The use of genetically modified T cells (T lymphocytes) to target cancer is a promising approach, especially for cancers that are difficult to treat using traditional methods. The two most common approaches revolve around genetically engineering T cells to introduce either a new T-cell receptor (TCR) or a chimeric antigen receptor (CAR) (Humphries 2013). Adoptive T-cell therapy involves removing a patient's T cells, modifying them ex vivo, and then reinfusing the modified cells back into the same patient (Figure 1). In addition to this so-called autologous approach, several companies worldwide are working on developing therapies that can be produced from a single donor and then used to treat thousands of patients (allogeneic approach). In both of these approaches, the modification of the T cells takes place outside of the patient's body (ex vivo gene therapy).
Figure 1. Workflow for T-cell-based therapies.
High transduction efficiency is essential in adoptive T-cell therapies to efficiently introduce TCR/CAR genes into T lymphocytes. In this context, RetroNectin GMP grade reagent has been used to enhance viral transduction and expand the naïve T-cell population, and it is manufactured as a quality-assured product according to guidelines for Good Manufacturing Practice (GMP). Our RetroNectin GMP grade reagent has been used in over 68 protocols for gene therapy clinical trials, at 44 institutions worldwide. We also supply a GMP-grade anti-CD3 antibody for T-cell activation as well as LymphoONE T-cell culture medium, which are optimized for use with RetroNectin reagent.
RetroNectin reagent is a recombinant human fibronectin fragment that contains three functional domains: the cell-binding domain (C-domain), the heparin-binding domain (H-domain), and the CS-1 sequence. RetroNectin reagent enhances lentiviral- and retroviral-mediated gene transduction by aiding the co-localization of target cells and viral particles. Specifically, virus particles bind RetroNectin reagent via interaction with the H-domain, and target cells bind mainly through the interaction of cell surface integrin receptors VLA-5 and VLA-4 with the fibronectin C-domain and CS-1 sites, respectively (Figure 2). By facilitating close physical proximity, RetroNectin reagent can enhance viral-mediated gene transfer to target cells expressing integrin receptors VLA-4 and VLA-5.
Figure 2. Structure and function of RetroNectin reagent's recombinant human fibronectin fragment.
Dr. Steven Rosenberg at the National Institutes of Health (US), one of the pioneers of adoptive T-cell therapy, is conducting clinical trials of TCR/CAR gene therapy. His group uses RetroNectin GMP grade reagent to transduce patient-derived lymphocytes with TCR/CAR genes that recognize cancer antigens (e.g., MART-1, gp100, or NY-ESO-1) for therapy (Kochenderfer et al. 2012; Robbins et al. 2011; Zhang et al. 2013). Researchers at Mie University Hospital (Japan), in collaboration with Takara Bio Inc., are conducting clinical research on TCR/CAR gene therapy for esophageal cancer.
Relapsed/Refractory Acute Lymphoid Leukemia (R/R ALL) is another cancer with extremely poor prognosis as few therapeutic options are available. Scientists at Memorial Sloan-Kettering Cancer Center (US) reported an immunotherapy strategy for the treatment of five adult patients with acute lymphoblastic leukemia. Each patient's T cells were isolated, altered by the introduction of DNA that would cause the cells to target CD19 and thus attack tumor cells, and infused back into the patient's bloodstream. According to researchers, all patients achieved tumor eradication and complete remission. RetroNectin GMP grade reagent was used during T-cell transduction (Brentjens et al. 2013). Additional selected publications citing RetroNectin GMP grade reagent used in clinical studies are also listed below.
It was very clear to us even 10 years ago that the use of RetroNectin-coated plates markedly, massively improved gene transfer. The methodologies that many of us now use have been developed over a number of years. Once you have a system that works, you become very reliant and dependent on those reagents."
—Dr. Brentjens
Robbins, P. F. et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917–924 (2011).
Stroncek, D. F. et al. Myeloid cells in peripheral blood mononuclear cell concentrates inhibit the expansion of chimeric antigen receptor T cells. Cytotherapy 18, 893–901 (2016).
Tang, X. Y. et al. Third-generation CD28/4-1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukemia: A non-randomised, open-label phase I trial protocol. BMJ Open 6, e013904 (2016).
Tomuleasa, C. et al. Chimeric antigen receptor T-cells for the treatment of B-cell acute lymphoblastic leukemia. Front. Immunol. 19, 239 (2018).
Zhang, L. et al. Evaluation of γ-retroviral vectors that mediate the inducible expression of IL-12 for clinical application. J. Immunother. 35, 430–439 (2013).
What if your own immune cells could fight off cancer? That's the idea behind cancer immunotherapy. Dr. Steven Rosenberg's group at the National Cancer Institute uses RetroNectin reagent to introduce T-cell receptor genes recognizing specific cancer antigens into a patient's own lymphocytes. These engineered cells are then returned to the patient, where they specifically target cancer cells expressing the antigen. That's Good Science!
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1.05 | Turning immune cells into cancer-fighting ninjas
What if your own immune cells could fight off cancer? That's the idea behind cancer immunotherapy. Dr. Steven Rosenberg's group at the National Cancer Institute uses RetroNectin reagent to introduce T-cell receptor genes recognizing specific cancer antigens into a patient's own lymphocytes. These engineered cells are then returned to the patient, where they specifically target cancer cells expressing the antigen. That's Good Science!
