Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies

Mirci-Danicar, Oana; Gianella‐Borradori, Athos; Binlich, Florence; Balandraud, Svetlana; Vitry, Fabien; Thomas, Elisabeth; Philippe, Anne; Fouliard, Sylvain; Dupouy, Sandra; Marchiq, Ibtissam; Almena-Carrasco, Maria; Ferry, Nicolas; Arnould, Sylvain; Konto, Cyril; Benjamin, Reuben; Graham, Charlotte; Yallop, Deborah; Jóźwik, Agnieszka; Pagliuca, Antonio; Mufti, Ghulam J.; Patten, Piers; Kassam, Shireen; Devereux, Stephen; Kazmi, Majid; Cuthill, Kirsty; Potter, Victoria; Kühnl, Andrea; Metaxa, Victoria; Bonganay, Laarni; Stewart, Orla; Ellard, Rose; Catt, Lorraine; Lewis, Jen; Farzaneh, Farzin; Chappell, Jackie; Mason, Alice; Chu, Vicky; Dunlop, Alan; Saleem, Adeel; Cheung, Gary; Munro, Helena; Giemza, Elka; Qasim, Waseem; Veys, Paul; Ciocârlie, Oana; Lucchini, Giovanna; Pinner, Danielle; Chu, Jan; Amrolia, Persis; Rao, Kanchan; Chiesa, Robert; Silva, Juliana; Hill, Annette; Finch, Maria; Young, Lindsey; Hara, Harvinder; Samarasinghe, Sujith; Rao, Anupama; Vora, Ajay; Gilmour, Kimberly C.; Rivat, Christine; Murphy, Clare; Ahsan, Gulrukh; Shamsah, Rasha Said; James, Jesmina; Inglott, Sarah; Wright, Gary; Adams, Stuart; Izotova, Natalia; Jain, Nitin; Konopleva, Marina; Wierda, William G.; Jabbour, Elias; Kantarjian, Hagop; Kebrieai, Partow; Jones, Emily; McGee, Kara; Maus, Marcela V.; Frigault, Matthew J.; Brown, Jami; Toncheva, Vesselina; Casey, Kevin; Hock, Hanno; McKeown, Meaghan A; Mathews, Richard; Spitzer, Thomas R.; Boissel, Nicolas; Raffoux, Emmanuel; Lengliné, Etienne; Itzykson, Raphaël; Rabian, Florence; Azoulay, Élie; Clappier, Emmanuelle; Caillat‐Zucman, Sophie; Meunier, Martine; Celli-Lebras, Karine; Tremorin, Marie-Thérèse; Baruchel, André; Yakouben, Karima; Mechinaud-Heloury, Françoise; Grain, Audrey; Alimi, Aurélia; Roupret, Julie; Chaillou, Delphine; Madelaine, Isabelle; Cavé, Hélène; Caye-Eude, Aurélie; Fenneteau, Odile; Lainey, Élodie; Naudin, J.; Mohty, Mohamad; Brissot, Éolia; Duléry, Rémy; Malard, Florent; Mediavilla, Clemence; Bonnin, Agnès; Vekhoff, Anne; Ledraa, Tounes; Larghero, Jérôme; Daguenel-Nguyen, Anne

doi:10.1016/s0140-6736(20)32334-5

Cited by 267 publications

(199 citation statements)

References 18 publications

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“…In addition, the tolerable number of potentially alloreactive CAR T cells infused into the recipient has yet to be established (87). Several allogeneic CAR T cell products have been tested in clinical trials (90)(91)(92), with the most recent inducing remission in patients with relapsed and/or refractory B-ALL. As expected, however, allogeneic CAR T cell persistence remains shorter as compared with autologous approaches.…”

