Abstract
Recent progress in chimeric antigen receptor-modified T-cell (CAR-T cell) technology in cancer therapy is extremely promising, especially in the treatment of patients with B-cell acute lymphoblastic leukemia. In contrast, due to the hostile immunosuppressive microenvironment of a solid tumor, CAR T-cell accessibility and survival continue to pose a considerable challenge, which leads to their limited therapeutic efficacy. In this study, we constructed two anti-MUC1 CAR-T cell lines. One set of CAR-T cells contained SM3 single chain variable fragment (scFv) sequence specifically targeting the MUC1 antigen and co-expressing interleukin (IL) 12 (named SM3-CAR). The other CAR-T cell line carried the SM3 scFv sequence modified to improve its binding to MUC1 antigen (named pSM3-CAR) but did not co-express IL-12. When those two types of CAR-T cells were injected intratumorally into two independent metastatic lesions of the same MUC1(+) seminal vesicle cancer patient as part of an interventional treatment strategy, the initial results indicated no side-effects of the MUC1 targeting CAR-T cell approach, and patient serum cytokines responses were positive. Further evaluation showed that pSM3-CAR effectively caused tumor necrosis, providing new options for improved CAR-T therapy in solid tumors.
Highlights
T-cell based immunotherapy is becoming a hotspot of the cancer therapeutics area
Immunohistochemistry confirmed Mucin 1 (MUC1) expression in patient tumor biopsies. For this patient, MUC1 can be used as a chimeric antigen receptors (CARs)-T cell therapy antigen
Antitumor effects of CAR-T cell approaches in solid malignancies were disappointing. This was, in part, due to off-tumor on-target toxicities, as has been observed in CAR-based clinical studies that have targeted carbonic anhydrase IX (CAIX), which is overexpressed in renal cell carcinoma and expressed at low levels in normal tissues, including the liver (Lamers et al, 2013)
Summary
Using gene transfer technologies, patient T-cells can be genetically modified to stably express single-chain variable fragments (scFv) or ligands capable of binding antigens or receptors, respectively, to confer novel major histocompatibility complex (MHC)—independent antigen specificities on tumor cells. These structures are called chimeric antigen receptors (CARs) and contain three basic elements—the extracellular antigen binding domain, transmembrane domain, and cytoplasmic signaling domain. Second- or third-generation CARs were designed by including additional signaling domains, such as CD28 and/or 4-1BB, that potentiate T-cell effector functions and activate co-stimulatory pathways, resulting in upregulation of genes encoding anti-apoptotic proteins and increased cytokine secretion. A complete remission among 30 children and adults who received CD19-targeting CAR-T cell therapy for relapsed or refractory acute lymphoblastic leukemia (ALL) was achieved with 90% success rates (Porter et al, 2011, Davila and Brentjens, 2013; Grupp et al, 2013, Jensen and Riddell, 2014; Maude et al, 2014, 2015; Pegram et al, 2014; Turtle, 2014; Condomines et al, 2015; Jonnalagadda et al, 2015)
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