Medicine and Health Sciences Commons^™

Durable Immunity To Ebv After Rituximab And Third-Party Lmp-Specific T Cells: A Children's Oncology Group Study, Birte Wistinghausen, Robert J Hayashi, Et Al.

2020-Current year OA Pubs

Posttransplant lymphoproliferative disease (PTLD) in pediatric solid organ transplant (SOT) recipients is characterized by uncontrolled proliferation of Epstein-Barr virus-infected (EBV+) B cells due to decreased immune function. This study evaluated the feasibility, safety, clinical and immunobiological outcomes in pediatric SOT recipients with PTLD treated with rituximab and third-party latent membrane protein-specific T cells (LMP-TCs). Newly diagnosed (ND) patients without complete response to rituximab and all patients with relapsed/refractory (R/R) disease received LMP-TCs. Suitable LMP-TC products were available for all eligible subjects. Thirteen of 15 patients who received LMP-TCs were treated within the prescribed 14-day time frame. LMP-TC therapy was generally …

Intratumoral T-Cell Receptor Repertoire Composition Predicts Overall Survival In Patients With Pancreatic Ductal Adenocarcinoma, Vikram S Pothuri, Graham D Hogg, Leah Conant, Nicholas Borcherding, C Alston James, Jacqueline Mudd, Greg Williams, Yongwoo David Seo, William G Hawkins, Venu G Pillarisetty, David G Denardo, Ryan C Fields

2020-Current year OA Pubs

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is refractory to immune checkpoint inhibitor therapy. However, intratumoral T-cell infiltration correlates with improved overall survival (OS). Herein, we characterized the diversity and antigen specificity of the PDAC T-cell receptor (TCR) repertoire to identify novel immune-relevant biomarkers. Demographic, clinical, and TCR-beta sequencing data were collated from 353 patients across three cohorts that underwent surgical resection for PDAC. TCR diversity was calculated using Shannon Wiener index, Inverse Simpson index, and "True entropy." Patients were clustered by shared repertoire specificity. TCRs predictive of OS were identified and their associated transcriptional states were characterized …

Myeloid Lineage Switch Following Cd7-Targeted Chimeric Antigen Receptor T-Cell Therapy In Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia, Ibrahim Aldoss, David Spencer, Et Al.

2020-Current year OA Pubs

No abstract provided.

Idasanutlin And Navitoclax Induce Synergistic Apoptotic Cell Death In T-Cell Acute Lymphoblastic Leukemia, Kimberly B Johansson, Megan S Zimmerman, Iryna V Dmytrenko, Feng Gao, Daniel C Link

2020-Current year OA Pubs

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy in which activating mutations in the Notch pathway are thought to contribute to transformation, in part, by activating c-Myc. Increased c-Myc expression induces oncogenic stress that can trigger apoptosis through the MDM2-p53 tumor suppressor pathway. Since the great majority of T-ALL cases carry inactivating mutations upstream in this pathway but maintain wildtype MDM2 and TP53, we hypothesized that T-ALL would be selectively sensitive to MDM2 inhibition. Treatment with idasanutlin, an MDM2 inhibitor, induced only modest apoptosis in T-ALL cells but upregulated the pro-apoptotic BH3 domain genes BAX and BBC3, prompting …

An "Off-The-Shelf" Cd2 Universal Car-T Therapy For T-Cell Malignancies, Jingyu Xiang, Jessica M Devenport, Alun J Carter, Karl W Staser, Miriam Y Kim, Julie O' Neal, Julie K Ritchey, Michael P Rettig, Feng Gao, Garrett Rettig, Rolf Turk, Byung Ha Lee, Matthew L Cooper, John F Dipersio

2020-Current year OA Pubs

T-cell malignancies are associated with frequent relapse and high morbidity, which is partly due to the lack of effective or targeted treatment options. To broaden the use of CAR-T cells in pan T-cell malignancies, we developed an allogeneic "universal" CD2-targeting CAR-T cell (UCART2), in which the CD2 antigen is deleted to prevent fratricide, and the T-cell receptor is removed to prevent GvHD. UCART2 demonstrated efficacy against T-ALL and CTCL and prolonged the survival of tumor-engrafted NSG mice in vivo. To evaluate the impact of CD2 on CAR-T function, we generated CD19 CAR-T cells (UCART19) with or without CD2 deletion, single-cell …

T Cell Control Of Inflammaging, Irina Shchukina, Pavla Bohacova, Maxim N Artyomov

