CAR-T cell therapy in gastrointestinal tumors and hepatic carcinoma: From bench to bedside

Abstract

The chimeric antigen receptor (CAR) is a genetically engineered receptor that combines a scFv domain, which specifically recognizes the tumor-specific antigen, with T cell activation domains. CAR-T cell therapies have demonstrated tremendous efficacy against hematologic malignancies in many clinical trials. Recent studies have extended these efforts to the treatment of solid tumors. However, the outcomes of CAR-T cell therapy for solid tumors are not as remarkable as the outcomes have been for hematologic malignancies. A series of hurdles has arisen with respect to CAR-T cell-based immunotherapy, which needs to be overcome to target solid tumors. The major challenge for CAR-T cell therapy in solid tumors is the selection of the appropriate specific antigen to demarcate the tumor from normal tissue. In this review, we discuss the application of CAR-T cells to gastrointestinal and hepatic carcinomas in preclinical and clinical research. Furthermore, we analyze the usefulness of several specific markers in the study of gastrointestinal tumors and hepatic carcinoma.

Trial Watch: Adoptively transferred cells for anticancer immunotherapy

“…While ACT-based immunotherapy is intensively investigated as a treatment for hematological malignancies (including several types of leukemia and lymphoma), a large proportion of ongoing clinical trials investigates the impact of ACT in patients with non-hematological tumors (Table 1). Although glioblastoma (NCT02575261, NCT02661282, NCT02937844), neuroblastoma (NCT02573896, NCT02761915, NCT02765243, NCT02919046) and melanoma (NCT02498756, NCT02619058, NCT02621021, NCT02652455, NCT02654821, NCT02870244, NCT03068624, NCT03158935) remain the most common indications for which ACT-based immunotherapy is being tested, growing interest focuses on digestive neoplasms, 144 notably hepatocellular carcinoma for which no less than 23 studies have been initiated (Table 1). ACT is also being evaluated as an immunotherapeutic intervention for squamous cell, nasopharyngeal, esophageal, breast, lung, renal and reproductive tract carcinomas.…”

Emerging Therapies in the Management of Advanced-Stage Gastric Cancer

“…Several forms of immunotherapy, including adoptive T-cell therapies that have shown efficacy against other tumor types, are undergoing clinical trials involving patients with advanced-stage GC/GEC (Table 3 ). A novel form of immunotherapy, chimeric antigen receptor T-cell (CAR-T) therapy that has been approved for the treatment of some hematological malignancies, needs special mention here because it may also be a promising therapy for patients with advanced-stage GC/GEC in the future (Zhang et al, 2016 ). Briefly, CARs are genetically modified receptors that identify tumor Ag in a non-MHC-restricted fashion, contrary to normal T-cells whose activity against tumor cells is limited by MHC (Dai et al, 2016 ).…”

CAR-T cell therapy in ovarian cancer: from the bench to the bedside

“…The structure of CARs comprises four parts: an extracellular antigen recognition region with single-chain variable fragments (scFvs), which derive from an antigen-specific mAb and recognize and bind specific tumor-related antigens independent of major histocompatibility complex (MHC) molecule restriction; an extracellular stalk (hinge) domain that typically comprises either Fc domains or the spacer domain from a cluster of differentiation 4 (CD4) and CD8 [ 12 , 13 ]; a transmembrane domain that is usually derived from CD8, CD3-ζ, CD4, OX40, and H2-K b [ 14 ]; and an intracellular signaling tail including a signal-transduction component of a T-cell receptor (TCR) (e.g., CD3ζ immunoreceptor tyrosine-based activation motif domain) and/or a costimulatory receptor (e.g., CD28, CD27, 4-1BB, or OX40) (Figure 1 ) [ 15 ]. The scFvs, formed by a combination of antibody heavy- and light-chain amino acid sequences with a short peptide linker, are attached to the hinge region, where they act as extracellular antigen-binding domains [ 16 ]. The variable region binds antigens and is capable of enormous combinatorial diversity, enabling the recognition of a myriad of specific molecular conformations [ 17 ].…”

“…Newly generated fourth-generation CARs, also named TRUCK T cells, were engineered to produce cytokines, particularly interleukin (IL)-12, which can regulate the antitumor microenvironment. IL-15 and granulocyte-macrophage colony-stimulating factor (GM-CSF) also contribute to this strategy [ 16 ]. A more recent study, which generated allogeneic universal T cells deficient of both programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen (CTLA-4) pathways (inhibitory pathways for immune escape), was attempted using human lymphocytes in vitro [ 26 ].…”