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Oncolytic viruses encoding bispecific T cell engagers: a blueprint for emerging immunovirotherapies.

ABSTRACT: Bispecific T cell engagers (BiTEs) are an innovative class of immunotherapeutics that redirect T cells to tumor surface antigens. While efficacious against certain hematological malignancies, limited bioavailability and severe toxicities have so far hampered broader clinical application, especially against solid tumors. Another emerging cancer immunotherapy are oncolytic viruses (OVs) which selectively infect and replicate in malignant cells, thereby mediating tumor vaccination effects. These oncotropic viruses can serve as vectors for tumor-targeted immunomodulation and synergize with other immunotherapies. In this article, we discuss the use of OVs to overcome challenges in BiTE therapy. We review the current state of the field, covering published preclinical studies as well as ongoing clinical investigations. We systematically introduce OV-BiTE vector design and characteristics as well as evidence for immune-stimulating and anti-tumor effects. Moreover, we address additional combination regimens, including CAR T cells and immune checkpoint inhibitors, and further strategies to modulate the tumor microenvironment using OV-BiTEs. The inherent complexity of these novel therapeutics highlights the importance of translational research including correlative studies in early-phase clinical trials. More broadly, OV-BiTEs can serve as a blueprint for diverse OV-based cancer immunotherapies.

SUBMITTER: Heidbuechel JPW

PROVIDER: S-EPMC8052795 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Bispecific T cell engagers and their synergistic tumor immunotherapy with oncolytic viruses.

Project description:Tumor immunotherapy, especially T cell based therapy, is becoming the main force in clinical tumor therapies. Bispecific T cell engager (BiTE) uses the single chain variable fragments (scFv) of two antibodies to redirect T cells to kill target cells. BiTEs for hematologic tumors has been approved for clinical use, and BiTEs for solid tumors showed therapeutic effects in clinical trials. Oncolytic viruses (OVs) of the adenovirus expressing p53 and herpes simplex virus expressing GM-CSF was approved for clinical use in 2003 and 2015, respectively, while other OVs showed therapeutic effects in clinical trials. However, BiTE and Oncolytic virus (OV) have their own limitations. We propose that OV-BiTE has a synergistic effect on tumor immunotherapy. Feng Yu et al. designed the first OV-BiTE in 2014, which remarkably eradicated tumors in mice. Here we review the latest development of the structure, function, preclinical studies and/or clinical trials of BiTE and OV-BiTE and provide perspective views for optimizing the design of OV-BiTE. There is no doubt that OV-BiTE is becoming an exciting new platform for tumor immunotherapy and will enter clinical trial soon. Exploring the therapeutic effects and safety of OV-BiTE for synergistic tumor immunotherapy will bring new hope to tumor patients.

| S-EPMC8263669 | biostudies-literature

Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies.

Project description:Harnessing the power of immune cells, especially T cells, to enhance anti-tumor activities has become a promising strategy in clinical management of hematologic malignancies. The emerging bispecific antibodies (BsAbs), which recruit T cells to tumor cells, exemplified by bispecific T cell engagers (BiTEs), have facilitated the development of tumor immunotherapy. Here we discussed the advances and challenges in BiTE therapy developed for the treatment of hematologic malignancies. Blinatumomab, the first BiTE approved for the treatment of acute lymphocytic leukemia (ALL), is appreciated for its high efficacy and safety. Recent studies have focused on improving the efficacy of BiTEs by optimizing treatment regimens and refining the molecular structures of BiTEs. A considerable number of bispecific T cell-recruiting antibodies which are potentially effective in hematologic malignancies have been derived from BiTEs. The elucidation of mechanisms of BiTE action and neonatal techniques used for the construction of BsAbs can improve the treatment of hematological malignancies. This review summarized the features of bispecific T cell-recruiting antibodies for the treatment of hematologic malignancies with special focus on preclinical experiments and clinical studies.

| S-EPMC8091790 | biostudies-literature

Bispecific Antibody-Based Immune-Cell Engagers and Their Emerging Therapeutic Targets in Cancer Immunotherapy.

