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Cryogel-supported stem cell factory for customized sustained release of bispecific antibodies for cancer immunotherapy.

ABSTRACT: Combining stem cells with biomaterial scaffolds provides a promising strategy for the development of drug delivery systems. Here we propose an innovative immunotherapeutic organoid by housing human mesenchymal stromal cells (MSCs), gene-modified for the secretion of an anti-CD33-anti-CD3 bispecific antibody (bsAb), in a small biocompatible star-shaped poly(ethylene glycol)-heparin cryogel scaffold as a transplantable and low invasive therapeutic machinery for the treatment of acute myeloid leukemia (AML). The macroporous biohybrid cryogel platform displays effectiveness in supporting proliferation and survival of bsAb-releasing-MSCs overtime in vitro and in vivo, avoiding cell loss and ensuring a constant release of sustained and detectable levels of bsAb capable of triggering T-cell-mediated anti-tumor responses and a rapid regression of CD33⁺ AML blasts. This therapeutic device results as a promising and safe alternative to the continuous administration of short-lived immunoagents and paves the way for effective bsAb-based therapeutic strategies for future tumor treatments.

SUBMITTER: Aliperta R

PROVIDER: S-EPMC5311951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Bispecific antibodies in cancer immunotherapy.

Project description:Following the clinical success of immune checkpoint antibodies targeting CTLA-4, PD-1 or PD-L1 in cancer treatment, bispecific antibodies are now emerging as a growing class of immunotherapies with potential to further improve clinical efficacy and safety. We describe three classes of immunotherapeutic bispecific antibodies: (a) cytotoxic effector cell redirectors; (b) tumor-targeted immunomodulators; and (c) dual immunomodulators. Cytotoxic effector cell redirectors are dominated by T-cell redirecting compounds, bispecific compounds engaging a tumor-associated antigen and the T-cell receptor/CD3 complex, thereby redirecting T-cell cytotoxicity to malignant cells. This is the most established class of bispecific immunotherapies, with two compounds having reached the market and numerous compounds in clinical development. Tumor-targeted immunomodulators are bispecific compounds binding to a tumor-associated antigen and an immunomodulating receptor, such as CD40 or 4-1BB. Such compounds are usually designed to be inactive until binding the tumor antigen, thereby localizing immune stimulation to the tumor environment, while minimizing immune activation elsewhere. This is expected to induce powerful activation of tumor-specific T cells with reduced risk of immune-related adverse events. Finally, dual immunomodulators are bispecific compounds that bind two distinct immunomodulating targets, often combining targeting of PD-1 or PD-L1 with that of LAG-3 or TIM-3. The rationale is to induce superior tumor immunity compared to monospecific antibodies to the same targets. In this review, we describe each of these classes of bispecific antibodies, and present examples of compounds in development.

| S-EPMC5933537 | biostudies-literature

Potent ex vivo armed T cells using recombinant bispecific antibodies for adoptive immunotherapy with reduced cytokine release.

Project description:BackgroundT cell-based immunotherapies using chimeric antigen receptors (CAR) or bispecific antibodies (BsAb) have produced impressive responses in hematological malignancies. However, major hurdles remained, including cytokine release syndrome, neurotoxicity, on-target off-tumor effects, reliance on autologous T cells, and failure in most solid tumors. BsAb armed T cells offer a safe alternative.MethodsWe generated ex vivo armed T cells (EATs) using IgG-[L]-scFv-platformed BsAb, where the anti-CD3 (huOKT3) scFv was attached to the light chain of a tumor-binding IgG. BsAb density on EAT, in vitro cytotoxicity, cytokine release, in vivo trafficking into tumors, and their antitumor activities were evaluated in multiple cancer cell lines and patient-derived xenograft mouse models. The efficacy of EATs after cryopreservation was studied, and gamma delta (γδ) T cells were investigated as unrelated alternative effector T cells.ResultsThe antitumor potency of BsAb armed T cells was substantially improved using the IgG-[L]-scFv BsAb platform. When compared with separate BsAb and T cell injection, EATs released less TNF-α, and infiltrated tumors faster, while achieving robust antitumor responses. The in vivo potency of EAT therapy depended on BsAb dose for arming, EAT cell number per injection, total number of EAT doses, and treatment schedule intensity. The antitumor efficacy of EATs was preserved following cryopreservation, and EATs using γδ T cells were safe and as effective as αβ T cell-EATs.ConclusionsEATs exerted potent antitumor activities against a broad spectrum of human cancer targets with remarkable safety. The antitumor potency of EATs depended on BsAb dose, cell number and total dose, and schedule. EATs were equally effective after cryopreservation, and the feasibility of third-party γδ-EATs offered an alternative for autologous T cell sources.

