Publications by authors named "Justin Taylor"

110 Publications

Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms.

Leukemia 2021 Jun 25. Epub 2021 Jun 25.

H3 Biomedicine, Cambridge, MA, USA.

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1-40 mg, n = 65) and schedule II (21 days on/7 days off, 7-20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.
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http://dx.doi.org/10.1038/s41375-021-01328-9DOI Listing
June 2021

Messenger RNA expressing PfCSP induces functional, protective immune responses against malaria in mice.

NPJ Vaccines 2021 Jun 18;6(1):84. Epub 2021 Jun 18.

Walter Reed Army Institute of Research, Silver Spring, MD, USA.

Human malaria affects the vast majority of the world's population with the Plasmodium falciparum species causing the highest rates of morbidity and mortality. With no licensed vaccine and leading candidates achieving suboptimal protection in the field, the need for an effective immunoprophylactic option continues to motivate the malaria research community to explore alternative technologies. Recent advances in the mRNA discipline have elevated the long-neglected platform to the forefront of infectious disease research. As the immunodominant coat protein of the invasive stage of the malaria parasite, circumsporozoite protein (PfCSP) was selected as the antigen of choice to assess the immunogenic and protective potential of an mRNA malaria vaccine. In mammalian cell transfection experiments, PfCSP mRNA was well expressed and cell associated. In the transition to an in vivo murine model, lipid nanoparticle (LNP) encapsulation was applied to protect and deliver the mRNA to the cell translation machinery and supply adjuvant activity. The immunogenic effect of an array of factors was explored, such as formulation, dose, number, and interval of immunizations. PfCSP mRNA-LNP achieved sterile protection against infection with two P. berghei PfCSP transgenic parasite strains, with mRNA dose and vaccination interval having a greater effect on outcome. This investigation serves as the assessment of pre-erythrocytic malaria, PfCSP mRNA vaccine candidate resulting in sterile protection, with numerous factors affecting protective efficacy, making it a compelling candidate for further investigation.
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http://dx.doi.org/10.1038/s41541-021-00345-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213722PMC
June 2021

Humoral immunogenicity of the seasonal influenza vaccine before and after CAR-T-cell therapy.

medRxiv 2021 May 11. Epub 2021 May 11.

Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B-cell malignancies are immunocompromised and at risk for serious infections. Vaccine immunogenicity is unknown in this population. We conducted a prospective observational study of the humoral immunogenicity of 2019-2020 inactivated influenza vaccines (IIV) in children and adults immediately prior to (n=7) or 13-57 months after (n=15) CD19-, CD20-, or BCMA-targeted CAR-T-cell therapy, as well as controls (n=8). Individuals post-CAR-T-cell therapy were in remission. We tested for antibodies to 4 vaccine strains at baseline and ≥1 time point after IIV using neutralization and hemagglutination inhibition assays. An antibody response was defined as a ≥4-fold titer increase from baseline at the first post-vaccine time point. Baseline A(H1N1) titers in the CAR-T cohorts were significantly lower compared to controls. Antibody responses to ≥1 vaccine strain occurred in 2 (29%) individuals before CAR-T-cell therapy; one individual maintained a response for >3 months post-CAR-T-cell therapy. Antibody responses to ≥1 vaccine strain occurred in 6 (40%) individuals vaccinated after CAR-T-cell therapy. An additional 2 (29%) and 6 (40%) individuals had ≥2-fold increases (at any time) in the pre- and post-CAR-T cohorts, respectively. There were no identified clinical or immunologic predictors of antibody responses. Neither severe hypogammaglobulinemia nor B-cell aplasia precluded antibody responses. These data support consideration for vaccination before and after CAR-T-cell therapy for influenza and other relevant pathogens such as SARS-CoV-2, irrespective of hypogammaglobulinemia or B-cell aplasia. Larger studies are needed to determine correlates of vaccine immunogenicity and durability in CAR-T-cell therapy recipients.

