scholarly journals Improved anti-leukemia activities of adoptively transferred T cells expressing bispecific T-cell engager in mice

2016 ◽  
Vol 6 (6) ◽  
pp. e430-e430 ◽  
Author(s):  
X Liu ◽  
D M Barrett ◽  
S Jiang ◽  
C Fang ◽  
M Kalos ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bispecific T Cell Engager

scholarly journals LILRB1 Blockade Enhances Bispecific T Cell Engager Antibody–Induced Tumor Cell Killing by Effector CD8+ T Cells

2019 ◽  
Vol 203 (4) ◽  
pp. 1076-1087 ◽  
Author(s):  
Aeryon Kim ◽  
Chia-Jung Han ◽  
Ian Driver ◽  
Aleksandra Olow ◽  
Andrew K. Sewell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
Cd8 T Cells ◽  
Cell Killing ◽  
Tumor Cell Killing ◽  
Bispecific T Cell Engager

scholarly journals Correction: LILRB1 Blockade Enhances Bispecific T Cell Engager Antibody–Induced Tumor Cell Killing by Effector CD8+ T Cells

2019 ◽  
Vol 203 (7) ◽  
pp. 2023-2024
Author(s):  
Aeryon Kim ◽  
Chia-Jung Han ◽  
Ian Driver ◽  
Aleksandra Olow ◽  
Andrew K. Sewell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
Cd8 T Cells ◽  
Cell Killing ◽  
Tumor Cell Killing ◽  
Bispecific T Cell Engager

scholarly journals A bispecific T cell engager targeting Glypican-1 redirects T cell cytolytic activity to kill prostate cancer cells

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Maria E. Lund ◽  
Christopher B. Howard ◽  
Kristofer J. Thurecht ◽  
Douglas H. Campbell ◽  
Stephen M. Mahler ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cell Lines ◽  
Inflammatory Cytokines ◽  
Cytolytic Activity ◽  
Activated T Cells ◽  
Bispecific T Cell Engager

Abstract Background Glypican-1 is a heparan sulfate proteoglycan that is overexpressed in prostate cancer (PCa), and a variety of solid tumors. Importantly, expression is restricted in normal tissue, making it an ideal tumor targeting antigen. Since there is clinical and preclinical evidence of the efficacy of Bispecific T cell Engager (BiTE) therapy in PCa, we sought to produce and test the efficacy of a GPC-1 targeted BiTE construct based on the Miltuximab® sequence. Miltuximab® is a clinical stage anti-GPC-1 antibody that has proven safe in first in human trials. Methods The single chain variable fragment (scFv) of Miltuximab® and the CD3 binding sequence of Blinatumomab were combined in a standard BiTE format. Binding of the construct to immobilised recombinant CD3 and GPC-1 antigens was assessed by ELISA and BiaCore, and binding to cell surface-expressed antigens was measured by flow cytometry. The ability of MIL-38-CD3 to activate T cells was assessed using in vitro co-culture assays with tumour cell lines of varying GPC-1 expression by measurement of CD69 and CD25 expression, before cytolytic activity was assessed in a similar co-culture. The release of inflammatory cytokines from T cells was measured by ELISA and expression of PD-1 on the T cell surface was measured by flow cytometry. Results Binding activity of MIL-38-CD3 to both cell surface-expressed and immobilised recombinant GPC-1 and CD3 was retained. MIL-38-CD3 was able to mediate the activation of peripheral blood T cells from healthy individuals, resulting in the release of inflammatory cytokines TNF and IFN-g. Activation was reliant on GPC-1 expression as MIL-38-CD3 mediated only low level T cell activation in the presence of C3 cells (constitutively low GPC-1 expression). Activated T cells were redirected to lyse PCa cell lines PC3 and DU-145 (GPC-1 moderate or high expression, respectively) but could not kill GPC-1 negative Raji cells. The expression of PD-1 was up-regulated on the surface of MIL-38-CD3 activated T cells, suggesting potential for synergy with checkpoint inhibition. Conclusions This study reports preclinical findings into the efficacy of targeting GPC-1 in PCa with BiTE construct MIL-38-CD3. We show the specificity and efficacy of the construct, supporting its further preclinical development.

