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Mark B Geyer, Renier J Brentjens
The past several years have been marked by extraordinary advances in clinical applications of immunotherapy. In particular, adoptive cellular therapy utilizing chimeric antigen receptor (CAR)-modified T cells targeted to CD19 has demonstrated substantial clinical efficacy in children and adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) and durable clinical benefit in a smaller subset of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin lymphoma (B-NHL)...
November 2016: Cytotherapy
Andrew D Fesnak, Carl H June, Bruce L Levine
The immune system evolved to distinguish non-self from self to protect the organism. As cancer is derived from our own cells, immune responses to dysregulated cell growth present a unique challenge. This is compounded by mechanisms of immune evasion and immunosuppression that develop in the tumour microenvironment. The modern genetic toolbox enables the adoptive transfer of engineered T cells to create enhanced anticancer immune functions where natural cancer-specific immune responses have failed. Genetically engineered T cells, so-called 'living drugs', represent a new paradigm in anticancer therapy...
August 23, 2016: Nature Reviews. Cancer
Anthony Visioni, Joseph Skitzki
A significant function of the immune system is the surveillance and elimination of aberrant cells that give rise to cancer. Even when tumors are well established and metastatic, immune-mediated spontaneous regressions have been documented. While there are have been various forms of immunotherapy, one of the most widely studied for almost 40 years is adoptive cellular immunotherapy, but its success has yet to be fully realized. Adoptive cell transfer (ACT) is a therapeutic modality that has intrigued physicians and researchers for its many theoretical benefits...
September 20, 2016: Cancers
Julie C Fitzgerald, Scott L Weiss, Shannon L Maude, David M Barrett, Simon F Lacey, J Joseph Melenhorst, Pamela Shaw, Robert A Berg, Carl H June, David L Porter, Noelle V Frey, Stephan A Grupp, David T Teachey
OBJECTIVE: Initial success with chimeric antigen receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after chimeric antigen receptor-modified T cell therapy...
September 14, 2016: Critical Care Medicine
Nadia Mensali, Fan Ying, Vincent Oei Yi Sheng, Weiwen Yang, Even Walseng, Shraddha Kumari, Lars-Egil Fallang, Arne Kolstad, Wolfgang Uckert, Karl Johan Malmberg, Sébastien Wälchli, Johanna Olweus
T cells engineered to express chimeric antigen receptors (CARs) targeted to CD19 are effective in treatment of B-lymphoid malignancies. However, CARs recognize all CD19 positive (pos) cells, and durable responses are linked to profound depletion of normal B cells. Here, we designed a strategy to specifically target patient B cells by utilizing the fact that T-cell receptors (TCRs), in contrast to CARs, are restricted by HLA. Two TCRs recognizing a peptide from CD20 (SLFLGILSV) in the context of foreign HLA-A*02:01 (CD20p/HLA-A2) were expressed as 2A-bicistronic constructs...
May 2016: Oncoimmunology
Ahmed Z Gad, Shahenda El-Naggar, Nabil Ahmed
Over the last two decades, harnessing the power of the immune system has shown substantial promise. Specifically, the successes that chimeric antigen receptor (CAR) T cells achieved in the treatment of hematologic malignancies provided a concrete platform for further development in solid tumors. Considering that the latter contribute more than three quarters of cancer-related deaths in humans makes it clear that solid tumors represent the larger medical challenge, but also the larger developmental promise in the market...
November 2016: Cytotherapy
Elena Faitschuk, Andreas A Hombach, Lukas P Frenzel, Clemens-Martin Wendtner, Hinrich Abken
Adoptive cell therapy of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR)-modified T cells targeting CD19 induced lasting remission of this refractory disease in a number of patients. However, the treatment is associated with prolonged "on-target off-tumor" toxicities due to the targeted elimination of healthy B cells demanding more selectivity in targeting CLL cells. We identified the immunoglobulin M Fc receptor (FcμR), also known as the Fas apoptotic inhibitory molecule-3 or TOSO, as a target for a more selective treatment of CLL by CAR T cells...
September 29, 2016: Blood
Partow Kebriaei, Harjeet Singh, M Helen Huls, Matthew J Figliola, Roland Bassett, Simon Olivares, Bipulendu Jena, Margaret J Dawson, Pappanaicken R Kumaresan, Shihuang Su, Sourindra Maiti, Jianliang Dai, Branden Moriarity, Marie-Andrée Forget, Vladimir Senyukov, Aaron Orozco, Tingting Liu, Jessica McCarty, Rineka N Jackson, Judy S Moyes, Gabriela Rondon, Muzaffar Qazilbash, Stefan Ciurea, Amin Alousi, Yago Nieto, Katy Rezvani, David Marin, Uday Popat, Chitra Hosing, Elizabeth J Shpall, Hagop Kantarjian, Michael Keating, William Wierda, Kim Anh Do, David A Largaespada, Dean A Lee, Perry B Hackett, Richard E Champlin, Laurence J N Cooper
BACKGROUND: T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR. METHODS: T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines...