Key Points: Influenza vaccination was immunogenic pre- and post-CAR-T-cell therapy, despite hypogammaglobulinemia and B-cell aplasia.Vaccination with inactivated vaccines can be considered before CAR-T-cell therapy and in individuals with remission after therapy.
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http://dx.doi.org/10.1101/2021.05.10.21256634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132269PMC
May 2021

Development of a VRC01-class germline targeting immunogen derived from anti-idiotypic antibodies.

Cell Rep 2021 May;35(5):109084

Fred Hutchinson Cancer Research Center, Vaccines and Infectious Diseases Division, Seattle, WA 98109, USA; University of Washington, Department of Global Health, Seattle, WA 98195, USA. Electronic address:

An effective HIV-1 vaccine will likely need to elicit broadly neutralizing antibodies (bNAbs). Broad and potent VRC01-class bNAbs have been isolated from multiple infected individuals, suggesting that they could be reproducibly elicited by vaccination. Several HIV-1 envelope-derived germline-targeting immunogens have been designed to engage naive VRC01-class precursor B cells. However, they also present off-target epitopes that could hinder development of VRC01-class bNAbs. We characterize a panel of anti-idiotypic monoclonal antibodies (ai-mAbs) raised against inferred-germline (iGL) VRC01-class antibodies. By leveraging binding, structural, and B cell sorting data, we engineered a bispecific molecule derived from two ai-mAbs; one specific for VRC01-class heavy chains and one specific for VRC01-class light chains. The bispecific molecule preferentially activates iGL-VRC01 B cells in vitro and induces specific antibody responses in a murine adoptive transfer model with a diverse polyclonal B cell repertoire. This molecule represents an alternative non-envelope-derived germline-targeting immunogen that can selectively activate VRC01-class precursors in vivo.
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http://dx.doi.org/10.1016/j.celrep.2021.109084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127986PMC
May 2021

Antibodies against vaccine-preventable infections after CAR-T cell therapy for B cell malignancies.

JCI Insight 2021 Jun 8;6(11). Epub 2021 Jun 8.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

BACKGROUNDLittle is known about pathogen-specific humoral immunity after chimeric antigen receptor-modified T (CAR-T) cell therapy for B cell malignancies.METHODSWe conducted a prospective cross-sectional study of CD19-targeted or B cell maturation antigen-targeted (BCMA-targeted) CAR-T cell therapy recipients at least 6 months posttreatment and in remission. We measured pathogen-specific IgG against 12 vaccine-preventable infections and the number of viral and bacterial epitopes to which IgG was detected ("epitope hits") using a serological profiling assay. The primary outcome was the proportion of participants with IgG levels above a threshold correlated with seroprotection for vaccine-preventable infections.RESULTSWe enrolled 65 children and adults a median of 20 months after CD19- (n = 54) or BCMA- (n = 11) CAR-T cell therapy. Among 30 adults without IgG replacement therapy (IGRT) in the prior 16 weeks, 27 (90%) had hypogammaglobulinemia. These individuals had seroprotection to a median of 67% (IQR, 59%-73%) of tested infections. Proportions of participants with seroprotection per pathogen were comparable to population-based studies, but most individuals lacked seroprotection to specific pathogens. Compared with CD19-CAR-T cell recipients, BCMA-CAR-T cell recipients were half as likely to have seroprotection (prevalence ratio, 0.47; 95% CI, 0.18-1.25) and had fewer pathogen-specific epitope hits (mean difference, -90 epitope hits; 95% CI, -157 to -22).CONCLUSIONSeroprotection for vaccine-preventable infections in adult CD19-CAR-T cell recipients was comparable to the general population. BCMA-CAR-T cell recipients had fewer pathogen-specific antibodies. Deficits in both groups support the need for vaccine and immunoglobulin replacement therapy studies.FUNDINGSwiss National Science Foundation (Early Postdoc Mobility grant P2BSP3_188162), NIH/National Cancer Institute (NIH/NCI) (U01CA247548 and P01CA018029), NIH/NCI Cancer Center Support Grants (P30CA0087-48 and P30CA015704-44), American Society for Transplantation and Cellular Therapy, and Juno Therapeutics/BMS.
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http://dx.doi.org/10.1172/jci.insight.146743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262349PMC
June 2021

Protective antibodies against human parainfluenza virus type 3 infection.