scholarly journals 788 A novel T- lymphocyte binding aptamer assembled into a bispecifc compound for the treatment of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A823-A823
Author(s):  
Irit Carmi Levy ◽  
Erez Lavi ◽  
Neta Zilony Hanin ◽  
Zohar Pode ◽  
Karin Mizrahi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Tumor Targeting ◽  
Specific Antigen ◽  
Therapeutic Agents ◽  
List Type ◽  
Bispecific T Cell Engager

BackgroundT-cell engagers are bispecific molecules directed against the CD3 complex on one end and a tumor specific antigen on the other end, allowing a physical link of T cell to a tumor cell, resulting in tumor killing and immune activation. Bispecific molecules harnessing and redirecting T-cells towards tumor cells are a promising therapeutic agents. Aptamers are single stranded oligonucleotides with binding and recognition propensities similar to those of antibodies. Aptamers have a number of advantages over bispecific antibodies including shorter generation time and low immunogenicity. Thus, aptamers capable of targeting T cells would have great potential for use as anti-cancer therapeuticsMethodsSystematic evolution of ligands by exponential enrichment (SELEX) methodology was employed in order to identify a novel CD3e binding aptamer. CD3 binding aptamer was subsequently linked into a bispecific T cell engager structure with a tumor-targeting aptameric arm. The tumor-targeting aptamer is developed by Aummune's proprietary tailored therapeutic platform.1 based on identifying functional aptamer sequences capable of specifically killing targeted tumor cells and sparing healthy tissue .Exemplary bispecific aptamers were tested for T cell stimulation by flow cytometry. In vivo antitumor activity was investigated in syngeneic and in xenograft tumor models.ResultsWe have successfully identified a novel CD3e –targeting aptamer with a Kd of 31nM. A bispecific T cell engager comprised of this aptamer and a tumor-targeting aptamer induced a potent stimulation of T cells in vitro, resulting in CD69 upregulation and IFNg secretion.Next, the CD3e targeting aptamer was hybridized to tumoricidal aptamers identified by Aummune's platform (VS12) to target either the human colon carcinoma HCT116 cells or (VS32) the murine triple negative breast cancer 4T1 cells. Both bispecific entities (CS6-VS12 and CS6-VS32) effectively lead to inhibition of tumor growth in vivo and increased survival in the corresponding models.ConclusionsOur data above provide a proof-of-concept for Aummune's Bispecific Aptamer efficacy and provide a framework for the clinical development of this novel tailored immune therapeutic agents. Indeed, we are currently in the process of developing a first-in-human clinical study in subjects with solid tumors.ReferenceMamet N, et al, Commun Biol 2020.

Immunotherapy combinations overcome resistance to bispecific T cell engager treatment in T cell–cold solid tumors

2021 ◽  
Vol 13 (608) ◽  
pp. eabd1524
Author(s):  
Brian Belmontes ◽  
Deepali V. Sawant ◽  
Wendy Zhong ◽  
Hong Tan ◽  
Anupurna Kaul ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Immune Checkpoint Blockade ◽  
Clinical Activity ◽  
Cell Trafficking ◽  
Critical Determinant ◽  
Immune Correlates ◽  
Combination Strategies ◽  
Bispecific T Cell Engager

Therapeutic approaches are needed to promote T cell–mediated destruction of poorly immunogenic, “cold” tumors typically associated with minimal response to immune checkpoint blockade (ICB) therapy. Bispecific T cell engager (BiTE) molecules induce redirected lysis of cancer cells by polyclonal T cells and have demonstrated promising clinical activity against solid tumors in some patients. However, little is understood about the key factors that govern clinical responses to these therapies. Using an immunocompetent mouse model expressing a humanized CD3ε chain (huCD3e mice) and BiTE molecules directed against mouse CD19, mouse CLDN18.2, or human EPCAM antigens, we investigated the pharmacokinetic and pharmacodynamic parameters and immune correlates associated with BiTE efficacy across multiple syngeneic solid-tumor models. These studies demonstrated that pretreatment tumor-associated T cell density is a critical determinant of response to BiTE therapy, identified CD8+ T cells as important targets and mediators of BiTE activity, and revealed an antagonistic role for CD4+ T cells in BiTE efficacy. We also identified therapeutic combinations, including ICB and 4-1BB agonism, that synergized with BiTE treatment in poorly T cell–infiltrated, immunotherapy-refractory tumors. In these models, BiTE efficacy was dependent on local expansion of tumor-associated CD8+ T cells, rather than their recruitment from circulation. Our findings highlight the relative contributions of baseline T cell infiltration, local T cell proliferation, and peripheral T cell trafficking for BiTE molecule–mediated efficacy, identify combination strategies capable of overcoming resistance to BiTE therapy, and have clinical relevance for the development of BiTE and other T cell engager therapies.

