{"id":3883,"date":"2019-07-16T12:47:08","date_gmt":"2019-07-16T03:47:08","guid":{"rendered":"http:\/\/163.180.4.222\/lab\/?p=3883"},"modified":"2019-07-16T12:47:08","modified_gmt":"2019-07-16T03:47:08","slug":"boosting-engineered-t-cells","status":"publish","type":"post","link":"https:\/\/biochemistry.khu.ac.kr\/lab\/?p=3883","title":{"rendered":"Boosting engineered T cells"},"content":{"rendered":"

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After decades of work, researchers have finally begun to see broadly reproducible success of engineered T cells in the treatment of cancer. Chimeric antigen receptors (CARs) are synthetic molecules that combine the antigen specificity of monoclonal antibodies with the signaling of the T cell receptor (TCR) to direct patient-derived (autologous) T cells to seek out and destroy cancer cells. T cells engineered to express CARs targeting the B cell antigen CD19 can induce durable remissions in many patients with refractory B cell neoplasms (1<\/em><\/a>\u20133<\/em><\/a>), and two CAR\u2013T cell products have recently been approved by the U.S. Food and Drug Administration to treat B cell leukemia and lymphoma. Despite these successes in hematological cancers, CAR\u2013T cell activity against solid tumors has been limited. On page 162, Ma\u00a0et al.<\/em>\u00a0(4<\/em><\/a>) describe a platform that uses a vaccine-boosting strategy to improve the efficacy of CAR\u2013T cells to target solid tumors.<\/p>\n

Cellular immunotherapy of solid tumors presents several distinct barriers: After infusion, engineered T cells must traffic to sites of tumor residence, infiltrate a highly disorganized tumor architecture, and survive in a hostile tumor microenvironment. Several studies have shown that despite successful trafficking and infiltration, CAR\u2013T cells quickly become dysfunctional after encountering tumors (5<\/em><\/a>,\u00a06<\/em><\/a>). Ma\u00a0et al.<\/em>\u00a0devised a clever strategy to boost CAR\u2013T cell proliferation and survival with vaccination (see the figure). The authors previously developed a membrane-integrating phospholipid polymer that could be linked to small molecules or peptides, resulting in expression of a desired target antigen on the cell surface after \u201cimmunization\u201d with this molecule (7<\/em><\/a>). By binding to albumin after injection, these amphiphilic polymers are directed to lymph nodes, where they are preferentially displayed on resident antigen-presenting cells (APCs), which prevents their loss in systemic circulation.<\/p>\n

Ma\u00a0et al.<\/em>\u00a0demonstrated that these amphiphilic polymers linked to fluorescein isothiocyanate (FITC) as the antigen (amph-FITC) are stably expressed on the surface of APCs, and that delivery to mice of anti-FITC\u2013engineered CAR\u2013T cells followed by immunization with amph-FITC significantly improved T cell proliferation in vivo. Notably, this effect relied on costimulatory signals delivered to T cells by APCs expressing amph-FITC, identifying the need for CAR-independent costimulation in this system. Expanding these findings to a tumor-antigen model, the authors used a CAR targeting a splice variant of epidermal growth factor receptor, EGFRvIII, which is commonly expressed in glioma, in combination with a vaccine containing an amphiphilic polymer linked to the EGFRvIII target antigen. In mice with EGFRvIII+<\/sup>\u00a0gliomas, vaccination resulted in improved CAR\u2013T cell proliferation and survival, and improved infiltration of activated CAR\u2013T cells into tumor sites compared to CAR\u2013T cell delivery alone.<\/p>\n

A potential limitation of the EGFRvIII strategy is that the CAR targets a linear epitope in the EGFRvIII protein, which is more readily targeted than the more common conformational epitopes of cancer-specific antigens. To develop a generalized therapeutic strategy, Ma\u00a0et al.<\/em>\u00a0constructed a dual-targeted \u201ctandem CAR,\u201d composed of a CAR targeted to a tumor antigen linked to a CAR targeting FITC. In mouse models of melanoma and breast cancer, they demonstrated that delivery of these tandem CARs followed by vaccination with amph-FITC leads to significantly improved antitumor activity, obviating the need to have a vaccine individualized for each target antigen and independent of whether the epitope is linear or conformational.<\/p>\n

Vaccine-based strategies have long been explored as a method to improve antitumor immunity, and several recent studies have combined vaccination with CAR\u2013T cells to treat various solid tumors in mice and patients (8<\/em><\/a>\u201310<\/em><\/a>). These approaches all follow the same paradigm: selecting (or engineering) T cells with known TCR specificity and engineering these to express CARs, thus generating a T cell product with dual specificity. These studies have demonstrated feasibility but with limited antitumor efficacy.<\/p>\n

Previous clinical trials may provide clues about the limited activity of these strategies. Persistent TCR stimulation of CAR\u2013T cell products can lead to \u201cterminal\u201d differentiation, a state of irreversible T cell dysfunction (11<\/em><\/a>). Furthermore, strategies to disrupt\u00a0TCR<\/em>\u00a0genes in CAR\u2013T cells, both as a means to prevent off-target TCR-driven T cell activity that causes side effects, and to improve CAR-driven antitumor efficacy, are being explored (12<\/em><\/a>). The conceptual innovation of the approach taken by Ma\u00a0et al.<\/em>\u00a0is to bypass the major histocompatibility complexes (MHCs) that present antigens to TCRs needed for traditional vaccine responses, while preserving the immune stimulation provided by vaccination. Another conceptual innovation of this approach is that it uses the CAR not only for tumor targeting but also as a machine to enhance T cell activity, demonstrating that this chimeric molecule may have multifunctionality. Exploring how these synthetic CAR molecules can be used more efficiently, effectively, and creatively will open doors to new therapeutic platforms.<\/p>\n

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