MAbs 2021 Jan-Dec;13(1):1912884

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Human parainfluenza virus type III (HPIV3) is a common respiratory pathogen that afflicts children and can be fatal in vulnerable populations, including the immunocompromised. There are currently no effective vaccines or therapeutics available, resulting in tens of thousands of hospitalizations per year. In an effort to discover a protective antibody against HPIV3, we screened the B cell repertoires from peripheral blood, tonsils, and spleen from healthy children and adults. These analyses yielded five monoclonal antibodies that potently neutralized HPIV3 . These HPIV3-neutralizing antibodies targeted two non-overlapping epitopes of the HPIV3 F protein, with most targeting the apex. Prophylactic administration of one of these antibodies, PI3-E12, resulted in potent protection against HPIV3 infection in cotton rats. Additionally, PI3-E12 could also be used therapeutically to suppress HPIV3 in immunocompromised animals. These results demonstrate the potential clinical utility of PI3-E12 for the prevention or treatment of HPIV3 in both immunocompetent and immunocompromised individuals.
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http://dx.doi.org/10.1080/19420862.2021.1912884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078717PMC
April 2021

Identification of 2,2-Dimethylbutanoic Acid (HST5040), a Clinical Development Candidate for the Treatment of Propionic Acidemia and Methylmalonic Acidemia.

J Med Chem 2021 04 13;64(8):5037-5048. Epub 2021 Apr 13.

HemoShear Therapeutics Inc., 501 Locust Avenue, Charlottesville, Virginia 22902, United States.

Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare autosomal recessive disorders of propionyl-CoA (P-CoA) catabolism, caused by a deficiency in the enzymes P-CoA carboxylase and methylmalonyl-CoA (M-CoA) mutase, respectively. PA and MMA are classified as intoxication-type inborn errors of metabolism because the intramitochondrial accumulation of P-CoA, M-CoA, and other metabolites results in secondary inhibition of multiple pathways of intermediary metabolism, leading to organ dysfunction and failure. Herein, we describe the structure-activity relationships of a series of short-chain carboxylic acids which reduce disease-related metabolites in PA and MMA primary hepatocyte disease models. These studies culminated in the identification of 2,2-dimethylbutanoic acid (, HST5040) as a clinical candidate for the treatment of PA and MMA. Additionally, we describe the in vitro and in vivo absorption, distribution, metabolism, and excretion profile of HST5040, data from preclinical studies, and the synthesis of the sodium salt of HST5040 for clinical trials.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00124DOI Listing
April 2021

Minor intron retention drives clonal hematopoietic disorders and diverse cancer predisposition.

Nat Genet 2021 05 12;53(5):707-718. Epub 2021 Apr 12.

Human Oncology and Pathogenesis Program, Memorial Sloan KetterAbsolute numbers of live mature hematopoietic cellsing Cancer Center, New York, NY, USA.

Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles of the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections among minor introns, hematopoiesis and cancers are unclear. Here, we identify that impaired minor intron excision via ZRSR2 loss enhances hematopoietic stem cell self-renewal. CRISPR screens mimicking nonsense-mediated decay of minor intron-containing mRNA species converged on LZTR1, a regulator of RAS-related GTPases. LZTR1 minor intron retention was also discovered in the RASopathy Noonan syndrome, due to intronic mutations disrupting splicing and diverse solid tumors. These data uncover minor intron recognition as a regulator of hematopoiesis, noncoding mutations within minor introns as potential cancer drivers and links among ZRSR2 mutations, LZTR1 regulation and leukemias.
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http://dx.doi.org/10.1038/s41588-021-00828-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177065PMC
May 2021

A human monoclonal antibody blocks malaria transmission and defines a highly conserved neutralizing epitope on gametes.

