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Cells for Immunotherapy Engineered for Targeting

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Cells for Immunotherapy Engineered for Targeting (19) TZZ¥_Z¥__T (11) EP 3 105 317 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 35/17 (2015.01) C12N 5/0783 (2010.01) 19.09.2018 Bulletin 2018/38 (86) International application number: (21) Application number: 15706399.1 PCT/EP2015/053162 (22) Date of filing: 13.02.2015 (87) International publication number: WO 2015/121454 (20.08.2015 Gazette 2015/33) (54) CELLS FOR IMMUNOTHERAPY ENGINEERED FOR TARGETING ANTIGEN PRESENT BOTH ON IMMUNE CELLS AND PATHOLOGICAL CELLS MANIPULIERTE ZELLEN FÜR DIE IMMUNTHERAPIE ZUR ABZIELUNG AUF ANTIGEN IN IMMUNZELLEN WIE AUCH ERREGERZELLEN CELLULES DESTINÉES À L’IMMUNOTHÉRAPIE MODIFIÉES POUR CIBLER UN ANTIGÈNE PRÉSENT À LA FOIS SUR LES CELLULES IMMUNITAIRES ET LES CELLULES PATHOLOGIQUES (84) Designated Contracting States: • MIHARA KEICHIRO ET AL: "Activated AL AT BE BG CH CY CZ DE DK EE ES FI FR GB T-cell-mediated immunotherapy with a chimeric GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO receptor against CD38 in B-cell non-Hodgkin PL PT RO RS SE SI SK SM TR lymphoma", JOURNAL OF IMMUNOTHERAPY, RAVEN PRESS, NEW YORK, NY, US, vol. 32, no. (30) Priority: 14.02.2014 DK 201470076 7, 1 September 2009 (2009-09-01), pages 737-743, XP009132660, ISSN: 1053-8550 (43) Date of publication of application: • K MIHARA ET AL: "T-cell immunotherapy with a 21.12.2016 Bulletin 2016/51 chimeric receptor against CD38 is effective in eliminating myeloma cells", LEUKEMIA, vol. 26, (60) Divisional application: no. 2, 12 August 2011 (2011-08-12), pages 18154305.9 365-367, XP055138116, ISSN: 0887-6924, DOI: 10.1038/leu.2011.205 (73) Proprietor: Cellectis • H. TORIKAI ET AL: "A foundation for universal 75013 Paris (FR) T-cell based immunotherapy: T cells engineered to express a CD19-specific (72) Inventors: chimeric-antigen-receptor and eliminate • DUCHATEAU, Philippe expression of endogenous TCR", BLOOD, vol. 91210 Draveil (FR) 119, no. 24, 14 June 2012 (2012-06-14), pages • POIROT, Laurent 5697-5705, XP055071623, ISSN: 0006-4971, DOI: 75020 Paris (FR) 10.1182/blood-2012-01-405365 • M. SADELAIN ET AL: "The Basic Principles of (74) Representative: Zacco Denmark A/S Chimeric Antigen Receptor Design", CANCER Arne Jacobsens Allé 15 DISCOVERY, vol. 3, no. 4, 1 April 2013 2300 Copenhagen S (DK) (2013-04-01), pages388-398, XP055133523, ISSN: 2159-8274, DOI: 10.1158/2159-8290.CD-12-0548 (56) References cited: WO-A1-2013/074916 US-A1- 2013 315 884 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 3 105 317 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 3 105 317 B1 • CÉCILESCHIFFER MANNIOUI ET AL: "Treatment of B cells malignancies with anti-CD19 CAR+, TCR-, CD52- allogeneic T cells", JOURNAL FOR IMMUNOTHERAPY OF CANCER, BIOMED CENTRAL LTD, LONDON, UK, vol. 1, no. Suppl 1, 7 November 2013 (2013-11-07), page P34, XP021167243, ISSN: 2051-1426, DOI: 10.1186/2051-1426-1-S1-P34 2 EP 3 105 317 B1 Description Field of the invention 5 [0001] The present invention relates to methods of developing genetically engineered, preferably non-alloreactive, T- cells for immunotherapy, which are endowed with Chimeric Antigen Receptors targeting an antigen marker that is common to both the pathological cells and the immune cells (ex: CD38). [0002] The method comprises expressing a CAR directed against said antigen marker and inactivating the genes in the T-cells contributing to the presence of said antigen marker on the surface of said T-cells. This inactivation is typically 10 performed by using transgenes encoding RNA-guided endonucleases (ex: Cas9/CRISPR), meganucleases, Zinc-finger nucleases or TAL nucleases. The engineered T-cells direct their immune activity towards malignant, infected cells or defective immune cells, while avoiding their mutual destruction, auto-stimulation or aggregation. The invention opens the way to standard and affordable adoptive immunotherapy strategies using immune cells for treating cancer, infections and auto-immune diseases. 15 Background of the invention [0003] Adoptive immunotherapy, which involves the transfer of autologous antigen-specific immune cells generated ex vivo, is a promising strategy to treat viral infections and cancer. The T cells used for adoptive immunotherapy, for 20 instance, can be generated either by expansion of antigen-specific T-cells or redirection of T-cells through genetic engineering (Park, Rosenberg et al. 2011). [0004] Novel specificities in T-cells have been successfully generated through the genetic transfer of transgenic T- cell receptors or chimeric antigen receptors (CARs) (Jena, Dotti et al. 2010). CARs are synthetic receptors consisting of a targeting moiety that is associated with one or more signaling domains in a single fusion molecule. In general, the 