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WO 2019/002633 Al 03 January 2019 (03.01.2019) W !P O PCT

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WO 2019/002633 Al 03 January 2019 (03.01.2019) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2019/002633 Al 03 January 2019 (03.01.2019) W !P O PCT (51) International Patent Classification: Published: A61K 39/00 (2006.01) A61P 35/00 (2006.01) — with international search report (Art. 21(3)) A61K 35/17 (2015.01) (21) International Application Number: PCT/EP2018/067857 (22) International Filing Date: 02 July 2018 (02.07.2018) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: PA201770542 30 June 2017 (30.06.2017) DK PCT/EP20 17/076798 19 October 2017 (19.10.2017) EP PCT/EP2018/053343 09 February 2018 (09.02.2018) EP (71) Applicant: CELLECTIS [FR/FR] ; 8 Rue de la Croix Jarry, 75013 Paris (FR). = (72) Inventors: SOURDIVE, David; 19, rue Louise Michel, = 92300 Levallois-Perret (FR). DUCLERT, Aymeric; 6 = ter rue Victorine, 94100 St Maur des Fosses (FR). SI- = MON, Mathieu; 76, Avenue Mozart, 75016 Paris (FR). = DUCHATEAU, Philippe; Bateau Fawen Quai des Dames, ≡ 91210 Draveil (FR). WILLIAMS, Alan Marc; 246 1, 8th = avenue, #2A, New York City, New York 10027 (US). ≡ POIROT, Laurant; 10 rue de la reunion, 75020 Paris (FR). ≡ (74) Agent: ZACCO DENMARK A S; Arne Jacobsens Alle = 15, 2300 K0benhavn S (DK). = (81) Designated States (unless otherwise indicated, for every ~ kind of national protection available): AE, AG, AL, AM, = AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, = CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, = DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, ≡ HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, = KR, KW,KZ, LA, LC, LK, LR, LS, LU, LY,MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, = OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, ≡ SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, = TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every = kind of regional protection available): ARIPO (BW, GH, = GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). © (54) Title: CELLULAR IMMUNOTHERAPY FOR REPETITIVE ADMINISTRATION (57) Abstract: The present invention provides composition kits and methods for treating cancer in a human by immunotherapy using successive doses of CAR-T cells with no or reduced anamnestic immune reaction in one individual (P). CELLU LAR IM M UNOTH ERAPY FO R REPETITIVE ADM INISTRATION FI ELD O F THE INVENTION The present invention relates t o a set of n pharmaceutical unit doses comprising engineered cells and a pharmaceutically acceptable vehicle, suitable for cellular immunotherapy, inducing no or reduced anamnestic response. BACKGROUND O F THE INVENTION Adoptive immunotherapy is one of the promising strategies t o treat diseases such as viral infections or cancer. The cells used for adoptive immunotherapy can be generated either by differentiation of immune cell progenitors, expansion of antigen-specific T-cells or redirection of T- cells or of differentiated immune cell progenitors through genetic engineering (Park, Rosenberg et al. 2011). For directing cells towards specific pathological cells, transgenic T-cell receptors (TCR) or chimeric antigen receptors (CARs) can be successfully expressed at the cell surface, even in the absence of endogenous TCR. These synthetic receptors comprise a targeting moiety that is associated with one or more signaling domains in a single fusion molecule or consists in several non-covalently linked transmembrane domains as described in (WO2014039523A1). In numerous studies, the binding moiety of a CAR can redirect the activity of the immune cells expressing it, towards a specific molecule, preferably expressed on a tumor or pathological cell. Thus, single-chain antibody (scFv), comprising the light and heavy variable fragments of a monoclonal antibody joined by a flexible linker can be very efficient. Binding moieties based on receptor or ligand domains have also been used successfully. Such extracellular domains are linked t o signaling domains initially derived from the cytoplasmic region of the CD28, CD3zeta, 4-1BB or from the Fc receptor gamma chains in CAR of first, second and third generations. Binding of CAR t o pathological cells results in signaling and triggers a cascade of events including degranulation, release of cytokines, and eventually leading t o the destruction of target cells. Thus, CARs allow cytotoxic T-cells t o be re-directed against specific antigens expressed at the surface of tumor cells including lymphomas (Jena, Dotti et al. 2010) and