scholarly journals Discovery Strategies to Maximize the Clinical Potential of T-Cell Engaging Antibodies for the Treatment of Solid Tumors

Antibodies ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 65
Author(s):  
Vladimir Voynov ◽  
Paul J. Adam ◽  
Andrew E. Nixon ◽  
Justin M. Scheer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Clinical Data ◽  
Solid Tumor ◽  
Clinical Studies ◽  
Mode Of Action ◽  
Cytotoxic T Cells ◽  
Molecular Structures ◽  
Bispecific Antibodies

T-cell Engaging bispecific antibodies (TcEs) that can re-direct cytotoxic T-cells to kill cancer cells have been validated in clinical studies. To date, the clinical success with these agents has mainly been seen in hematologic tumor indications. However, an increasing number of TcEs are currently being developed to exploit the potent mode-of-action to treat solid tumor indications, which is more challenging in terms of tumor-cell accessibility and the complexity of the tumor microenvironment (TME). Of particular interest is the potential of TcEs as an immunotherapeutic approach for the treatment of non-immunogenic (often referred to as cold) tumors that do not respond to checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) antibodies. This has led to considerable discovery efforts for, firstly, the identification of tumor selective targeting approaches that can safely re-direct cytotoxic T-cells to cancer cells, and, secondly, bispecific antibodies and their derivatives with drug-like properties that promote a potent cytolytic synapse between T-cells and tumor cells, and in the most advanced TcEs, have IgG-like pharmacokinetics for dosing convenience. Based on encouraging pre-clinical data, a growing number of TcEs against a broad range of targets, and using an array of different molecular structures have entered clinical studies for solid tumor indications, and the first clinical data is beginning to emerge. This review outlines the different approaches that have been taken to date in addressing the challenges of exploiting the TcE mode-of-action for a broad range of solid indications, as well as opportunities for future discovery potential.

scholarly journals TCR β chain–directed bispecific antibodies for the treatment of T cell cancers

2021 ◽  
Vol 13 (584) ◽  
pp. eabd3595 ◽  
Author(s):  
Suman Paul ◽  
Alexander H. Pearlman ◽  
Jacqueline Douglass ◽  
Brian J. Mog ◽  
Emily Han-Chung Hsiue ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cancer Cells ◽  
Cell Cancer ◽  
Bispecific Antibodies ◽  
Target Antigen ◽  
Human T Cell ◽  
Selective Targeting ◽  
Β Chain

Immunotherapies such as chimeric antigen receptor (CAR) T cells and bispecific antibodies redirect healthy T cells to kill cancer cells expressing the target antigen. The pan-B cell antigen–targeting immunotherapies have been remarkably successful in treating B cell malignancies. Such therapies also result in the near-complete loss of healthy B cells, but this depletion is well tolerated by patients. Although analogous targeting of pan-T cell markers could, in theory, help control T cell cancers, the concomitant healthy T cell depletion would result in severe and unacceptable immunosuppression. Thus, therapies directed against T cell cancers require more selective targeting. Here, we describe an approach to target T cell cancers through T cell receptor (TCR) antigens. Each T cell, normal or malignant, expresses a unique TCR β chain generated from 1 of 30 TCR β chain variable gene families (TRBV1 to TRBV30). We hypothesized that bispecific antibodies targeting a single TRBV family member expressed in malignant T cells could promote killing of these cancer cells, while preserving healthy T cells that express any of the other 29 possible TRBV family members. We addressed this hypothesis by demonstrating that bispecific antibodies targeting TRBV5-5 (α-V5) or TRBV12 (α-V12) specifically lyse relevant malignant T cell lines and patient-derived T cell leukemias in vitro. Treatment with these antibodies also resulted in major tumor regressions in mouse models of human T cell cancers. This approach provides an off-the-shelf, T cell cancer selective targeting approach that preserves enough healthy T cells to maintain cellular immunity.