25 binding moiety of a CAR consists of an antigen-binding domain of a single-chain antibody (scFv), comprising the light and variable fragments of a monoclonal antibody joined by a flexible linker. Binding moieties based on receptor or ligand domains have also been used successfully. The signaling domains for first generation CARs are derived from the cytoplasmic region of the CD3zeta or the Fc receptor gamma chains. First generation CARs have been shown to successfully redirect T cell cytotoxicity, however, they failed to provide prolonged expansion and anti-tumor activityin 30 vivo. Signaling domains from co-stimulatory molecules including CD28, OX-40 (CD134), and 4-1BB (CD137) have been added alone (second generation) or in combination (third generation) to enhance survival and increase proliferation of CAR modified T cells. CARs have successfully allowed T cells to be redirected against antigens expressed at the surface of tumor cells from various malignancies including lymphomas and solid tumors (Jena, Dotti et al. 2010). [0005] The current protocol for treatment of patients using adoptive immunotherapy is based on autologous cell transfer. 35 In this approach, T lymphocytes are recovered from patients, genetically modified or selected ex vivo, cultivated in vitro in order to amplify the number of cells if necessary and finally infused into the patient. In addition to lymphocyte infusion, the host may be manipulated in other ways that support the engraftment of the T cells or their participation in an immune response, for example pre-conditioning (with radiation or chemotherapy) and administration of lymphocyte growth factors (such as IL-2). Each patient receives an individually fabricated treatment, using the patient’s own lymphocytes (i.e. an 40 autologous therapy). Autologous therapies face substantial technical and logistic hurdles to practical application, their generation requires expensive dedicated facilities and expert personnel, they must be generated in a short time following a patient’s diagnosis, and in many cases, pretreatment of the patient has resulted in degraded immune function, such that the patient’s lymphocytes may be poorly functional and present in very low numbers. Because of these hurdles, each patient’s autologous cell preparation is effectively a new product, resulting in substantial variations in efficacy and 45 safety. [0006] Ideally, one would like to use a standardized therapy in which allogeneic therapeutic cells could be pre-man- ufactured, characterized in detail, and available for immediate administration to patients. By allogeneic it is meant that the cells are obtained from individuals belonging to the same species but are genetically dissimilar. However, the use of allogeneic cells presently has many drawbacks. In immune-competent hosts allogeneic cells are rapidly rejected, a 50 process termed host versus graft rejection (HvG), and this substantially limits the efficacy of the transferred cells. In immune-incompetent hosts, allogeneic cells are able to engraft, but their endogenous T-cell receptors (TCR) specificities may recognize the host tissue as foreign, resulting in graft versus host disease (GvHD), which can lead to serious tissue damage and death. [0007] In order to provide allogeneic T-cells, the inventors previously disclosed a method to genetically engineer T- 55 Cells, in which different effector genes, in particular those encoding T-cell receptors, were inactivated by using specific TAL-nucleases, better known under the trade mark TALEN™ (Cellectis, 8, rue de la Croix Jarry, 75013 PARIS). This method has proven to be highly efficiency in primary cells using RNA transfection as part of a platform allowing the mass production of allogeneic T-cells (WO 2013/176915; Torikai et al., Blood, 2012, 119(24):5697-705). 3 EP 3 105 317 B1 [0008] CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells (white blood cells),in particular T-cells, including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling. Structural information about this protein can be found in the UniProtKB/Swiss-Prot database under reference P28907.ln humans, the CD38 protein 5 is encoded by the CD38 gene which located on chromosome 4. CD38 is a multifunctional ectoenzyme that catalyzes the synthesis and hydrolysis of cyclic ADP-ribose (cADPR) from NAD+ to ADP-ribose. These reaction products are deemed essential for the regulation of intracellular Ca2+. Also, loss of CD38 function was associated with impaired immune responses and metabolic disturbances (Malavasi F., et al. (2008). "Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology". Physiol. Rev. 88(3): 841-86). 10 [0009] Mihara et al. (J limmunother, 2009, 32(7):737-743) discloses activated T cell mediating immunotherapy with a chimeric receptor against CD38 in B -cell non Hodgkin lymphoma.
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