2020-Current year OA Pubs

T cells are a critical component of the immune system, found in abundance in blood, secondary lymphoid organs, and peripheral tissues. As individuals age, T cells are particularly susceptible to changes, making them one of the most affected immune subsets. These changes can have significant implications for age-related dysregulations, including the development of low-grade inflammation - a hallmark of aging known as inflammaging. In this review, we first present age-related changes in the functionality of the T cell compartment, including dysregulation of cytokine and chemokine production and cytotoxicity. Next, we discuss how these changes can contribute to the development and …

Prostate Cancer Immunotherapy: Improving Clinical Outcomes With A Multi-Pronged Approach, Dhivya Sridaran, Elliot Bradshaw, Carl Deselm, Russell Pachynski, Kiran Mahajan, Nupam P Mahajan

2020-Current year OA Pubs

Cancer immunotherapy has gained traction in recent years owing to remarkable tumor clearance in some patients. Despite the notable success of immune checkpoint blockade (ICB) in multiple malignancies, engagement of the immune system for targeted prostate cancer (PCa) therapy is still in its infancy. Multiple factors contribute to limited response, including the heterogeneity of PCa, the cold tumor microenvironment, and a low number of neoantigens. Significant effort is being invested in improving immune-based PCa therapies. This review is a summary of the status of immunotherapy in treating PCa, with a discussion of multiple immune modalities, including vaccines, adoptively transferred T …

Intrinsic Tumor Resistance To Car T Cells Is A Dynamic Transcriptional State That Is Exploitable With Low-Dose Radiation, Alexander B Kim, Ssu-Yu Chou, Solomon Kang, Eric Kwon, Matthew Inkman, Jeff Szymanski, Neal Andruska, Cian Colgan, Jin Zhang, Joanna C Yang, Nathan Singh, Carl J Deselm

2020-Current year OA Pubs

Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement for hematologic malignancies, with some patients achieving long-term remission. However, the majority of treated patients still die of their disease. A consistent predictor of response is tumor quantity, wherein a higher disease burden before CAR T-cell therapy portends a worse prognosis. Focal radiation to bulky sites of the disease can decrease tumor quantity before CAR T-cell therapy, but whether this strategy improves survival is unknown. We find that substantially reducing systemic tumor quantity using high-dose radiation to areas of bulky disease, which is commonly done clinically, is less impactful on …

Influenza Vaccine Format Mediates Distinct Cellular And Antibody Responses In Human Immune Organoids, Jenna M Kastenschmidt, Elizabeth Levendosky, Naresha Saligrama, Et Al.

2020-Current year OA Pubs

Highly effective vaccines elicit specific, robust, and durable adaptive immune responses. To advance informed vaccine design, it is critical that we understand the cellular dynamics underlying responses to different antigen formats. Here, we sought to understand how antigen-specific B and T cells were activated and participated in adaptive immune responses within the mucosal site. Using a human tonsil organoid model, we tracked the differentiation and kinetics of the adaptive immune response to influenza vaccine and virus modalities. Each antigen format elicited distinct B and T cell responses, including differences in their magnitude, diversity, phenotype, function, and breadth. These differences culminated …

Hgf/C-Met Pathway Inhibition Combined With Chemotherapy Increases Cytotoxic T-Cell Infiltration And Inhibits Pancreatic Tumour Growth And Metastasis, Alpha Raj Mekapogu, Zhihong Xu, Srinivasa Pothula, Chamini Perera, Tony Pang, S M Zahid Hosen, Vishnu Damalanka, James Janetka, David Goldstein, Romano Pirola, Jeremy Wilson, Minoti Apte

2020-Current year OA Pubs

Pancreatic cancer (PC) is a deadly cancer with a high mortality rate. The unique characteristics of PC, including desmoplasia and immunosuppression, have made it difficult to develop effective treatment strategies. Pancreatic stellate cells (PSCs) play a crucial role in the progression of the disease by interacting with cancer cells. One of the key mediators of PSC - cancer cell interactions is the hepatocyte growth factor (HGF)/c-MET pathway. Using an immunocompetent in vivo model of PC as well as in vitro experiments, this study has shown that a combined approach using HGF/c-MET inhibitors to target stromal-tumour interactions and chemotherapy (gemcitabine) to …

Tarlatamab, A First-In-Class Dll3-Targeted Bispecific T-Cell Engager, In Recurrent Small-Cell Lung Cancer: An Open-Label, Phase I Study, Luis Paz-Ares, Ramaswamy Govindan, Et Al.

2020-Current year OA Pubs

PURPOSE: Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC. Tarlatamab (AMG 757), a bispecific T-cell engager molecule, binds both DLL3 and CD3 leading to T-cellb-mediated tumor lysis. Herein, we report phase I results of tarlatamab in patients with SCLC.

PATIENTS AND METHODS: This study evaluated tarlatamab in patients with relapsed/refractory SCLC. The primary end point was safety. Secondary end points included antitumor activity by modified RECIST 1.1, overall survival, and pharmacokinetics.