PS2 - 172 Preclinical Validation of a Novel CD33/CD3 Bispecific T-Cell Engager (BiTE) Antibody to Target Patient-Derived Glioblastoma Cells

2016 ◽  
Vol 43 (S4) ◽  
pp. S13-S14
Author(s):  
P. Vora ◽  
C. Venugopal ◽  
C. Choksi ◽  
M. Qazi ◽  
J. Adams ◽  
...  
Keyword(s):  
T Cells ◽  
Brain Tumor ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adult Brain ◽  
Poor Overall Survival ◽  
Bispecific T Cell Engager ◽  
Bite Antibody

Glioblastoma (GBM), an aggressive primary adult brain tumor, is feared for its near uniformly fatal prognosis. Despite the use of aggressive treatment including surgical resection, radiotherapy and chemotherapy, the outcome of patients with GBM has failed to improve significantly. Numerous studies have implicated CD133+GBM subpopulation as driver of chemo- and radio-resistance. CD133 expression correlates with disease progression, recurrence, and poor overall survival of GBM patients. Here, we describe the preclinical evaluation of a recombinant CD133xCD3 bispecific T-cell engager (BiTE) antibody that redirects human polyclonal T cells to CD133+GBM cells, inducing very potent anti-tumor response. CD133-specific BiTE was constructed; with one arm recognizing the tumor antigen (CD133) while the second is specific to CD3 antigen. Using CD133high and CD133low primary GBM lines, we validated the binding of BiTEs to CD133+GBMs and CD3+T cells. In order to test the ability of BiTEs to functionally elicit CD133-specific cytotoxic responses in vitro, we performed killing assays. We observed CD133-specific BiTE mediated T cell activation and redirection to kill CD133-expressing GBM cells in a co-culture of T cells and GBM cells. The killing was more efficient in CD133high GBMs compared to CD133low GBMs, validating its specificity to target CD133+BTICs. Treatment with BiTEs yielded significant reductions in brain tumor burden in vivo. These data offers compelling evidence that BiTE-mediated cytotoxicity against treatment-resistant CD133+GBMs could provide a very potent, specific and can be a novel therapeutic strategy for GBM patients.

A novel bispecific single-chain antibody for ADAM17 and CD3 induces T-cell-mediated lysis of prostate cancer cells

2012 ◽  
Vol 445 (1) ◽  
pp. 135-144 ◽  
Author(s):  
Kosuke Yamamoto ◽  
Ahmad Trad ◽  
Anja Baumgart ◽  
Linda Hüske ◽  
Inken Lorenzen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Single Chain ◽  
Normal Cells ◽  
Bispecific T Cell Engager

ADAM17 (A disintegrin and metalloproteinase 17) is a membrane-bound protease that cleaves various cell surface proteins, including cytokines and cytokine receptors. Recently it was shown that ADAM17 is highly expressed on the surface of many cancer cells, whereas normal cells express low levels of ADAM17, implying that ADAM17 is a potential immunotherapeutic target. We have generated a monoclonal antibody against human ADAM17, which recognized the membrane proximal cysteine-rich extension of the ADAM17 protein. Unlike normal cells, tumour cell lines, such as a prostate cancer cell line, pancreatic cancer cell lines, a breast cancer cell line and a non-small lung cancer cell line, expressed ADAM17 on the cell surface. Using the sequence of the antibody we generated an ADAM17-specific scFv (single-chain variable fragment) and fused this to a CD3-specific scFv to generate a bispecific T-cell engager antibody [A300E-BiTE (bispecific T-cell engager antibody)]. Specificity was demonstrated on cells in which ADAM17 was knocked down with a specific shRNA (short hairpin RNA). A300E-BiTE recognized ADAM17 and CD3 on the cell surface of tumour cells and T-cells respectively. In the presence of primary human peripheral blood mononuclear cells or human T-cells the addition of A300E-BiTE led to ADAM17-specific killing of prostate tumour cells indicating a novel strategy for the treatment of cancer.

scholarly journals The landscape of bispecific T cell engager in cancer treatment