Nat Commun 2021 03 19;12(1):1750. Epub 2021 Mar 19.

Pathogenesis and Immunity Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Malaria elimination requires tools that interrupt parasite transmission. Here, we characterize B cell receptor responses among Malian adults vaccinated against the first domain of the cysteine-rich 230 kDa gamete surface protein Pfs230, a key protein in sexual stage development of P. falciparum parasites. Among nine Pfs230 human monoclonal antibodies (mAbs) that we generated, one potently blocks transmission to mosquitoes in a complement-dependent manner and reacts to the gamete surface; the other eight show only low or no blocking activity. The structure of the transmission-blocking mAb in complex with vaccine antigen reveals a large discontinuous conformational epitope, specific to domain 1 of Pfs230 and comprising six structural elements in the protein. The epitope is conserved, suggesting the transmission-blocking mAb is broadly functional. This study provides a rational basis to improve malaria vaccines and develop therapeutic antibodies for malaria elimination.
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http://dx.doi.org/10.1038/s41467-021-21955-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979743PMC
March 2021

Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study.

Lancet 2021 Mar;397(10277):892-901

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients.

Methods: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529.

Findings: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date.

Interpretation: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients.

Funding: Loxo Oncology.
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http://dx.doi.org/10.1016/S0140-6736(21)00224-5DOI Listing
March 2021

A Moving Target: Inactivating BTK Mutations as Drivers of Follicular Lymphoma.

Clin Cancer Res 2021 Apr 12;27(8):2123-2125. Epub 2021 Feb 12.

Division of Hematology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.

Drugs that target Bruton tyrosine kinase (BTK) have been highly successful and changed the landscape of therapies in B-cell lymphomas. However, their lower rates of effectiveness in follicular lymphoma are unexplained. Recent work describes inactivating BTK mutations that show that at least some follicular lymphomas do not require BTK..
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0140DOI Listing
April 2021

Orientation of Antigen Display on Self-Assembling Protein Nanoparticles Influences Immunogenicity.

Vaccines (Basel) 2021 Jan 29;9(2). Epub 2021 Jan 29.

Malaria Biologics Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.

Self-assembling protein nanoparticles (SAPN) serve as a repetitive antigen delivery platform with high-density epitope display; however, antigen characteristics such as size and epitope presentation can influence the immunogenicity of the assembled particle and are aspects to consider for a rationally designed effective vaccine. Here, we characterize the folding and immunogenicity of heterogeneous antigen display by integrating (a) dual-stage antigen SAPN presenting the () merozoite surface protein 1 subunit, PfMSP1, and cell-traversal protein for ookinetes and sporozoites, PfCelTOS, in addition to (b) a homogenous antigen SAPN displaying two copies of PfCelTOS. Mice and rabbits were utilized to evaluate antigen-specific humoral and cellular induction as well as functional antibodies via growth inhibition of the blood-stage parasite. We demonstrate that antigen orientation and folding influence the elicited immune response, and when appropriately designed, SAPN can serve as an adaptable platform for an effective multi-antigen display.
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http://dx.doi.org/10.3390/vaccines9020103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911071PMC
January 2021

Liposomal cytarabine and daunorubicin (CPX-351/Vyxeos)-associated distinct purpuric subtype of toxic erythema of chemotherapy: A retrospective review of 54 patients.

J Am Acad Dermatol 2021 Feb 2. Epub 2021 Feb 2.

Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, Department of Dermatology, New York, New York. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2021.01.096DOI Listing
February 2021

Tissue-resident CD4 T helper cells assist the development of protective respiratory B and CD8 T cell memory responses.