Project description:Cancer is the second leading cause of death worldwide after cardiovascular diseases. Harnessing the power of immune cells is a promising strategy to improve the antitumor effect of cancer immunotherapy. Recent progress in recombinant DNA technology and antibody engineering has ushered in a new era of bispecific antibody (bsAb)-based immune-cell engagers (ICEs), including T- and natural-killer-cell engagers. Since the first approval of blinatumomab by the United States Food and Drug Administration (US FDA), various bsAb-based ICEs have been developed for the effective treatment of patients with cancer. Simultaneously, several potential therapeutic targets of bsAb-based ICEs have been identified in various cancers. Therefore, this review focused on not only highlighting the action mechanism, design and structure, and status of bsAb-based ICEs in clinical development and their approval by the US FDA for human malignancy treatment, but also on summarizing the currently known and emerging therapeutic targets in cancer. This review provides insights into practical considerations for developing next-generation ICEs.

| S-EPMC9146966 | biostudies-literature

Bispecific T-cell engagers for cancer immunotherapy.

Project description:Bispecific T-cell engagers (BiTEs) are a new class of immunotherapeutic molecules intended for the treatment of cancer. These molecules enhance the patient's immune response to tumors by retargeting T cells to tumor cells. BiTEs are constructed of two single-chain variable fragments (scFv) connected in tandem by a flexible linker. One scFv binds to a T-cell-specific molecule, usually CD3, whereas the second scFv binds to a tumor-associated antigen. This structure and specificity allows a BiTE to physically link a T cell to a tumor cell, ultimately stimulating T-cell activation, tumor killing and cytokine production. BiTEs have been developed, which target several tumor-associated antigens, for a variety of both hematological and solid tumors. Several BiTEs are currently in clinical trials for their therapeutic efficacy and safety. This review examines the salient structural and functional features of BiTEs, as well as the current state of their clinical and preclinical development.

| S-EPMC4445461 | biostudies-literature

Bispecific T-Cell Engagers Targeting Membrane-Bound IgE.

Project description:The increased incidence of allergies and asthma has sparked interest in IgE, the central player in the allergic response. Interaction with its high-affinity receptor FcεRI leads to sensitization and allergen presentation, extracellular membrane-proximal domain in membrane IgE can act as an antigen receptor on B cells, and the interaction with low-affinity IgE receptor CD23 additionally influences its homeostatic range. Therapeutic anti-IgE antibodies act by the inhibition of IgE functions by interfering with its receptor binding or by the obliteration of IgE-B cells, causing a reduction of serum IgE levels. Fusion proteins of antibody fragments that can act as bispecific T-cell engagers have proven very potent in eliciting cytotoxic T-lymphocyte-mediated killing. We have tested five anti-IgE Fc antibodies, recognizing different epitopes on the membrane-expressed IgE, for the ability to elicit specific T-cell activation when expressed as single-chain Fv fragments fused with anti-CD3ε single-chain antibody. All candidates could specifically stain the cell line, expressing the membrane-bound IgE-Fc and bind to CD3-positive Jurkat cells, and the specific activation of engineered CD3-overexpressing Jurkat cells and non-stimulated CD8-positive cells was demonstrated for 8D6- and ligelizumab-based bispecific antibodies. Thus, such anti-IgE antibodies have the potential to be developed into agents that reduce the serum IgE concentration by lowering the numbers of IgE-secreting cells.

| S-EPMC8615095 | biostudies-literature

Bispecific T-Cell Engagers (BiTEs) as Treatment of B-Cell Lymphoma.

Project description: Not available

| S-EPMC5085271 | biostudies-literature

CAR T-cell-mediated delivery of bispecific innate immune cell engagers for neuroblastoma.

Project description:Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric solid tumor that expresses cell-surface GPC2 and GD2 with a tumor microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells to express a GPC2-directed CAR and simultaneously secrete a bispecific innate immune cell engager (BiCE) targeting both GD2 and CD16a. In vitro, GPC2.CAR-GD2.BiCE T-cells induce GPC2-dependent cytotoxicity and secrete GD2.BiCE that promotes GD2-dependent activation of antitumor innate immunity. In vivo, GPC2.CAR-GD2.BiCE T-cells locally deliver GD2.BiCE and increase intratumor retention of NK-cells. In mice bearing neuroblastoma patient-derived xenografts and reconstituted with human CD16a-expressing immune cells, GD2.BiCEs enhance GPC2.CAR antitumor efficacy. A CAR.BiCE strategy should be considered for tumor histologies where antigen escape limits CAR efficacy, especially for solid tumors like neuroblastoma that are infiltrated by innate immune cells.

| S-EPMC11336212 | biostudies-literature

For whom the T cells troll? Bispecific T-cell engagers in glioblastoma.