September 1, 2016: Journal of Clinical Investigation
Chiara F Magnani, Nice Turazzi, Fabrizio Benedicenti, Andrea Calabria, Erika Tenderini, Sarah Tettamanti, Greta M P Giordano Attianese, Laurence J N Cooper, Alessandro Aiuti, Eugenio Montini, Andrea Biondi, Ettore Biagi
Chimeric antigen receptor (CAR)-modified T-cell adoptive immunotherapy is a remarkable therapeutic option proven effective in the treatment of hematological malignancies. In order to optimize cell manufacturing, we sought to develop a novel clinical-grade protocol to obtain CAR-modified cytokine-induced killer cells (CIKs) using the Sleeping Beauty (SB) transposon system. Administration of irradiated PBMCs overcame cell death of stimulating cells induced by non-viral transfection, enabling robust gene transfer together with efficient T-cell expansion...
June 13, 2016: Oncotarget
Marco Ruella, Carl H June
Genetic redirection of T lymphocytes allows us to unleash these potent cellular immune effectors against cancer. Chimeric antigen receptor (CAR) T cells are the best-in-class example that genetic engineering of T cells can lead to deep and durable responses, as has been shown in several clinical trials for CD19+ B cell malignancies. As a consequence, in the last few years, several academic institutions and commercial partners have started developing anti-CD19 CAR T cell products. Although most of these T cell products are highly effective in vivo, basic differences among them can generate different performance characteristics and thereby impact their long-term clinical outcome...
October 2016: Current Hematologic Malignancy Reports
Hilde Almåsbak, Tanja Aarvak, Mohan C Vemuri
The development of novel targeted therapies with acceptable safety profiles is critical to successful cancer outcomes with better survival rates. Immunotherapy offers promising opportunities with the potential to induce sustained remissions in patients with refractory disease. Recent dramatic clinical responses in trials with gene modified T cells expressing chimeric antigen receptors (CARs) in B-cell malignancies have generated great enthusiasm. This therapy might pave the way for a potential paradigm shift in the way we treat refractory or relapsed cancers...
2016: Journal of Immunology Research
Olalekan O Oluwole, Marco L Davila
T cells kill microbial-infected and malignant cells by detection of nonself antigens with the TCR. Tumor reactivity can be encoded genetically by introducing a chimeric antigen receptor (CAR) into T cells. CARs are composed of an antigen-binding domain and an intracellular T cell activation domain. Early human trials evaluating CD19-targeted CAR T cells for chronic lymphocytic leukemia (CLL) showed limited responses until CARs included a costimulation domain, and conditioning chemotherapy was given before T cell infusion...
June 27, 2016: Journal of Leukocyte Biology
Erlend Strønen, Mireille Toebes, Sander Kelderman, Marit M van Buuren, Weiwen Yang, Nienke van Rooij, Marco Donia, Maxi-Lu Böschen, Fridtjof Lund-Johansen, Johanna Olweus, Ton N Schumacher
Accumulating evidence suggests that clinically efficacious cancer immunotherapies are driven by T cell reactivity against DNA mutation-derived neoantigens. However, among the large number of predicted neoantigens, only a minority is recognized by autologous patient T cells, and strategies to broaden neoantigen-specific T cell responses are therefore attractive. We found that naïve T cell repertoires of healthy blood donors provide a source of neoantigen-specific T cells, responding to 11 of 57 predicted human leukocyte antigen (HLA)-A*02:01-binding epitopes from three patients...
June 10, 2016: Science
Hollie J Jackson, Sarwish Rafiq, Renier J Brentjens
The engineered expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. Early clinical trials using CAR T cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm for this approach. Important lessons have been derived from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in haematological and solid malignancies...
June 2016: Nature Reviews. Clinical Oncology
David Killock
No abstract text is available yet for this article.
April 2016: Nature Reviews. Clinical Oncology
Peter Sidaway
No abstract text is available yet for this article.
April 2016: Nature Reviews. Clinical Oncology
Kole T Roybal, Levi J Rupp, Leonardo Morsut, Whitney J Walker, Krista A McNally, Jason S Park, Wendell A Lim
T cells can be re-directed to kill cancer cells using chimeric antigen receptors (CARs) or T cell receptors (TCRs). This approach, however, is constrained by the rarity of tumor-specific single antigens. Targeting antigens also found on bystander tissues can cause life-threatening adverse effects. A powerful way to enhance ON-target activity of therapeutic T cells is to engineer them to require combinatorial antigens. Here, we engineer a combinatorially activated T cell circuit in which a synthetic Notch receptor for one antigen induces the expression of a CAR for a second antigen...
February 11, 2016: Cell
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