Don Siegel

NUCLEAR REACTIONS 3 He (32 S, α) 31 S, E= 128 MeV; measured reaction products, Eγ, Iγ; deduced γ-ray energies, levels, T 1/2, resonances. Comparison with the shell-model code NuShellX calculations. Modern Markov chain Monte Carlo-based Bayesian statistical techniques. The Doppler Shift Lifetimes (DSL2) facility at the TRIUMF Isotope Separator and Accelerator (ISAC-II) facility.

FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl] amino]-3-phenylpropanoyl] amino]-4-methylpentanoyl] amino] hexanoyl] piperidine-4-carboxylic acid Chemical compound C ([C@ H](C (= O) N [C@ H](CC (C) C) C (= O) N [C@ H](CCCCN) C (= O) N1CCC (N)(CC1) C (O)= O) NC (= O)[C@ H](N) CC= 1C= CC= CC= 1) C1= CC= CC= C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 4

Chimeric antigen receptors (CARs) targeting CD19 demonstrate remarkable clinical outcomes in patients (pts) with B-cell malignancies. Importantly, all four FDA-approved CD3ζ-based CAR T cell therapies use the same FMC63-derived single-chain variable fragment (scFv) to target CD19+ tumors. Although response rates are high in diffuse large B cell lymphoma, only ~40% of pts achieve durable, long-term remissions. Improved CAR T cell therapies are therefore needed. We have previously shown that a novel killer immunoglobulin receptor (KIR)-based CAR expressed in T cells as a multichain receptor with DAP12 (KIR-CAR T) has enhanced anti-tumor activity in several preclinical solid tumor models suggesting that this platform may show better activity in lymphoma. Some recent studies report that lower-affinity CD19 binders compared to the benchmark FMC63-scFv yield equivalent or increased anti-tumor …

Abstract We show that red cell exchange (RCE) treats hyperleukocytosis in acute leukemia. RCE provided similar leukoreduction to standard therapeutic leukoreduction and could be superior in patients with severe anemia or monocytic leukemias or when requiring rapid treatment.

Background We conducted a phase I clinical trial that infused CCR5 gene–edited CD4+ T cells to determine how these T cells can better enable HIV cure strategies. Methods The aim of trial was to develop RNA-based approaches to deliver zinc finger nuclease (ZFN), evaluate the effect of CCR5 gene–edited CD4+ T cells on the HIV-specific T cell response, test the ability of infused CCR5 gene–edited T cells to delay viral rebound during analytical treatment interruption, and determine whether individuals heterozygous for CCR5 Δ32 preferentially benefit. We enrolled 14 individuals living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured the time to viral rebound after ART withdrawal, the persistence of CCR5-edited CD4+ T cells, and whether infusion of 10 billion CCR5-edited CD4+ T cells augmented the HIV-specific immune response …

Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study’s primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset …

In the version of this article initially published, author Don L. Siegel (Perelman School of Medicine at the University of Pennsylvania) was omitted from the author list and the Author Contribution statement. His contribution is as follows: DLS helped with some of the phage display methods. Upon request, the University of Pennsylvania evaluated DLS’s authorship contributions and recommended inclusion of DLS as an author. ZF and X. He disagree with this correction. JS, TH, DCM, JM, BX did not respond to the correction request. The errors have been corrected in the HTML and PDF versions of the article.

The present invention relates to compositions and methods for treating diseases, disorders or conditions associated with the expression of the glycosyl-phosphatidylinositol (GPI)-linked GDNF family protein α-receptor 4 (GFRα4).

