sample was sent to an outside institution for multiparameter flow cytometry at 6 months post HSCT [2]. This test demonstrated a small population of abnormal cells positive for CD45 (bright) and CD19 but lacking CD10, CD20, CD38, CD34, and the myeloid antigens CD13 and CD33 (Fig. 1). The pretreatment phenotype and details of therapy received were not available to the laboratory at the time of analysis. The population identified occupied a region of multiparameter space in which no normal B cell would fall; because of this, the test was interpreted as positive for MRD, although this would be an unusual phenotype for B-ALL. These findings were a cause of consternation given the clinical implications of MRD pre-B-ALL to the patient. Clinically this was a highly unanticipated result: diagnostic testing performed at the treating institution including bone marrow morphology, cytogenetic analysis, donor chimerism studies, and flow cytometry based MRD testing for pre-B-ALL did not indicate any residual preB-ALL. Upon reconsidering the case, we recalled that the manufacturing process for BPX-501 T cells uses a CD19 * George L. Chen george.chen@roswellpark.org

Immune signatures associated with improved progression-free and overall survival for myeloma patients treated with AHSCT

Multiple therapeutic options exist for multiple myeloma (MM), including autologous hematopoietic stem cell transplantation (AHSCT). Measurement of minimal residual disease (MRD) and immune reconstitution is rapidly becoming an integral part of the care of MM patients. We investigated comprehensive immune profiling (IP) associated with progression-free survival (PFS) and overall survival (OS). From August 2007 to January 2014, 101 consecutive MM patients underwent peripheral blood IP and marrow MRD testing before and approximately 100 days after AHSCT. Higher pre-AHSCT CD19+ B-cell counts correlated with improved 2-year PFS (83% [highest quartile] vs 53% [lowest quartile]; P = .01) and OS (93% [highest quartile] vs 63% [lowest quartile]; P = .0003). This effect was seen primarily in patients with MRD-positive marrow tests. Higher γδ T-cell counts post-AHSCT correlated with improved 2-year PFS (65% [highest quartile] vs 45% [lowest quartile]; P = .02) and OS (89% [highest quartile] vs 65% [lowest quartile]; P = .01). Higher CD4+ central memory (CM) cell counts post-AHSCT were associated with improved 2-year OS (95% [upper quartile] vs 47% [lowest quartile]; P = .0003) but not PFS. The higher γδ T-cell and CD4+ CM-cell count associations were primarily observed in MRD-negative patients post-AHSCT and in patients not receiving maintenance therapy. This proof-of-concept study demonstrates that IP before and after AHSCT can be of complementary prognostic value for depth of response. Maintenance therapy seems to overcome negative IP. IP and MRD should be measured in clinical trials of maintenance therapy with novel agents post-AHSCT for MM to confirm their utility for prognosis and management.

BMT CTN Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling: Summary and Recommendations From the Organizing Committee

The Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling was convened on December 1, 2016 at the American Society of Hematology meeting to discuss the emerging data and technologies for minimal residual disease assessment and immune profiling in myeloma. Particular emphasis was placed on developing strategies to incorporate these techniques into clinical trial design. This document reviews the literature, summarizes the topics discussed in the workshop, and provides recommendations for integration of these techniques into future clinical trial design.