Article

Morgan, RA, Dudley, ME, Wunderlich, JR, Hughes, MS, Yang, JC, Sherry, RM et al.. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314: 126-129

Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
Science (Impact Factor: 31.48). 11/2006; 314(5796):126-9. DOI: 10.1126/science.1129003
Source: PubMed

ABSTRACT Through the adoptive transfer of lymphocytes after host immunodepletion, it is possible to mediate objective cancer regression in human patients with metastatic melanoma. However, the generation of tumor-specific T cells in this mode of immunotherapy is often limiting. Here we report the ability to specifically confer tumor recognition by autologous lymphocytes from peripheral blood by using a retrovirus that encodes a T cell receptor. Adoptive transfer of these transduced cells in 15 patients resulted in durable engraftment at levels exceeding 10% of peripheral blood lymphocytes for at least 2 months after the infusion. We observed high sustained levels of circulating, engineered cells at 1 year after infusion in two patients who both demonstrated objective regression of metastatic melanoma lesions. This study suggests the therapeutic potential of genetically engineered cells for the biologic therapy of cancer.

Download full-text

Full-text

Available from: Nicholas P Restifo, Sep 01, 2015
1 Follower
 · 
216 Views
 · 
150 Downloads
  • Source
    • "Practices of immunotherapy, for example in treating cancer patient can be traced to William Coley in the late 1800s, when he treated cancer patients with certain kinds of bacteria, known as Coley toxins. Since then, several studies have reported the uses of immunotherapies such as T-cell adoptive immunotherapy for lymphoblastic leukemia [2], cancer regression and autoimmunity by clonal repopulation with antitumour lymphocytes [3], therapeutic antibodies and immunologic conjugate [4], cancer regression by transferring genetically engineered lymphocytes [5], safety and tumour responses with lambrolizumab (anti-PD-1) in melanoma [6], improved survival in patients with metastatic melanoma [7] to mention a few. Immunotherapy is a way of increasing the survival rate of immunocompromised patients. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In the recent years, mushrooms are distinguished asimportant natural resources of immunotherapy whichcan be used as immunomodulating and immunostimulating in the management of some immunodeficiency diseases such as cancer, tumour, HIV, tuberculosis etc. Mushroom of the genus Pleurotus are good sources of several bioactive compounds which are able to augment or complement a desired immune response. Such bioactive compounds are polysaccharopeptides, polysaccharide-proteins, functional proteins (ubiquinone-9, nebrodeolysin, ubiquitin-like peptide and glycoprotein), glucans, proteoglycans and many others. Most of these bioactive compounds follow the immunomodulatory pathway mechanism of polysaccharide (β-glucan) from mushrooms by stimulating activities for both innate and adaptive immune systems. They proliferate and activate innate immune system components such as natural killer (NK) cells, neutrophils, and macrophages, and stimulate cytokines expression and secretion. Thesecytokines in turn activate adaptive immunity through the promotion of Bcells for antibodies production and stimulation of T-cell differentiation to T helper (Th1 and Th2) cells, which mediate cell and humoral immunities, respectively. In this review, the immunotherapeutic potential of oyster mushroom in relation to bioactive compounds produced is shown and this suggests that the oyster mushrooms are one of the most important natural products and functional foods.
  • Source
    • "Ideally between 0.1x10 10 and 10x10 10 cells should be produced. The retrovirus used in the above mentioned TCR trials was a bicistronic vector; it coexpresses the two TCR chains by linking them with an internal ribosome entry site (IRES) [9] [11]. When Engels et al. compared several vectors side by side in their ability to transduce murine and human T cells, they were able to show that the pMP71 vector proved to be most efficient with an up to 75-fold increase of transgene expression in human T cells compared to standard Moloney murine leukemia derived vectors (Mo-MLV) [22]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The genetic engineering of T cells can lead to enhanced immune-mediated tumour destruction and harbors a great potential for the treatment of cancer. Recent efforts have centered on the design of receptors to re-direct the specificity of T cells towards tumour antigens by means of viral gene transfer. This strategy has shown great success in a number of phase one clinical trials. However, there are still challenges to overcome. On the one hand, T cell function can be further improved to optimize the therapeutic outcome. On the other hand, so called safety switches are required to deal with possible on and off target toxicities. In this review, we will give a brief summary of the success and risks of T cell gene therapy before discussing in detail current strategies to enhance effector function, persistence and safety of adoptively transferred T cells.
    Current Gene Therapy 01/2015; 15(3). DOI:10.2174/1566523215666150126123037 · 4.91 Impact Factor
  • Source
    • "Initial trials using gene-modified T cells to treat various tumor types did not show antitumor responses in a substantial number of patients (Kershaw et al., 2006; Morgan et al., 2006; Till et al., 2008; Johnson et al., 2009; Lamers et al., 2013a,b). Despite that some recent trials using either a CD19 CAR to treat B cell leukemias (Kalos et al., 2011; Davila et al., 2014; Lee et al., 2014; Maude et al., 2014) or an NY-ESO TCR to treat melanoma and synovial carcinoma (Robbins et al., 2011) showed significant clinical activities, the majority of the studies performed so far fail to demonstrate substantial antitumor effects (Gilham et al., 2012; Kunert et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Therapy with autologous T cells that have been gene-engineered to express chimeric antigen receptors (CAR) or T cell receptors (TCR) provides a feasible and broadly applicable treatment for cancer patients. In a clinical study in advanced renal cell carcinoma (RCC) patients with CAR T cells specific for Carbonic Anhydrase IX (CAIX) we observed toxicities which (most likely) indicated in vivo function of CAR T cells as well as low T cell persistence and clinical response rates. The latter observations were confirmed by later clinical trials in other solid tumor types and other gene-modified T cells. To improve the efficacy of T cell therapy, we have re-defined in vitro conditions to generate T cells with young phenotype, a key correlate with clinical outcome. For their impact on gene modified T cell phenotype and function, we have tested various anti-CD3/CD28 mAb-based T cell activation and expansion conditions as well as several cytokines prior to and/or post gene transfer using two different receptors: CAIX CAR and MAGE-C2(ALK)/HLA-A2 TCR. In a total set of 16 healthy donors, we observed that T cell activation with soluble anti-CD3/CD28 mAbs in the presence of both IL15 and IL21 prior to TCR gene transfer resulted in enhanced proportions of gene-modified T cells with a preferred in vitro phenotype and better function. T cells generated according to these processing methods demonstrated enhanced binding of pMHC, and an enhanced proportion of CD8+,CD27+,CD62L+,CD45RA+ T cells. These new conditions will be translated into a GMP protocol in preparation of a clinical adoptive therapy trial to treat patients with MAGE-C2-positive tumors.
    Human Gene Therapy Methods 11/2014; 25(6). DOI:10.1089/hgtb.2014.051 · 1.64 Impact Factor
Show more