Immunotherapy of B-Cell Lymphoma With CD3x19 Bispecific Antibodies: Costimulation via CD28 Prevents “Veto” Apoptosis of Antibody-Targeted Cytotoxic T Cells

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4750-4757 ◽  
Author(s):  
Peter T. Daniel ◽  
Arne Kroidl ◽  
Joachim Kopp ◽  
Isrid Sturm ◽  
Gerhard Moldenhauer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Cells ◽  
B Cell Lymphoma ◽  
Bispecific Antibodies ◽  
Lymphoma Cells ◽  
B Lymphoma ◽  
B Lymphoma Cells

Bispecific antibodies (CD3x19) against the CD3ɛ-chain of the T-cell–receptor/CD3 complex and the CD19 antigen on B cells can target polyclonal, nontumor-specific T cells to B lymphoma cells. This induces T-cell activation, and generation of cytotoxic T cells (CTLs). These polyclonal CTLs, targeted by the CD3x19 bispecific antibodies, can lyse CD19+ B-lymphoma cells. In a xenotransplant model in severe combined immunodeficiency deficient (SCID) mice, we and others observed that CD28 triggering is required for efficient elimination of B-lymphoma cells and cure from the tumor in addition to CD3x19 administration. We also showed that the activation and targeting of CTLs to the target cell by signal one alone, ie, the CD3x19 mab, induces T-cell death by apoptosis. In blocking experiments we showed that this “veto” apoptosis is mediated by the CD95/Fas ligand. Addition of anti-CD28 (signal 2) renders the T cells resistant for veto apoptosis both in vitro and in vivo. We therefore conclude that the role of costimulation in immunotherapy with bispecific antibodies or other T-cell–based immune strategies is not only to facilitate T-cell activation but also to prevent T-cell deletion by apoptosis.

Human Multiple Myeloma and Breast Cancer Cells Evade Immune Rejection Through Expression of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 6.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2942-2942
Author(s):  
Mathias Witzens-Harig ◽  
Dirk Hose ◽  
Simone Jünger ◽  
Christina Pfirschke ◽  
Nisit Khandelwal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cell Adhesion Molecule ◽  
Cytotoxic T Cells ◽  
Cd8 T Cell ◽  
Related Cell

Abstract Abstract 2942 Tumor-specific cytotoxic T cells are common in tumor patients, but ineffectively react against autologous tumor cells. Here, we demonstrate in multiple myeloma and breast cancer that human tumor cells escape recognition by tumor-specific CD8+ T cells through carcinoembryonic antigen-related cell adhesion molecule-6 (CEACAM-6) expression. We demonstrate for the first time CEACAM-6 expression in primary and established myeloma and examined the effects of altered CEACAM expression on cytotoxic T cell activity and cytokine secretion against myeloma and breast cancer cells in vitro —, and in vivo, using a xenotransplant mouse model. Cytotoxic T cells from multiple myeloma patients reacted against myeloma antigens presented by dendritic cells, but not against autologous myeloma cells, which expressed CEACAM6. Gene knockdown or blocking of CEACAM6 on myeloma cells restored CD8+ T-cell reactivity against malignant plasma cells. SiRNA-mediated CEACAM6 knockdown or inhibition by specific mAbs also restored cytokine secretion, cytotoxic activity, and antigen-specific lysis of CEACAM6-positive breast cancer cells. Moreover, CEACAM-6 inhibition was a prerequisite for efficient treatment of xenotransplanted breast tumors by adoptive T cell transfer. CEACAM6 thus plays an important role in inhibiting CD8+ T-cell responses against hematological and epithelial human tumors. Therapeutic targeting of CEACAM6 may be a promising strategy for improving cancer immunotherapy. Disclosures: No relevant conflicts of interest to declare.