destruction of these target cells. The current protocol for the treatment of patients using adoptive immunotherapy is based on autologous cell transfer. Under this approach, T lymphocytes recovered from a given patient, are genetically modified or selected ex vivo, cultivated in vitro in order to amplify the number of cells and finally re-infused into the patient. Autologous transfer of engineered immune cells was reported to induce undesired immune reaction including cytokine storm, GVHD (that may be an autoimmune disease), or immune reaction against the edited molecules that sometimes comprised mouse antibody fragments ( Villa NY, Rahman MM, McFadden G, Cogle CR. Therapeutics for Graft -versus-Host Disease: From Conventional Therapies to Novel Virotherapeutic Strategies. Lamfers MLM, Chiocca EA, eds. Viruses. 2016;8(3):85. doi:10.3390/v8030085). In addition, autologous therapies face su bstantial 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 present in low numbers, may be poorly functional or even dysfunctional. Because of these hurdles, each patient's autologous cell preparation is effectively a new product, resulting in substantial variations in efficacy and safety. To answer the need of providing engineered cells that could be used in all patients with limited undesired immune reaction against the host, cells from healthy individuals engineered to destroy cancer cells may be used. However, T cells from one individual when transferred to another individual can be detrimental to the host resulting in graft versus host disease (GvHD) and leading t o potentially serious tissue damage and death. The molecular mechanisms responsible for acute or chronic GVHD have been at least partially identified. Recognition of MHC disparities between the donor and recipient through specific TCR(s) that can lead to T cells proliferation and t o the development of GvHD in recipients of allogeneic cells. To overcome this problem, new techniques of gene editing have been used to reduce the expression of TCR genes encoding the various subunits of the endogenous TCR (Domain-swapped T cell receptors improve the safety of TCR gene therapy. (Bethune MT, Gee MH, Bunse M, et al. Domain-swapped T cell receptors improve the safety of TCR gene therapy. Rath S, ed. eLife. 2016;5:el9095. doi:10.7554/eLife.l9095). Thus, so called "Allogeneic TCR KO therapeutic cells" or "off the shelve- ready to use- CART cells" have been engineered to be redirected against pathological cells, cancerous, or infected and to induce no or reduced GVHD. Infusion of such TCR-KO cells into patients significantly reduced GVHD or significantly reduces the risk of GVHD and increased survival in patients suffering refractory AML in at least two pediatric patients (Gray N, 2016. http://www. biopharmadive.com/news/cellectis-t-cell- therapy-clears-leukemia-in-second-baby/418862/). One problem met with allogeneic cell therapy or organ transplant, or even with autologous cell therapies or grafts expressing ectopic antigens, lies in a possible immunological reaction and rejection of grafted cells, tissues or organs (the "Graft") when an individual has been previously exposed to one or more antigen(s) present on the Graft (born by cells) and not tolerated by the immune system. In case of re exposure to said antigen, an "Anamnestic Response" is likely to reject efficiently and/or rapidly the Graft. Such situations are known to happen especially when the graft bears macromolecular features (e.g. proteins, sugars, lipids or combinations thereof) that are not present in the grafted individual (or not tolerated by its immune system). The case is observed when the grafts bear molecules, such as HLA alleles products, that are different from those of the individual if the individual has been exposed to, in the past. Graft rejection due to an anamnestic response that involves different compartments of the immune system. Thus, the rejected antigen(s) are recognized by antibodies and/or by specific receptors of T lymphocytes (TCRs). Yet it may be desirable t o perform two or more consecutive Grafts and to minimize anamnestic Responses (any immune response due to repeated exposure), especially for treating solid cancer. Thus, when using adoptive engineered T-cell immunotherapy t o target antigens born by cancer cells, it may be useful to make repeated and consecutive treatments targeting the same or different antigen of the same cancer marker. It may be also useful to make successive treatments targeting a different antigen in case of new, or relapse or even refractory cancer.
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