Sci Immunol 2021 Jan;6(55)

Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.

Much remains unknown about the roles of CD4 T helper cells in shaping localized memory B cell and CD8 T cell immunity in the mucosal tissues. Here, we report that lung T helper cells provide local assistance for the optimal development of tissue-resident memory B and CD8 T cells after the resolution of primary influenza virus infection. We have identified a population of T cells in the lung that exhibit characteristics of both follicular T helper and T cells, and we have termed these cells as resident helper T (T) cells. Optimal T cell formation was dependent on transcription factors involved in T follicular helper and resident memory T cell development including BCL6 and Bhlhe40. We show that T cells deliver local help to CD8 T cells through IL-21-dependent mechanisms. Our data have uncovered the presence of a tissue-resident helper T cell population in the lung that plays a critical role in promoting the development of protective B cell and CD8 T cell responses.
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http://dx.doi.org/10.1126/sciimmunol.abb6852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056937PMC
January 2021

Advances in Acute Myeloid Leukemia: Recently Approved Therapies and Drugs in Development.

Cancers (Basel) 2020 Nov 1;12(11). Epub 2020 Nov 1.

Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy comprised of various cytogenetic and molecular abnormalities that has notoriously been difficult to treat with an overall poor prognosis. For decades, treatment options were limited to either intensive chemotherapy with anthracycline and cytarabine-based regimens (7 + 3) or lower intensity regimens including hypomethylating agents or low dose cytarabine, followed by either allogeneic stem cell transplant or consolidation chemotherapy. Fortunately, with the influx of rapidly evolving molecular technologies and new genetic understanding, the treatment landscape for AML has dramatically changed. Advances in the formulation and delivery of 7 + 3 with liposomal cytarabine and daunorubicin (Vyxeos) have improved overall survival in secondary AML. Increased understanding of the genetic underpinnings of AML has led to targeting actionable mutations such as , and , and BCL2 or hedgehog pathways in more frail populations. Antibody drug conjugates have resurfaced in the AML landscape and there have been numerous advances utilizing immunotherapies including immune checkpoint inhibitors, antibody-drug conjugates, bispecific T cell engager antibodies, chimeric antigen receptor (CAR)-T therapy and the development of AML vaccines. While there are dozens of ongoing studies and new drugs in the pipeline, this paper serves as a review of the advances achieved in the treatment of AML in the last several years and the most promising future avenues of advancement.
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http://dx.doi.org/10.3390/cancers12113225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692236PMC
November 2020

Antimalarial antibody repertoire defined by plasma IG proteomics and single B cell IG sequencing.

JCI Insight 2020 11 19;5(22). Epub 2020 Nov 19.

Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.

Plasma antimalarial Ab can mediate antiparasite immunity but has not previously been characterized at the molecular level. Here, we develop an innovative strategy to characterize humoral responses by integrating profiles of plasma immunoglobulins (IGs) or Abs with those expressed on B cells as part of the B cell receptor. We applied this strategy to define plasma IG and to determine variable (V) gene usage after vaccination with the Plasmodium falciparum zygote antigen Pfs25. Using proteomic tools coupled with bulk immunosequencing data, we determined human antigen-binding fragment [F(ab')2] peptide sequences from plasma IG of adults who received 4 doses of Pfs25-EPA/Alhydrogel. Specifically, Pfs25 antigen-specific F(ab')2 peptides (Pfs25-IG) were aligned to cDNA sequences of IG heavy (IGH) chain complementarity determining region 3 from a data set generated by total peripheral B cell immunosequencing of the entire vaccinated population. IGHV4 was the most commonly identified IGHV subgroup of Pfs25-IG, a pattern that was corroborated by V heavy/V light chain sequencing of Pfs25-specific single B cells from 5 vaccinees and by matching plasma Pfs25-IG peptides and V-(D)-J sequences of Pfs25-specific single B cells from the same donor. Among 13 recombinant human mAbs generated from IG sequences of Pfs25-specific single B cells, a single IGHV4 mAb displayed strong neutralizing activity, reducing the number of P. falciparum oocysts in infected mosquitoes by more than 80% at 100 μg/mL. Our approach characterizes the human plasma Ab repertoire in response to the Pfs25-EPA/Alhydrogel vaccine and will be useful for studying circulating Abs in response to other vaccines as well as those induced during infections or autoimmune disorders.
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http://dx.doi.org/10.1172/jci.insight.143471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710313PMC
November 2020