Immunotherapy of B-Cell Lymphoma With CD3x19 Bispecific Antibodies: Costimulation via CD28 Prevents “Veto” Apoptosis of Antibody-Targeted Cytotoxic T Cells

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4750-4757 ◽  
Author(s):  
Peter T. Daniel ◽  
Arne Kroidl ◽  
Joachim Kopp ◽  
Isrid Sturm ◽  
Gerhard Moldenhauer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Cells ◽  
B Cell Lymphoma ◽  
Bispecific Antibodies ◽  
Lymphoma Cells ◽  
B Lymphoma ◽  
B Lymphoma Cells

Abstract Bispecific antibodies (CD3x19) against the CD3ɛ-chain of the T-cell–receptor/CD3 complex and the CD19 antigen on B cells can target polyclonal, nontumor-specific T cells to B lymphoma cells. This induces T-cell activation, and generation of cytotoxic T cells (CTLs). These polyclonal CTLs, targeted by the CD3x19 bispecific antibodies, can lyse CD19+ B-lymphoma cells. In a xenotransplant model in severe combined immunodeficiency deficient (SCID) mice, we and others observed that CD28 triggering is required for efficient elimination of B-lymphoma cells and cure from the tumor in addition to CD3x19 administration. We also showed that the activation and targeting of CTLs to the target cell by signal one alone, ie, the CD3x19 mab, induces T-cell death by apoptosis. In blocking experiments we showed that this “veto” apoptosis is mediated by the CD95/Fas ligand. Addition of anti-CD28 (signal 2) renders the T cells resistant for veto apoptosis both in vitro and in vivo. We therefore conclude that the role of costimulation in immunotherapy with bispecific antibodies or other T-cell–based immune strategies is not only to facilitate T-cell activation but also to prevent T-cell deletion by apoptosis.

scholarly journals Redirecting T cells to hematological malignancies with bispecific antibodies

Blood ◽  
2018 ◽  
Vol 131 (1) ◽  
pp. 30-38 ◽  
Author(s):  
Mireya Paulina Velasquez ◽  
Challice L. Bonifant ◽  
Stephen Gottschalk
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Clinical Studies ◽  
Hematological Malignancies ◽  
Lymphoblastic Leukemia ◽  
Bispecific Antibodies ◽  
Special Focus ◽  
Single Chain ◽  
Median Response

Abstract There is a need to improve outcomes for patients with recurrent and/or refractory hematological malignancies. Immunotherapy holds the promise to meet this need, because it does not rely on the cytotoxic mechanism of conventional therapies. Among different forms of immunotherapy, redirecting T cells to hematological malignancies with bispecific antibodies (BsAbs) is an attractive strategy. BsAbs are an “off-the-shelf” product that is easily scalable in contrast to adoptive T-cell therapies. Among these, the bispecific T-cell engager blinatumomab has emerged as the most successful BsAb to date. It consists of 2 single-chain variable fragments specific for CD19 present on B-cell malignancies and CD3 expressed on almost all T cells. Blinatumomab has shown potent antitumor activity as a single agent, particularly for acute lymphoblastic leukemia, resulting in its US Food and Drug Administration approval. However, although successful in inducing remissions, these are normally short-lived, with median response durations of <1 year. Nevertheless, the success of blinatumomab has reinvigorated the BsAb field, which is bustling with preclinical and clinical studies for not only B-cell–derived lymphoblastic leukemia and lymphoma but also acute myeloid leukemia and multiple myeloma. Here, we will review the successes and challenges of T-cell–targeted BsAbs for the immunotherapy of hematological malignancies with special focus on conducted clinical studies and strategies to improve their efficacy.

T cell exclusion, immune privilege, and the tumor microenvironment

Science ◽  
2015 ◽  
Vol 348 (6230) ◽  
pp. 74-80 ◽  
Author(s):  
Johanna A. Joyce ◽  
Douglas T. Fearon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Stromal Cells ◽  
Cytotoxic T Cells ◽  
Immune Privilege ◽  
Immune Attack ◽  
T Cell Exclusion

Effective immunotherapy promotes the killing of cancer cells by cytotoxic T cells. This requires not only that cancer-specific T cells be generated, but also that these T cells physically contact cancer cells. The coexistence in some patients of cancer cells and T cells that recognize them indicates that tumors may exhibit the phenomenon of immune privilege, in which immunogenic tissue is protected from immune attack. Here, we review the evidence that stromal cells of the tumor microenvironment mediate this restriction by excluding T cells from the vicinity of cancer cells. Overcoming this T cell checkpoint may thus enable optimal immunotherapy.