Section: Moving From Autologous To Allogeneic Productsmentioning

confidence: 99%

Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy

Abou‐El‐Enein

Elsallab

Feldman³

et al. 2021

Blood Cancer Discovery

142

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As of April 2021, there are five commercially available chimeric antigen receptor (CAR) T cell therapies for hematologic malignancies. With the current transition of CAR T cell manufacturing from academia to industry, there is a shift toward Good Manufacturing Practice (GMP)-compliant closed and automated systems to ensure reproducibility and to meet the increased demand for patients with cancer. In this review, we describe current CAR T cell clinical manufacturing models and discuss emerging technologic advances that embrace scaling and production optimization. We summarize measures being used to shorten CAR T cell manufacturing times and highlight regulatory challenges to scaling production for clinical use. Significance:As the demand for CAR T cell cancer therapy increases, several closed and automated production platforms are being deployed, and others are in development. This review provides a critical appraisal of these technologies, which can be leveraged to scale and optimize the production of nextgeneration CAR T cells. iNtRODUctiONChimeric antigen receptor (CAR)-modified T cells have emerged as an efficacious treatment for patients with certain hematologic malignancies (1). Currently, five CAR T cell products are approved for commercial use and available on the U.S. market: three for B-cell leukemia and lymphoma (tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel), one for mantle cell lymphoma (brexucabtagene autoleucel), and one for multiple myeloma (idecabtagene vicleucel; refs. 2-8). These therapies involve genetically modifying patient-derived (autologous) peripheral blood T cells to express a CAR directed against antigens present on the surface of targeted tumor cells, such as the CD19 molecule, or, in the case of idecabtagene vicleucel, B-cell maturation antigen (BCMA;. After antigen recognition, the intracellular signaling domains activate the immune effector and memory functions of the CAR T cells. Once activated, these T cells proliferate, infiltrate tumor sites, secrete cytokines, and release cytolytic granules to eliminate targeted cells in an antigen-dependent manner (1). All approved CAR T cell products are second-generation CARs that incorporate CD28 or CD137 (4-1BB) costimulatory signals, which are essential for eliciting a clinically relevant immune response (9-15). These CAR T cells were able to elicit complete responses (CR) in 32% to 67% of patients with lymphoma and showed better CR rates in patients with leukemia (16)(17)(18)(19).The increasing success of CAR T immunotherapies in relapsed/refractory hematologic malignancies sparked the interest of pharmaceutical companies, and several products targeting a variety of cancers are currently in the pipeline (20). However, many limitations to current CAR T cell manufacturing must be overcome before this modality can be fully integrated into routine clinical practice. First, most CAR T cell trials to date have used autologous peripheral blood and apheresis as the main cell sources for manufacturing

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Section: Moving From Autologous To Allogeneic Productsmentioning

confidence: 99%

Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy

Abou‐El‐Enein

Elsallab

Feldman³

et al. 2021

Blood Cancer Discovery

142

View full text Add to dashboard Cite

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“…The need to individually engineer each patient’s cells ex vivo is largely responsible for the high cost. A promising alternative, currently in clinical trials, is the use of allogeneic T cells, which could serve as ‘off-the-shelf’ cell therapies, eliminating the need to engineer custom therapies for each patient 156 , 157 . However, the use of allogeneic cells increases the risk of graft-versus-host disease 104 , necessitating further genetic engineering to limit rejection.…”

Section: Discussionmentioning

confidence: 99%

Theranostic cells: emerging clinical applications of synthetic biology

McNerney

Doiron

et al. 2021

Nat Rev Genet

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Synthetic biology seeks to redesign biological systems to perform novel functions in a predictable manner. Recent advances in bacterial and mammalian cell engineering include the development of cells that function in biological samples or within the body as minimally invasive diagnostics or theranostics for the real-time regulation of complex diseased states. Ex vivo and in vivo cell-based biosensors and therapeutics have been developed to target a wide range of diseases including cancer, microbiome dysbiosis and autoimmune and metabolic diseases. While probiotic therapies have advanced to clinical trials, chimeric antigen receptor (CAR) T cell therapies have received regulatory approval, exemplifying the clinical potential of cellular therapies. This Review discusses preclinical and clinical applications of bacterial and mammalian sensing and drug delivery platforms as well as the underlying biological designs that could enable new classes of cell diagnostics and therapeutics. Additionally, we describe challenges that must be overcome for more rapid and safer clinical use of engineered systems.

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“…Published results from both trials showed that the most common adverse effects were CRS (91%) and neurotoxicity (38%) which resulted in two treatment-related deaths. Overall survival was 55% and progression-free survival 27% [ 129 ]. Building on UCART19′s initial success, Cellectis, Allogene and Servier begun investigating the use of TCR and CD52 KO CAR T cells in conjunction with an anti-CD52 recombinant antibody to treat relapsed or refractory large B cell lymphoma or follicular lymphoma.…”

Section: Applications Of LV Vector Technologies For T Cell Engineeringmentioning

confidence: 99%

Lentiviral Vectors for T Cell Engineering: Clinical Applications, Bioprocessing and Future Perspectives

Labbé

Vessillier

Rafiq

2021

Viruses

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Lentiviral vectors have played a critical role in the emergence of gene-modified cell therapies, specifically T cell therapies. Tisagenlecleucel (Kymriah), axicabtagene ciloleucel (Yescarta) and most recently brexucabtagene autoleucel (Tecartus) are examples of T cell therapies which are now commercially available for distribution after successfully obtaining EMA and FDA approval for the treatment of blood cancers. All three therapies rely on retroviral vectors to transduce the therapeutic chimeric antigen receptor (CAR) into T lymphocytes. Although these innovations represent promising new therapeutic avenues, major obstacles remain in making them readily available tools for medical care. This article reviews the biological principles as well as the bioprocessing of lentiviral (LV) vectors and adoptive T cell therapy. Clinical and engineering successes, shortcomings and future opportunities are also discussed. The development of Good Manufacturing Practice (GMP)-compliant instruments, technologies and protocols will play an essential role in the development of LV-engineered T cell therapies.

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Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies

Cited by 267 publications

References 18 publications

Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy

Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy

Theranostic cells: emerging clinical applications of synthetic biology

Lentiviral Vectors for T Cell Engineering: Clinical Applications, Bioprocessing and Future Perspectives

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