Germ cell tumors and associated hematologic malignancies evolve from a common shared precursor.

J Clin Invest 2020 12;130(12):6668-6676

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Germ cell tumors (GCTs) are the most common cancer in men between the ages of 15 and 40. Although most patients are cured, those with disease arising in the mediastinum have distinctly poor outcomes. One in every 17 patients with primary mediastinal nonseminomatous GCTs develop an incurable hematologic malignancy and prior data intriguingly suggest a clonal relationship exists between hematologic malignancies and GCTs in these cases. To date, however, the precise clonal relationship between GCTs and the diverse additional somatic malignancies arising in such individuals have not been determined. Here, we traced the clonal evolution and characterized the genetic features of each neoplasm from a cohort of 15 patients with GCTs and associated hematologic malignancies. We discovered that GCTs and hematologic malignancies developing in such individuals evolved from a common shared precursor, nearly all of which harbored allelically imbalanced p53 and/or RAS pathway mutations. Hematologic malignancies arising in this setting genetically resembled mediastinal GCTs rather than de novo myeloid neoplasms. Our findings argue that this scenario represents a unique clinical syndrome, distinct from de novo GCTs or hematologic malignancies, initiated by an ancestral precursor that gives rise to the parallel evolution of GCTs and blood cancers in these patients.
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http://dx.doi.org/10.1172/JCI139682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685753PMC
December 2020

Safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents: a single-centre, single-arm, phase 2 trial.

Lancet Haematol 2020 Aug;7(8):e566-e574

Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: The median overall survival of patients with high-risk myelodysplastic syndromes refractory to hypomethylating agents is less than 6 months. Currently, no standard therapy for such patients exists. Preclinical studies have shown that inhibition of the nuclear export protein exportin 1 (XPO1) causes nuclear accumulation of p53 and disruption of NF-κB signalling, both relevant targets for myelodysplastic syndromes. We therefore aimed to assess the safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents.

Methods: We did a single-centre, single-arm, phase 2 trial at the Memorial Sloan Kettering Cancer Center in the USA. We included patients 18 years or older with high-risk myelodysplastic syndromes or oligoblastic acute myeloid leukaemia (defined as blasts ≥20% but ≤30%) refractory to hypomethylating agents and with an Eastern Cooperative Oncology Group performance status score of 0-2. Eligible patients received 3-week long cycles of oral selinexor (60 mg twice per week for 2 weeks, followed by 1 week off). The primary outcome was overall response rate. Complete remission, partial remission, marrow complete remission, or haematological improvement were included in the response categories for assessing the primary endpoint. The activity analysis included all patients who completed at least one full-scheduled post-treatment disease assessment. All patients who were given selinexor were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT02228525.

Findings: Between Sept 23, 2014, and March 13, 2018, 25 patients were enrolled on this study. The median follow-up was 8·5 months (IQR 3·1-12·2). Two patients did not meet the full eligibility criteria after baseline assessment; therefore, 23 patients were evaluable for activity assessment. In the 23 evaluable patients, overall response rate was 26% (95% CI 10-48) in six patients with marrow complete remission, with an additional 12 patients (52%, 95% CI 31-73) achieving stable disease. The most common grade 3 or 4 adverse events were thrombocytopenia (eight [32%] of 25 patients) and hyponatraemia (five [20%]). There were no drug-related serious adverse events and no treatment-related deaths.