Project description:Glioblastoma is the the most common primary brain tumor in adults. Onset of disease is followed by a uniformly lethal prognosis and dismal overall survival. While immunotherapies have revolutionized treatment in other difficult-to-treat cancers, these have failed to demonstrate significant clinical benefit in patients with glioblastoma. Obstacles to success include the heterogeneous tumor microenvironment (TME), the immune-privileged intracranial space, the blood-brain barrier (BBB) and local and systemic immunosuppressions. Monoclonal antibody-based therapies have failed at least in part due to their inability to access the intracranial compartment. Bispecific T-cell engagers are promising antibody fragment-based therapies which can bring T cells close to their target and capture them with a high binding affinity. They can redirect the entire repertoire of T cells against tumor, independent of T-cell receptor specificity. However, the multiple challenges posed by the TME, immune privilege and the BBB suggest that a single agent approach may be insufficient to yield durable, long-lasting antitumor efficacy. In this review, we discuss the mechanism of action of T-cell engagers, their preclinical and clinical developments to date. We also draw comparisons with other classes of multispecific antibodies and potential combinations using these antibody fragment therapies.

| S-EPMC8603282 | biostudies-literature

DNA-encoded bispecific T cell engagers and antibodies present long-term antitumor activity.

Project description:Specific antibody therapy, including mAbs and bispecific T cell engagers (BiTEs), are important new tools for cancer immunotherapy. However, these approaches are slow to develop and may be limited in their production, thus restricting the patients who can access these treatments. BiTEs exhibit a particularly short half-life and difficult production. The development of an approach allowing simplified development, delivery, and in vivo production would be an important advance. Here we describe the development of a designed synthetic DNA plasmid, which we optimized to permit high expression of an anti-HER2 antibody (HER2dMAb) and delivered it into animals through adaptive electroporation. HER2dMAb was efficiently expressed in vitro and in vivo, reaching levels of 50 μg/ml in mouse sera. Mechanistically, HER2dMAb blocked HER2 signaling and induced antibody-dependent cytotoxicity. HER2dMAb delayed tumor progression for HER2-expressing ovarian and breast cancer models. We next used the HER2dMAb single-chain variable fragment portion to engineer a DNA-encoded BiTE (DBiTE). This HER2DBiTE was expressed in vivo for approximately 4 months after a single administration. The HER2DBiTE was highly cytolytic and delayed cancer progression in mice. These studies illustrate an approach to generate DBiTEs in vivo, which represent promising immunotherapies for HER2+ tumors, including ovarian and potentially other cancers.

| S-EPMC6538381 | biostudies-literature

Combination therapies for the optimisation of Bispecific T-cell Engagers in cancer treatment

Project description:Summary Bispecific T-cell engagers (BiTEs) redirect endogenous T-cell populations to cells expressing tumour-associated antigens to induce tumour cell killing. This inherently relies upon a cytotoxic T-cell population that is able to be recruited. In many cancers, immune checkpoints and other immunosuppressive factors in the tumour microenvironment lead to a population of anergic T-cells which cannot be redirected to tumour killing and thus impede the efficacy of BiTE therapy. Furthermore, there is evidence that BiTE therapy itself can increase immune checkpoint expression, and this is thought to be a major escape mechanism for the BiTE therapy blinatumomab. To overcome these inadequate T-cell responses, BiTEs may be combined with checkpoint inhibitors, chemotherapy, costimulatory molecules or oncolytic viruses. Study of these combinations is needed to expand the use of BiTEs in solid malignancies. This review covers the rationale, preclinical evidence and any clinical trials for these combination therapies and a few other less-studied combinations.

| S-EPMC10439528 | biostudies-literature

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