FCγ Chimeric Receptor-Engineered T Cells: Methodology, Advantages, Limitations, and Clinical Relevance

Abstract

For many years, disappointing results have been generated by many investigations, which have utilized a variety of immunologic strategies to enhance the ability of a patient’s immune system to recognize and eliminate malignant cells. However, in recent years, immunotherapy has been used successfully for the treatment of hematologic and solid malignancies. The impressive clinical responses observed in many types of cancer have convinced even the most skeptical clinical oncologists that a patient’s immune system can recognize and reject his tumor if appropriate strategies are implemented. The success immunotherapy is due to the development of at least three therapeutic strategies. They include tumor-associated antigen (TAA)-specific monoclonal antibodies (mAbs), T cell checkpoint blockade, and TAA-specific chimeric antigen receptors (CARs) T cell-based immunotherapy. However, the full realization of the therapeutic potential of these approaches requires the development of strategies to counteract and overcome some limitations. They include off-target toxicity and mechanisms of cancer immune evasion, which obstacle the successful clinical application of mAbs and CAR T cell-based immunotherapies. Thus, we and others have developed the Fc gamma chimeric receptors (Fcγ-CRs)-based strategy. Like CARs, Fcγ-CRs are composed of an intracellular tail resulting from the fusion of a co-stimulatory molecule with the T cell receptor ζ chain. In contrast, the extracellular CAR single-chain variable fragment (scFv), which recognizes the targeted TAA, has been replaced with the extracellular portion of the FcγRIIIA (CD16). Fcγ-CR T cells have a few intriguing features. First, given in combination with mAbs, Fcγ-CR T cells mediate anticancer activity in vitro and in vivo by an antibody-mediated cellular cytotoxicity mechanism. Second, CD16-CR T cells can target multiple cancer types provided that TAA-specific mAbs with the appropriate specificity are available. Third, the off-target effect of CD16-CR T cells may be controlled by withdrawing the mAb administration. The goal of this manuscript was threefold. First, we review the current state-of-the-art of preclinical CD16-CR T cell technology. Second, we describe its in vitro and in vivo antitumor activity. Finally, we compare the advantages and limitations of the CD16-CR T cell technology with those of CAR T cell methodology.

Emerging CAR-T Cell Therapy for the Treatment of Triple-Negative Breast Cancer

“…The standard form of CAR-T cell redirection is restricted to a single tumor-associated antigen expressed on the tumor cell surface. A universal CAR-T cell that expresses a Fc-gamma receptor (FcγR)-CAR can be used to facilitate multiple therapeutic antibodies to redirect T cells to virtually any antigen expressing tumor cell (71). Since therapeutic antibodies that target antigens on solid tumors are available, use of FcγR-CAR-T cells in combination with these antibodies is a viable option to eliminate solid tumors.…”

In vitro elimination of epidermal growth factor receptor‐overexpressing cancer cells by CD32A‐chimeric receptor T cells in combination with cetuximab or panitumumab

“…The role of ADCC in the in vitro and in vivo antitumor activity of tumor antigen (TA)‐specific mAbs has stimulated interest in genetically engineering T cells with the CD16 chimeric receptor (CD16‐CR) . In these cells, the extracellular domain of CD16 was ligated to cytotoxic signaling molecules fused with or without T‐cell costimulatory molecules.…”

“…3 The role of ADCC in the in vitro and in vivo antitumor activity of tumor antigen (TA)-specific mAbs 6 has stimulated interest in genetically engineering T cells with the CD16 chimeric receptor (CD16-CR). 7,8 In these cells, the extracellular domain of CD16 was ligated to cytotoxic signaling molecules fused with 9,10 or without 11,12 T-cell costimulatory molecules. This strategy allows the rapid generation of polyclonal T cells with a potent cytotoxic activity when combined with mAbs, recognizing the TAs expressed on the tumor cell membrane.…”

Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

“…Fc gamma chimeric receptors (Fcγ-CRs) are similar to CAR-T based immunotherapies, though the CAR scFv recognising a targeted TAA is replaced by the extracellular portion of the FcγRIIIA (CD16). Together with therapeutic mAbs, they enhance anticancer activity by an antibody-mediated cellular cytotoxicity mechanism triggering downstream activating pathways resulting in perforin/granzyme-dependent tumour cell lysis [ 357 ].…”