Interpretation: Selinexor showed responses in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. Adverse events were manageable with supportive care implementation. Further studies are needed to compare selinexor with supportive care alone, and to identify patient subgroups that might benefit the most from selinexor treatment.

Funding: Karyopharm Therapeutics.
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http://dx.doi.org/10.1016/S2352-3026(20)30209-XDOI Listing
August 2020

Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms.

Blood 2020 09;136(13):1477-1486

Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY.

Large-scale sequencing studies of hematologic malignancies have revealed notable epistasis among high-frequency mutations. One of the most striking examples of epistasis occurs for mutations in RNA splicing factors. These lesions are among the most common alterations in myeloid neoplasms and generally occur in a mutually exclusive manner, a finding attributed to their synthetic lethal interactions and/or convergent effects. Curiously, however, patients with multiple-concomitant splicing factor mutations have been observed, challenging our understanding of one of the most common examples of epistasis in hematologic malignancies. In this study, we performed bulk and single-cell analyses of patients with myeloid malignancy who were harboring ≥2 splicing factor mutations, to understand the frequency and basis for the coexistence of these mutations. Although mutations in splicing factors were strongly mutually exclusive across 4231 patients (q < .001), 0.85% harbored 2 concomitant bona fide splicing factor mutations, ∼50% of which were present in the same individual cells. However, the distribution of mutations in patients with double mutations deviated from that in those with single mutations, with selection against the most common alleles, SF3B1K700E and SRSF2P95H/L/R, and selection for less common alleles, such as SF3B1 non-K700E mutations, rare amino acid substitutions at SRSF2P95, and combined U2AF1S34/Q157 mutations. SF3B1 and SRSF2 alleles enriched in those with double-mutations had reduced effects on RNA splicing and/or binding compared with the most common alleles. Moreover, dual U2AF1 mutations occurred in cis with preservation of the wild-type allele. These data highlight allele-specific differences as critical in regulating the molecular effects of splicing factor mutations as well as their cooccurrences/exclusivities with one another.
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http://dx.doi.org/10.1182/blood.2020006868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515689PMC
September 2020

BCR-ABL tyrosine kinase inhibitor (TKI)-induced nephropathy: An under-recognized phenomenon.

Leuk Res Rep 2020 8;14:100211. Epub 2020 Jun 8.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.1016/j.lrr.2020.100211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327424PMC
June 2020

Using PrEP to #STOPHIVATL: Findings from a Cross-Sectional Survey Among Gay Men and Transgender Women Participating in Gay Pride Events in Atlanta, Georgia, 2018.

Arch Sex Behav 2020 08 14;49(6):2193-2204. Epub 2020 May 14.

Office of Epidemiology, Fulton County Board of Health, Atlanta, GA, USA.

Assessing pre-exposure prophylaxis (PrEP) coverage and identifying reasons for disproportionate uptake among the varied social and cultural sub-groups of men who have sex with men (MSM) and transgender women who have sex with men (TWSM) are necessary precursors to setting attainable local PrEP. We report on findings of a cross-sectional survey among MSM/TWSM attending Gay pride events in Atlanta, Georgia, in 2018. Associations between PrEP awareness, uptake, and respondent characteristics were assessed using logistic regression. PrEP awareness did not differ by race, but current use was significantly lower among Blacks at substantial risk of HIV (p = .008). In multivariate analysis, clinician encounter in the past year was associated with awareness while age, income, drug use, sero-discordant sex, and multiple male partners were associated with current use. Among PrEP-naïve MSM/TWSM, the most common reasons for nonuse differed by race (poor knowledge of PrEP: Black-45% vs. non-Black-27%, p = .010, low perception of risk: Black-26% vs. non-Black-52%, p = .001). Key racial and socioeconomic disparities in active PrEP use and reasons for nonuse remain despite the recent increases in PrEP awareness and use among MSM/TWSM in Atlanta. Achieving overall improvement in uptake among all MSM/TWSM sub-groups will require tailoring PrEP educational messaging, optimizing communication modalities, expanding provider outreach, and identifying ways to defray costs for high-risk, underserved sub-groups in these populations.
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http://dx.doi.org/10.1007/s10508-020-01711-0DOI Listing
August 2020

Chemotherapy Options for Blastic Plasmacytoid Dendritic Cell Neoplasm.