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Shujie Zhou ◽  
Mingguo Liu ◽  
Fei Ren ◽  
Xiangjiao Meng ◽  
Jinming Yu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Immune Checkpoints ◽  
T Cell Infiltration ◽  
Combination Strategies ◽  
Response Predictors ◽  
Current Therapies ◽  
Antigen Loss ◽  
Bispecific T Cell Engager

AbstractT cell-based immunotherapies have revolutionized treatment paradigms in various cancers, however, limited response rates secondary to lack of significant T-cell infiltration in the tumor site remain a major problem. To address this limitation, strategies for redirecting T cells to treat cancer are being intensively investigated, while the bispecific T cell engager (BiTE) therapy constitutes one of the most promising therapeutic approaches. BiTE is a bispecific antibody construct with a unique function, simultaneously binding an antigen on tumor cells and a surface molecule on T cells to induce tumor lysis. BiTE therapy represented by blinatumomab has achieved impressive efficacy in the treatment of B cell malignancies. However, major mechanisms of resistance to BiTE therapy are associated with antigen loss and immunosuppressive factors such as the upregulation of immune checkpoints. Thus, modification of antibody constructs and searching for combination strategies designed to further enhance treatment efficacy as well as reduce toxicity has become an urgent issue, especially for solid tumors in which response to BiTE therapy is always poor. In particular, immunotherapies focusing on innate immunity have attracted increasing interest and have shown promising anti-tumor activity by engaging innate cells or innate-like cells, which can be used alone or complement current therapies. In this review, we depict the landscape of BiTE therapy, including clinical advances with potential response predictors, challenges of treatment toxicity and resistance, and developments of novel immune cell-based engager therapy.

scholarly journals Human macrophages engineered to secrete a bispecific T cell engager support antigen-dependent T cell responses to glioblastoma

2020 ◽  
Vol 8 (2) ◽  
pp. e001202
Author(s):  
Jennifer L Gardell ◽  
Lisa R Matsumoto ◽  
Harrison Chinn ◽  
Kole R DeGolier ◽  
Shannon A Kreuser ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Tumor Burden ◽  
Genetically Engineered ◽  
Tumor Site ◽  
Human Macrophages ◽  
Cell Responses ◽  
Bispecific T Cell Engager

BackgroundTargeted and effective treatment options are needed for solid tumors, including glioblastoma (GBM), where survival rates with standard treatments are typically less than 2 years from diagnosis. Solid tumors pose many barriers to immunotherapies, including therapy half-life and persistence, tumor penetrance, and targeting. Therapeutics delivered systemically may not traffic to the tumor site. If cellular therapies or drugs are able to access the tumor site, or can be delivered directly within the tumor, treatments may not persist for the duration necessary to reduce or eliminate tumor burden. An approach that allows durable and titratable local therapeutic protein delivery could improve antitumor efficacy while minimizing toxicities or unwanted on-target, off-tissue effects.MethodsIn this study, human monocyte-derived macrophages were genetically engineered to secrete a bispecific T cell engager (BiTE) specific to the mutated epidermal growth factor variant III (EGFRvIII) expressed by some GBM tumors. We investigated the ability of lentivirally modified macrophages to secrete a functional BiTE that can bind target tumor antigen and activate T cells. Secreted BiTE protein was assayed in a range of T cell functional assays in vitro and in subcutaneous and intracranial GBM xenograft models. Finally, we tested genetically engineered macrophages (GEMs) secreting BiTE and the proinflammatory cytokine interleukin (IL)-12 to amplify T cell responses in vitro and in vivo.ResultsTransduced human macrophages secreted a lentivirally encoded functional EGFRvIII-targeted BiTE protein capable of inducing T cell activation, proliferation, degranulation, and killing of antigen-specific tumor cells. Furthermore, BiTE secreting macrophages reduced early tumor burden in both subcutaneous and intracranial mouse models of GBM, a response which was enhanced using macrophages that were dual transduced to secrete both the BiTE protein and single chain IL-12, preventing tumor growth in an aggressive GBM model.ConclusionsThe ability of macrophages to infiltrate and persist in solid tumor tissue could overcome many of the obstacles associated with systemic delivery of immunotherapies. We have found that human GEMs can locally and constitutively express one or more therapeutic proteins, which may help recruit T cells and transform the immunosuppressive tumor microenvironment to better support antitumor immunity.

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