| S-EPMC8126293 | biostudies-literature

Taking up Cancer Immunotherapy Challenges: Bispecific Antibodies, the Path Forward?

Project description:As evidenced by the recent approvals of Removab (EU, Trion Pharma) in 2009 and of Blincyto (US, Amgen) in 2014, the high potential of bispecific antibodies in the field of immuno-oncology is eliciting a renewed interest from pharmaceutical companies. Supported by rapid advances in antibody engineering and the development of several technological platforms such as Triomab or bispecific T cell engagers (BiTEs), the "bispecifics" market has increased significantly over the past decade and may occupy a pivotal space in the future. Over 30 bispecific molecules are currently in different stages of clinical trials and more than 70 in preclinical phase. This review focuses on the clinical potential of bispecific antibodies as immune effector cell engagers in the onco-immunotherapy field. We summarize current strategies targeting various immune cells and their clinical interests. Furthermore, perspectives of bispecific antibodies in future clinical developments are addressed.

| S-EPMC6698871 | biostudies-literature

Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy.

Project description:The prosperity of immunological therapy for cancer has aroused enormous passion for exploiting the novel targets of cancer immunotherapy. After the approval of blinatumomab, a bispecific antibody (bsAb) targeting on CD19 for acute lymphoblastic leukemia, a few of CD47-targeted bsAbs for cancer immunotherapy, are currently in clinical research. In our review of CD47-targeted bsAbs, we described the fundamental of bsAbs. Then, we summarized the information of four undergoing phase I researches, reviewed the main toxicities relevant to CD47-targeted bsAb immunological therapy of on-target cytotoxicity to healthy cells and a remarkable antigen-sink. Finally, we described possible mechanisms of resistance to CD47-targeted bsAb therapy. More clinical researches are supposed to adequately confirm its security and efficacy in clinical practice.

| S-EPMC8297387 | biostudies-literature

Immunotherapy of hepatocellular carcinoma using chimeric antigen receptors and bispecific antibodies.

Project description:Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide with an overall survival rate of less than 15% in developed countries. Despite attempts at new therapeutic strategies, the majority of patients succumb to this cancer. Buttressed by the highly successful clinical impact in melanoma, immunotherapy is gaining momentum as the next treatment modality for many human cancers. Chimeric antigen receptors (CAR) contain the antigen binding moieties of a monoclonal antibody and the co-stimulatory and signaling domains associated with effector receptor signaling. Bispecific antibodies (BsAb) combine the binding specificities of two different monoclonal antibodies, one activating a receptor on a killer effector cell, while the other engaging a tumor-associated antigen to initiate tumor cytotoxicity. In this review, we survey the HCC targets for which CARs and bispecific antibodies have been generated. The pros and cons of these targets for T-cell and Natural Killer cell based immunotherapy will be discussed.

| S-EPMC5496242 | biostudies-literature

Cancer Immunotherapy with T Cells Carrying Bispecific Receptors That Mimic Antibodies.

Project description:Tumors are inherently heterogeneous in antigen expression, and escape from immune surveillance due to antigen loss remains one of the limitations of targeted immunotherapy. Despite the clinical use of adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells in lymphoblastic leukemia, treatment failure due to epitope loss occurs. Targeting multiple tumor-associated antigens (TAAs) may thus improve the outcome of CAR-T cell therapies. CARs developed to simultaneously target multiple targets are limited by the large size of each single-chain variable fragment and compromised protein folding when several single chains are linearly assembled. Here, we describe single-domain antibody mimics that function within CAR parameters but form a very compact structure. We show that antibody mimics targeting EGFR and HER2 of the ErbB receptor tyrosine kinase family can be assembled into receptor molecules, which we call antibody mimic receptors (amR). These amR can redirect T cells to recognize two different epitopes of the same antigen or two different TAAs in vitro and in vivo.

| S-EPMC6760241 | biostudies-literature

Bispecific Antibodies Enable Synthetic Agonistic Receptor-Transduced T Cells for Tumor Immunotherapy.