Gastrointestinal cancers (GICs) and neuroendocrine tumors (NETs) are often refractory to therapy after metastasis. Adoptive cell therapy using chimeric antigen receptor (CAR) T cells, though remarkably efficacious for treating leukemia, is yet to be developed for solid tumors such as GICs and NETs. Here we isolated a llama-derived nanobody, VHH1, and found that it bound cell surface adhesion protein CDH17 upregulated in GICs and NETs. VHH1-CAR T cells (CDH17CARTs) killed both human and mouse tumor cells in a CDH17-dependent manner. CDH17CARTs eradicated CDH17-expressing NETs and gastric, pancreatic and colorectal cancers in either tumor xenograft or autochthonous mouse models. Notably, CDH17CARTs do not attack normal intestinal epithelial cells, which also express CDH17, to cause toxicity, likely because CDH17 is localized only at the tight junction between normal intestinal …

Chimeric antigen receptor (CAR) T cell therapy has shown promise in treating hematologic cancers, but resistance is common and efficacy is limited in solid tumors. We found that CAR T cells autonomously propagate epigenetically programmed type I interferon signaling through chronic stimulation, which hampers antitumor function. EGR2 transcriptional regulator knockout not only blocks this type I interferon–mediated inhibitory program but also independently expands early memory CAR T cells with improved efficacy against liquid and solid tumors. The protective effect of EGR2 deletion in CAR T cells against chronic antigen-induced exhaustion can be overridden by interferon-β exposure, suggesting that EGR2 ablation suppresses dysfunction by inhibiting type I interferon signaling. Finally, a refined EGR2 gene signature is a biomarker for type I interferon–associated CAR T cell failure and …

The present invention relates to compositions and methods of use of anti-ADAMTS13 autoantibodies and fragments thereof. In one aspect, the invention includes a composition comprising an isolated anti-ADAMTS13 autoantibody or fragment thereof. In other aspects, methods are described for generating an in vivo model of thrombotic thrombocytopenic purpura (TTP) comprising introducing at least one anti-ADAMTS13 autoantibody or fragment thereof into a model organism and identifying an anti-autoimmune reagent for treating TTP.

Chimeric antigen receptor (CAR) T cells demonstrate remarkable success in treating hematological malignancies, but their effectiveness in non-hematopoietic cancers remains limited. This study proposes enhancing CAR T cell function and localization in solid tumors by modifying the epigenome governing tissue-residency adaptation and early memory differentiation. We identify that a key factor in human tissue-resident memory CAR T cell (CAR-TRM) formation is activation in the presence of the pleotropic cytokine, transforming growth factor β (TGF-β), which enforces a core program of both "stemness" and sustained tissue residency by mediating chromatin remodeling and concurrent transcriptional changes. This approach leads to a practical and clinically actionable in vitro production method for engineering peripheral blood T cells into a large number of "stem-like" CAR-TRM cells resistant to tumor-associated …

PD-1 checkpoint inhibitors have revolutionized the treatment of patients with different cancer histologies including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. However, only a subset of patients show a dramatic clinical response to treatment. Despite intense biomarker discovery efforts, no single robust, prognostic correlation has emerged as a valid outcome predictor. Immune competent, pet dogs develop spontaneous tumors that share similar features to human cancers including chromosome aberrations, molecular subtypes, immune signatures, tumor heterogeneity, metastatic behavior, and chemotherapeutic response. As such, they represent a valuable parallel patient population in which to investigate predictive biomarkers of checkpoint inhibition. However, the lack of a validated, non-immunogenic, canine anti-PD-1 antibody for pre-clinical use hinders this comparative approach and …

We conducted a phase I clinical trial of anti-BCMA chimeric antigen receptor T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later-line therapy (phase A, N = 10) or high-risk patients responding to first-line therapy (phase B, N = 20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade cytokine release syndrome (CRS) and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited partial response (PR) or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to minimal residual disease (MRD)–negative complete response/stringent complete response. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T-cell reexpansion and late-onset …

Antibody binding to a plasma metalloprotease, a disintegrin and metalloproteinase with thrombospondin type 1 repeats 13 (ADAMTS13), is necessary for the development of immune thrombotic thrombocytopenic purpura (iTTP). Inhibition of ADAMTS13-mediated von Willebrand factor (VWF) cleavage by such antibodies clearly plays a role in the pathophysiology of the disease, although the mechanisms by which they inhibit ADAMTS13 enzymatic function are not fully understood. At least some immunoglobulin G–type antibodies appear to affect the conformational accessibility of ADAMTS13 domains involved in both substrate recognition and inhibitory antibody binding. We used single-chain fragments of the variable region previously identified via phage display from patients with iTTP to explore the mechanisms of action of inhibitory human monoclonal antibodies. Using recombinant full-length ADAMTS13 …

Background: Chimeric antigen receptor (CAR) T cells have repeatedly demonstrated capacity to induce high rates of response and durable remissions for B cell cancers. In contrast, CAR T cells for the treatment of acute myeloid leukemia (AML) have not yet achieved this impact. We previously demonstrated that CD123 is expressed on AML blasts at high frequency, thus making it an attractive target antigen for AML-directed CAR T cells.Methods and Results: We conducted a pilot study of CD123-directed CAR T cells (CART-123) in adults with relapsed or refractory AML. The primary objective was safety with a secondary objective of anti-leukemia efficacy. Twenty-two subjects were screened, and 20 were eligible for the trial. Fludarabine and cyclophosphamide were used for lymphodepletion (LD). Twelve subjects were infused with CART-123. There were two treatment-related deaths due to cytokine release …

The invention includes a chimeric autoantibody receptor (CAAR) comprising an extracellular domain comprising an ADAMTS13 autoantigen or fragment thereof, compositions comprising the CAAR, nucleic acids encoding the CAAR, vectors comprising a nucleic acid encoding the CAAR, and recombinant cells comprising the CAAR.

Introduction: Immune thrombotic thrombocytopenic purpura (iTTP) is caused by antibody-mediated deficiency of the metalloprotease ADAMTS13, which cleaves VWF. Myocardial infarction and ischemic strokes are common and often fatal sequelae of iTTP. Inhibitory anti-ADAMTS13 antibodies appear to affect catalytic turnover more than apparent substrate binding affinity (PMID 37023370). Exploring how antibodies affect VWF cleavage by ADAMTS13 in physiologic conditions is needed to better understand the pathophysiology of iTTP. Hypothesis: Anti-ADAMTS13 antibodies may influence ADAMTS13 function by affecting catalytic turnover and/or apparent substrate binding affinity differently in physiologic conditions than in standard assay conditions. Aims: Characterize how single chain fragments of the variable loop (scFv’s) previously identified from a phage display library derived from several iTTP patients …

Methods: We are conducting a first-in-human trial of huCART19-IL18 in pts≥ 18 years old with CD19+ R/R B-cell NHL or CLL, who have had at least 2 prior lines of therapy including failure of prior CART. Using a modified Bayesian optimal interval dose titration design, we are exploring doses between 3 and 300 million huCART19-IL18+ cells. The product is administered as a single IV infusion following lymphodepleting (LD) chemotherapy. Bridging therapy is optional and huCART19-IL18 re-treatment is permitted for pts not achieving complete response (CR). Responses are assessed at 3, 6, 9, and 12 months (mo) using Lugano criteria for NHL and revised iwCLL criteria for CLL.Results: As of 3 March 2023, 16 pts have enrolled. 15 pts had huCART19-IL18 manufactured and all achieved a minimum protocol-defined dose. The 13 pts infused to date include 5 DLBCL, 4 FL, 2 MCL, 1 HGBCL, 1 THRBCL pts. The …

VENOUS, ARTERIAL AND IMMUNOTHROMBOSIS, AND DIAGNOSTICS HTRS2023. P4. 13 Antibody mediated pathophysiology of immune thrombotic thrombocytopenic purpura Konstantine Halkidis, 1 Chan Meng, 1 Szumam Liu, 1 Donald Siegel, 2 Walter Englander, 2 X. Long Zheng, 1 1 The University of Kansas Medical Center The University of Kansas Medical Center The University of Kansas Medical Center 2 University of Pennsylvania University of Pennsylvania University of Pennsylvania References:[1] EM Ostertag, ADAMTS13 autoantibodies cloned from patients with acquired thrombotic thrombocytopenic purpura: 1. Structural and functional characterization in vitro Transfusion 56:(2016) 1763-1774 Ostertag EM et al. ADAMTS13 autoantibodies cloned from patients with acquired thrombotic thrombocytopenic purpura: 1. Structural and functional characterization in vitro. Transfusion 2016; 56: 1763-1774.[2 …