Combining PD-1 blockade with T-cell redirecting bispecific antibodies for solid cancer therapy.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 98-98
Author(s):  
Chien-Hsing Chang ◽  
Yang Wang ◽  
Diane L Rossi ◽  
Rongxiu Li ◽  
Edmund A. Rossi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cell Lines ◽  
Scid Mice ◽  
Bispecific Antibodies ◽  
Human Pbmcs ◽  
In Vivo Models ◽  
3D Spheroids

98 Background: Bispecific antibodies (bsAbs) for redirecting T cells to cancers have shown promise in both preclinical and clinical studies. However, clinical results have been disappointing in solid cancers. We have applied the DOCK-AND-LOCK method to generate a novel class of trivalent bsAbs, each comprising an anti-CD3 scFv covalently conjugated to a stabilized dimer of different anti-tumor Fabs. Herein we report the characterization of two such constructs, (E1)-3s and (14)-3s, which activate T cells and target Trop-2- and CEACAM5-expressing cancer cells, respectively. Methods: Human breast and colonic cancer cell lines were grown in monolayer cultures or as 3D spheroids for in vitro evaluation. NOD/SCID mice carrying xenografts of MDA-MB-231 (a TNBC line constitutively expressing Trop-2 and PD-L1) were used for in vivo studies. A human PD-1 antagonistic murine hybridoma antibody was subsequently converted to its chimeric form (IMMU-cPD-1). Human PBMCs, or T cells isolated from buffy coats by negative selection, were used as effector cells in cytotoxicity assays. The effect of IMMU-cPD-1 on cancer cells pretreated with IFN-γ to induce the expression of PD-L1 was compared with those not pretreated. Results: (E1)-3s and (14)-3s, in the presence of human T cells, killed target cells grown as monolayers at low picomolar concentrations, with similar potency observed for drug-resistant cells. The antitumor efficacy was demonstrated for (E1)-3s plus human PBMCs in NOD/SCID mice bearing MDA-MB-231, and for human PBMCs combined with (E1)-3s or (14)-3s in 3D spheroids generated from target cell lines to mimic the in vivo behavior and microenvironment of these tumors. Moreover, with the addition of IMMU-cPD-1, the benefit of PD-1 blockade was indicated by increased cell death in 3D spheroids and longer survival of MDA-MB-231-bearing mice. Conclusions: These results highlight the potency of (E1)-3s and (14)-3s as T-cell redirecting bsAbs, emphasize the potential of combining such bsAbs with immune checkpoint inhibitors to improve the therapeutic activity in the immunotherapy of solid cancers, and provide a basis for using 3D spheroids as an alternative to in vivo models for evaluating T-cell functions.

scholarly journals Cross-presentation of a TAP-independent signal peptide induces CD8 T immunity to escaped cancers but necessitates anchor replacement

2021 ◽  
Author(s):  
Koen A. Marijt ◽  
Lisa Griffioen ◽  
Laura Blijleven ◽  
Sjoerd. H. van der Burg ◽  
Thorbald van Hall
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Signal Sequence ◽  
Cell Repertoire ◽  
Cross Presentation ◽  
Normal Tissues ◽  
Cell Immunity