Project description:PurposeGenetically engineered T cells are powerful anticancer treatments but are limited by safety and specificity issues. We herein describe an MHC-unrestricted modular platform combining autologous T cells, transduced with a targetable synthetic agonistic receptor (SAR), with bispecific antibodies (BiAb) that specifically recruit and activate T cells for tumor killing.Experimental designBiAbs of different formats were generated by recombinant expression. T cells were retrovirally transduced with SARs. T-cell activation, proliferation, differentiation, and T-cell-induced lysis were characterized in three murine and human tumor models in vitro and in vivo.ResultsMurine T cells transduced with SAR composed of an extracellular domain EGFRvIII fused to CD28 and CD3ζ signaling domains could be specifically recruited toward murine tumor cells expressing EpCAM by anti-EGFRvIII × anti-EpCAM BiAb. BiAb induced selective antigen-dependent activation, proliferation of SAR T cells, and redirected tumor cell lysis. Selectivity was dependent on the monovalency of the antibody for EGFRvIII. We identified FAS ligand as a major mediator of killing utilized by the T cells. Similarly, human SAR T cells could be specifically redirected toward mesothelin-expressing human pancreatic cancer cells. In vivo, treatment with SAR T cells and BiAb mediated antitumoral activity in three human pancreatic cancer cell xenograft models. Importantly, SAR activity, unlike CAR activity, was reversible in vitro and in vivo.ConclusionsWe describe a novel ACT platform with antitumor activity in murine and human tumor models with a distinct mode of action that combines adoptive T-cell therapy with bispecific antibodies.

| S-EPMC7611266 | biostudies-literature

In Situ Liver Expression of HBsAg/CD3-Bispecific Antibodies for HBV Immunotherapy.

Project description:Current therapies against hepatitis B virus (HBV) do not reliably cure chronic infection, necessitating new therapeutic approaches. The T cell response can clear HBV during acute infection, and the adoptive transfer of antiviral T cells during bone marrow transplantation can cure patients of chronic HBV infection. To redirect T cells to HBV-infected hepatocytes, we delivered plasmids encoding bispecific antibodies directed against the viral surface antigen (HBsAg) and CD3, expressed on almost all T cells, directly into the liver using hydrodynamic tail vein injection. We found a significant reduction in HBV-driven reporter gene expression (184-fold) in a mouse model of acute infection, which was 30-fold lower than an antibody only recognizing HBsAg. While bispecific antibodies triggered, in part, antigen-independent T cell activation, antibody production within hepatocytes was non-cytotoxic. We next tested the bispecific antibodies in a different HBV mouse model, which closely mimics the transcriptional template for HBV, covalently closed circular DNA (cccDNA). We found that the antiviral effect was noncytopathic, mediating a 495-fold reduction in HBsAg levels at day 4. At day 33, bispecific antibody-treated mice exhibited 35-fold higher host HBsAg immunoglobulin G (IgG) antibody production versus untreated groups. Thus, gene therapy with HBsAg/CD3-bispecific antibodies represents a promising therapeutic strategy for patients with HBV.

| S-EPMC5626922 | biostudies-literature

Dissecting the mechanisms underlying the Cytokine Release Syndrome (CRS) mediated by T Cell Bispecific Antibodies

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-06-17 | GSE234676 | GEO

Dissecting the mechanisms underlying the Cytokine Release Syndrome (CRS) mediated by T Cell Bispecific Antibodies

Project description:We performed bulk RNAsequencing of neutrophils isolated from whole blood treated with CD20-TCB to study the early kinetics of cytokine release in neutrophils.

2023-06-17 | GSE234673 | GEO

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