RESULTS: By July 19, 2022, 107 patients received tarlatamab in dose exploration (0.003 to 100 mg; …

Dual Targeting Of Cd19 And Cd22 With Bicistronic Car-T Cells In Patients With Relapsed/Refractory Large B-Cell Lymphoma, Claire Roddie, Nancy Bartlett, Et Al.

2020-Current year OA Pubs

Relapse after CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multiantigen targeting and programmed cell death protein-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in relapsed/refractory LBCL (NCT03289455). End points include toxicity (primary) and response rates (secondary). Fifty-two patients received AUTO3 and 48/52 received pembrolizumab. Median age was 59 years (range, 27-83), 46/52 had stage III/ IV disease and median follow-up was 21.6 months. AUTO3 was safe; grade 1-2 and grade 3 cytokine release syndrome affected 18/52 (34.6%) …

Inducing T Cell Dysfunction By Chronic Stimulation Of Car-Engineered T Cells Targeting Cancer Cells In Suspension Cultures, Mehmet Emrah Selli, Jack H Landmann, Corvin Arveseth, Nathan Singh

2020-Current year OA Pubs

Several pre-clinical models reveal that chronic chimeric antigen receptor (CAR) stimulation drives a dysfunctional state that mimics in vivo failure. In this protocol, we describe steps to induce T cell dysfunction by persistent and long-term stimulation of CAR-engineered T cells using antigen-expressing cancer cells in suspension cultures. We first described a validated method for manufacturing of CAR T cells, followed by a detailed method for chronic stimulation of CAR T cells and a strategy to evaluate these cells during the process of chronic stimulation. For complete details on the use and execution of this protocol, please refer to Singh et …

A Phase I First-In-Human Study Of Abbv-383, A B-Cell Maturation Antigen × Cd3 Bispecific T-Cell Redirecting Antibody, In Patients With Relapsed/Refractory Multiple Myeloma, Anita D'Souza, Ravi Vij, Et Al.

2020-Current year OA Pubs

PURPOSE: ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study.

METHODS: Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest …

The Ifn-Γ Receptor Promotes Immune Dysregulation And Disease In Sting Gain-Of-Function Mice, W. Alexander Stinson, Cathrine A. Miner, Fang R. Zhao, Annena Jane Lundgren, Subhajit Poddar, Jonathan J. Miner

2020-Current year OA Pubs

STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy (SAVI) in humans, a disease characterized by spontaneous lung inflammation and fibrosis. Mice with STING gain-of-function mutations (SAVI mice) develop αβ T cell-dependent lung disease and also lack lymph nodes. Although SAVI has been regarded as a type I interferonopathy, the relative contributions of the three interferon receptors are incompletely understood. Here, we show that STING gain of function led to upregulation of IFN-γ-induced chemokines in the lungs of SAVI mice and that deletion of the type II IFN receptor (IFNGR1), but not the type I IFN receptor (IFNAR1) or …

High-Resolution Imaging Of Protein Secretion At The Single-Cell Level Using Plasmon-Enhanced Fluorodot Assay, Anushree Seth, Ekansh Mittal, Jingyi Luan, Samhitha Kolla, Monty B Mazer, Hemant Joshi, Rohit Gupta, Priya Rathi, Zheyu Wang, Jeremiah J Morrissey, Joel D Ernst, Cynthia Portal-Celhay, Sharon Celeste Morley, Jennifer A Philips, Srikanth Singamaneni

2020-Current year OA Pubs

Secreted proteins mediate essential physiological processes. With conventional assays, it is challenging to map the spatial distribution of proteins secreted by single cells, to study cell-to-cell heterogeneity in secretion, or to detect proteins of low abundance or incipient secretion. Here, we introduce the "FluoroDOT assay," which uses an ultrabright nanoparticle plasmonic-fluor that enables high-resolution imaging of protein secretion. We find that plasmonic-fluors are 16,000-fold brighter, with nearly 30-fold higher signal-to-noise compared with conventional fluorescence labels. We demonstrate high-resolution imaging of different secreted cytokines in the single-plexed and spectrally multiplexed FluoroDOT assay that revealed cellular heterogeneity in secretion of multiple proteins …

Phase I Trial Of The Dll3/Cd3 Bispecific T-Cell Engager Bi 764532 In Dll3-Positive Small-Cell Lung Cancer And Neuroendocrine Carcinomas, Martin Wermke, Enriqueta Felip, Valentina Gambardella, Yasutoshi Kuboki, Daniel Morgensztern, Zohra Oum' Hamed, Meiruo Liu, Matus Studeny, Taofeek K Owonikoko