AbstractCancer cells frequently display defects in their antigen-processing pathway and thereby evade CD8 T cell immunity. We described a novel category of cancer antigens, named TEIPP, that emerge on cancers with functional loss of the peptide pump TAP. TEIPPs are non-mutated neoantigens despite their ‘self’ origin by virtue of their absence on normal tissues. Here, we describe the development of a synthetic long peptide (SLP) vaccine for the most immunogenic TEIPP antigen identified thus far, derived from the TAP-independent LRPAP1 signal sequence. LRPAP121–30-specific CD8 T cells were present in blood of all tested healthy donors as well as patients with non-small cell lung adenocarcinoma. SLPs with natural flanking, however, failed to be cross-presented by monocyte-derived dendritic cells. Since the C-terminus of LRPAP121–30 is an unconventional and weakly binding serine (S), we investigated if replacement of this anchor would result in efficient cross-presentation. Exchange into a valine (V) resulted in higher HLA-A2 binding affinity and enhanced T cell stimulation. Importantly, CD8 T cells isolated using the V-variant were able to bind tetramers with the natural S-variant and respond to TAP-deficient cancer cells. A functional screen with an array of N-terminal and C-terminal extended SLPs pointed at the 24-mer V-SLP, elongated at the N-terminus, as most optimal vaccine candidate. This SLP was efficiently cross-presented and consistently induced a strong polyclonal LRPAP121–30-specific CD8 T cells from the endogenous T cell repertoire. Thus, we designed a TEIPP SLP vaccine from the LRPAP1 signal sequence ready for validation in clinical trials.

scholarly journals Cytotoxic T cells isolated from healthy donors and cancer patients kill TGFβ-expressing cancer cells in a TGFβ-dependent manner

2021 ◽  
Author(s):  
Morten Orebo Holmström ◽  
Rasmus Erik Johansson Mortensen ◽  
Angelos Michail Pavlidis ◽  
Evelina Martinenaite ◽  
Stine Emilie Weis-Banke ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cytotoxic T Cells ◽  
Dependent Manner ◽  
Healthy Donors

600 In vitro anticancer and immunomodulatory activities of NBT-167, a dimer of resveratrol

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A635-A635
Author(s):  
Jeffrey Zhang ◽  
Everett Henry ◽  
L Harris Zhang ◽  
Wanying Zhang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Immune Cells ◽  
Cell Killing ◽  
Gamma Delta T Cells ◽  
Gamma Delta ◽  
Raw264.7 Macrophages

BackgroundResveratrol (3,4’,5-trihydroxystilbene), a stilbenoid isolated from many species of plants, is widely known for its antioxidative, anti-inflammatory, immunomodulatory and anticancer activities. Recently, novel resveratrol oligomers have been isolated from various plants; their diverse structures are characterized by the polymerization of two or more resveratrol units. Little is known regarding the anticancer and immunomodulating activities of these oligomers. In this study, we designed in vitro models to compare resveratrol side by side with its natural dimer NBT-167 for their anticancer and immunological activities.MethodsWe isolated resveratrol and its dimer (NBT-167) from plants. The potency of the compounds was compared side by side using cancer cell survival assays and immunological assays with various types of human cells including cancer cell lines, PBMCs and enriched NK, gamma delta T cells, THP-1 monocytic cells, HL-60 promyelocytic leukemia cells as well as mouse RAW264.7 macrophages.ResultsNBT-167 was found to be more potent than resveratrol in inhibiting growth of various cancer cells and modulation of cytokine production from anti-IgM, LPS, PHA or SEB stimulated PBMC. Both compounds similarly enhanced IL-2 stimulated NK and gamma delta T cell killing activity against K562 cells and modulated nitric oxide production from LPS/IFN-g induced RAW264.7 macrophages and phagocytotic activity of HL-60 cells. NBT-167 was slightly more potently than resveratrol in inhibiting chemotaxis of HL-60 cells and blocking cell cycle of THP-1 and HL-60 cells at G1/S transition. In addition, NBT-167, but not resveratrol, could increase IL-2 production and T cell proliferation stimulated with anti-CD3 and anti-CD28 and synergize with anti-PD-1 antibody to increase IL-2 and IFN-gamma production in co-culture of allotypic T cells and dendric cells (MLR).ConclusionsOur data showed that NBT-167, a dimer of resveratrol, had anticancer and immunomodulatory activities such as modulation of expression of cytokines in immune cells and induction of cancer cell-killing activities of NK and gamma delta T cells. Generally, NBT-167 appeared to have higher activities than resveratrol in modulating immune cells and inhibiting cancer cells. NBT-167 could be a promising cancer immunotherapeutic agent targeting both cancer cells and immune cells.

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