Hematol Oncol Clin North Am 2020 06 18;34(3):539-552. Epub 2020 Mar 18.

Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address:

BPDCN is ultimately a bone marrow disease requiring induction-type eradication therapy followed by hematopoietic stem cell transplant (HSCT) to achieve long-lasting remissions or cure. Various regimens have been applied to this disease with varying success. A cumulative review of the literature suggests more intense regimens have greater efficacy with acute lymphoblastic leukemia regimens preferred to acute myeloid leukemia regimens. This approach benefits fit patients who are eligible for HSCT; however, most BPDCN patients require other treatment options. The recent FDA approval of the CD123-targeted agent tagraxofusp provides a novel therapeutic alternative to traditional chemotherapy but with potential toxicities.
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http://dx.doi.org/10.1016/j.hoc.2020.01.011DOI Listing
June 2020

Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity.

Sci Immunol 2020 03;5(45)

Immune Cell Biology Laboratory, Department of Biomedicine, University of Basel, University Hospital Basel, CH-4031 Basel, Switzerland.

CD4 memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (T) cells, whereas the existence and functional significance of long-lived T follicular helper (T) cells are controversial. Here, we show that T cells are highly susceptible to NAD-induced cell death (NICD) during isolation from tissues, leading to their underrepresentation in prior studies. NICD blockade reveals the persistence of abundant T cells with high expression of hallmark T markers to at least 400 days after infection, by which time T cells are no longer found. Using single-cell RNA-seq, we demonstrate that long-lived T cells are transcriptionally distinct from T cells, maintain stemness and self-renewal gene expression, and, in contrast to T cells, are multipotent after recall. At the protein level, we show that folate receptor 4 (FR4) robustly discriminates long-lived T cells from T cells. Unexpectedly, long-lived T cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR-, HIF-1-, and cAMP-regulated genes. Late disruption of glycolysis/ICOS signaling leads to T cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of T and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct long-lived T cell subsets and establish T cells as an attractive target for the induction of durable adaptive immunity.
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http://dx.doi.org/10.1126/sciimmunol.aay5552DOI Listing
March 2020

Rare and private spliceosomal gene mutations drive partial, complete, and dual phenocopies of hotspot alterations.

Blood 2020 03;135(13):1032-1043

Computational Biology Program, Public Health Sciences Division, and.

Genes encoding the RNA splicing factors SF3B1, SRSF2, and U2AF1 are subject to frequent missense mutations in clonal hematopoiesis and diverse neoplastic diseases. Most "spliceosomal" mutations affect specific hotspot residues, resulting in splicing changes that promote disease pathophysiology. However, a subset of patients carries spliceosomal mutations that affect non-hotspot residues, whose potential functional contributions to disease are unstudied. Here, we undertook a systematic characterization of diverse rare and private spliceosomal mutations to infer their likely disease relevance. We used isogenic cell lines and primary patient materials to discover that 11 of 14 studied rare and private mutations in SRSF2 and U2AF1 induced distinct splicing alterations, including partially or completely phenocopying the alterations in exon and splice site recognition induced by hotspot mutations or driving "dual" phenocopies that mimicked 2 co-occurring hotspot mutations. Our data suggest that many rare and private spliceosomal mutations contribute to disease pathogenesis and illustrate the utility of molecular assays to inform precision medicine by inferring the potential disease relevance of newly discovered mutations.
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http://dx.doi.org/10.1182/blood.2019002894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099330PMC
March 2020
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