2020-Current year OA Pubs

Poorly differentiated neuroendocrine carcinomas such as small-cell lung cancer (SCLC) have poor survival and high relapse rates. DLL3 is found on these carcinomas and has become a target of increasing interest in recent years. The bispecific DLL3/CD3 T-cell engager BI 764532 has been shown to induce complete tumor regression in a human T cell-engrafted mouse model. Here, we describe the study design of a first-in-human, phase I, multicenter, open-label, non-randomized, dose-escalation study in patients with SCLC or other DLL3-positive neuroendocrine carcinomas. The study will determine the maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics and preliminary efficacy of BI 764532 …

Vaccine Protection Against The Sars-Cov-2 Omicron Variant In Macaques, Abishek Chandrashekar, Adrianus C. M. Boon, Et Al.

2020-Current year OA Pubs

The rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. In this study, we show that the mRNA-based BNT162b2 vaccine and the adenovirus-vector-based Ad26.COV2.S vaccine provide robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in cynomolgus macaques. We vaccinated 30 macaques with homologous and heterologous prime-boost regimens with BNT162b2 and Ad26.COV2.S. Following Omicron challenge, vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs. However, 4 vaccinated animals that had moderate Omicron-neutralizing antibody titers …

Cs1 Car-T Targeting The Distal Domain Of Cs1 (Slamf7) Shows Efficacy In High Tumor Burden Myeloma Model Despite Fratricide Of Cd8+Cs1 Expressing Car-T Cells, Julie O'Neal, Julie K Ritchey, Matthew L Cooper, Jessica Niswonger, L Sofía González, Emily Street, Michael P Rettig, Susan W Gladney, Leah Gehrs, Ramzi Abboud, Julie L Prior, Gabriel J Haas, Reyka G Jayasinghe, Li Ding, Armin Ghobadi, Ravi Vij, John F Dipersio

2020-Current year OA Pubs

Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains - the distal Variable (V) domain and the proximal Constant 2 (C2) domain. We generated and tested CS1-CAR-T targeting the V domain of CS1 (Luc90-CS1-CAR-T) and demonstrated anti-myeloma killing in vitro and in vivo using two mouse models. Since fratricide of CD8 + cells occurred during production, we generated fratricide resistant CS1 deficient Luc90- …

Phase I Clinical Trial Evaluating The Safety And Efficacy Of Adp-A2m10 Spear T Cells In Patients With Mage-A10+ Advanced Non-Small Cell Lung Cancer, George R Blumenschein, Siddhartha Devarakonda, Ramaswamy Govindan, Et Al

2020-Current year OA Pubs

BACKGROUND: ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T cells (ADP-A2M10) are genetically engineered autologous T cells that express a high-affinity melanoma-associated antigen A10 (MAGE-A10)-specific T-cell receptor (TCR) targeting MAGE-A10

METHODS: Eligible patients were HLA-A*02 positive with advanced NSCLC expressing MAGE-A10. Patients underwent apheresis; T cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Patients underwent lymphodepletion with varying doses/schedules of fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 were administered at 0.08-0.12×10

RESULTS: Eleven patients (male, n=6; female, n=5) with NSCLC (adenocarcinoma, n=8; squamous cell carcinoma, n=3) were treated. Five, three, and three …

Optimized Polyepitope Neoantigen Dna Vaccines Elicit Neoantigen-Specific Immune Responses In Preclinical Models And In Clinical Translation, Lijin Li, Xiuli Zhang, Xiaoli Wang, Samuel W Kim, John M Herndon, Michelle K Becker-Hapak, Beatriz M Carreno, Nancy B Myers, Mark A Sturmoski, Michael D Mclellan, Christopher A Miller, Tanner M Johanns, Benjamin R Tan, Gavin P Dunn, Timothy P Fleming, Ted H Hansen, S Peter Goedegebuure, William E Gillanders

2020-Current year OA Pubs

BACKGROUND: Preclinical studies and early clinical trials have shown that targeting cancer neoantigens is a promising approach towards the development of personalized cancer immunotherapies. DNA vaccines can be rapidly and efficiently manufactured and can integrate multiple neoantigens simultaneously. We therefore sought to optimize the design of polyepitope DNA vaccines and test optimized polyepitope neoantigen DNA vaccines in preclinical models and in clinical translation.

METHODS: We developed and optimized a DNA vaccine platform to target multiple neoantigens. The polyepitope DNA vaccine platform was first optimized using model antigens in vitro and in vivo. We then identified neoantigens in preclinical breast cancer …

Rethinking Immune Checkpoint Blockade: Beyond The T Cell, Xiuting Liu, Graham D Hogg, David G Denardo

2020-Current year OA Pubs

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune …