Biobank of cellular banks having specific homozygous HLA haplotypes and uses thereof for treating patients

Abstract

The present invention relates to a biobank comprising at least two cellular biobanks, wherein the cells of cellular biobank may be immune cells or hematopoietic stem and progenitor cells (HSPCs) or in vitro generated T cell progenitors, wherein the cells of each cellular bank have a specific homozygous human leucocyte antigen (HLA) haplotype. The present invention further relates to a method for selecting at least one cellular bank and to the use of a selected cellular bank as a medicament, in particular for treating immunodeficiency, immune disorders and / or diseases, lymphopenia or cancer and to reach a large number of patients.

Description

BIOBANK OF CELLULAR BANKS HAVING SPECIFIC HOMOZYGOUS HLA HAPLOTYPES AND USES THEREOF FOR TREATING PATIENTSFIELD OF INVENTION

[0001] The present invention relates to a biobank comprising cellular banks, preferably at least 2 different cellular banks, wherein the cells of each cellular bank have a specific homozygous HLA haplotype. The present invention further relates to a method for selecting a cellular bank from the biobank of the invention to be used for treating a subj ect and to the use of the selected cellular bank as a medicament, in particular for treating immunodeficiency, immune disorders, lymphopenia or cancer and reach a large number of patients.BACKGROUND OF INVENTION

[0002] The human leukocyte antigen (HLA) system refers to the major histocompatibility complex (MHC) in human. HLA molecules are cell surface glycoproteins encoded by genes present on the short arm chromosomes 6 (6p21). HLA genes are highly polymorphic, each person having one specific combination of two haplotypes for each HLA locus. The proteins encoded by HLA genes are also known as antigens. HLA system is essential for immune function, presenting endogenous and exogenous antigens to lymphocytes. HLA molecules thus play an important role in defense against diseases, against pathogens or against tumor cells through cell-mediated cytotoxic processes or through humoral immune response modulation as examples. They may also mediate autoimmune disease by presenting self-antigen (e.g., immune tolerance disruption) and may be the cause of graft rejection.

[0003] HLA molecules are divided in three classes: HLA class I (HLA-A, HLA-B, and HLA-C) and HLA class II (HLA-DP, HLA-DQ, and HLA-DR), and class III (not involved in adaptative immune response).

[0004] HLA class I molecules are expressed on the surface of almost all nucleated cells The molecules present endogenous peptides produced from digested proteins in the proteasome to CD8+ cytotoxic T cell receptors (TCR) ant killer cell immunoglobulin-like receptors (KIR).

[0005] HLA class II molecules are present on the surface of antigen-presenting cells (APC). These molecules display exogenous antigen peptides to CD4+ helper T cells receptors, inducing T cells stimulation. Activated CD4+ helper T cells then stimulate specific antigen antibodies produced by antibody-producing B cells.

[0006] HLA class III genes encode components of the complement system. These molecules do not have antigen presenting function.

[0007] HLA genes are one of the most polymorphic genes in human genome (more than 30.000 alleles uncovered to date). In the context of allogeneic transplant, the chance of having two individuals having a strict allelic matching is more than elusive even if the diversity is amply reduced due to the predominance of common and shared alleles across different population groups, promoting thus rejection of the donor tissue or cells by the recipient or promoting a Graft-versus-host disease (GvHD) in the case of hematopoietic stem cell transplant. Despite improvements in haploidentical transplantation, throughout the years, this procedure continues to associate with early and late complications, including infections, graft-versus-host disease, organ toxicity, among others.

[0008] Future directions have focused on innovative research on the basic biology of umbilical cord blood (UCB) cells, making the use of UCB units acceptable for more patients through promising therapeutic strategies. The optimal selection of cord blood units requires consideration of both quality of the unit, total nucleated cell (TNC) dose per kilogram (kg) of recipient body weight, and HLA match. Many clinical trials are in progress using cells derived from cryopreserved UCB units which include different subtypes such as T lymphocytes, mesenchymal stromal cells, NK (natural Killer) cells, expanded CD34+ cells, and cells derived from induced pluripotent stem cells altogether towards accelerating engraftment, immune reconstitution or for antitumoral activity. It has been described that the infusion of in vztro-derived human progenitor T -cells(ProTcell) provides a promising therapeutic strategy to supply patients with a new wave of T cell progenitors capable to accelerate the production of a mature lymphoid graft and polyclonal T cell repertoire which in turn may provide protection against severe viral and fungal infections and relapse of malignant diseases. Studies have shown that the infusion of an off-the-shelf expanded umbilical cord blood (UCB) cell product in addition to a conventional graft was safe and led to sustained myeloid recovery. Based on these encouraging results, prospective multicenter randomized trials utilizing this type of products have been conducted. In this context, cryopreserved UCB cells but also mobilized peripheral blood cells and iPS cells provide the ideal samples for the potential generation of off-the-shelf cellular therapy products. Selection criteria of samples based on HLA has not yet been described. Although the current trend for the use of “off-the- shelf’ cells is to bypass the histocompatibility barrier, the present invention aims to reduce the level of HLA disparity to improve further outcomes allogenic cell transplantation and outcomes of allogeneic cell therapy.

[0009] Thus, in this context the invention relates to a biobank comprising cellular banks (“off-the-shelf’ cellular banks), wherein said cellular banks have a specific homozygous HLA haplotype, to fit with a high number / a large proportion of patients and improve the outcome of allogenic cell transplantation or allogeneic cell therapy.SUMMARY

[0010] The present invention relates to an in vitro method for selecting at least one cellular bank to be administered to a subject from a biobank comprising at least two different cellular banks, each of the at least two cellular banks being different from each other and comprising T cell progenitors, wherein the T cell progenitors of a cellular bank have the same HLA homozygous haplotype, wherein said method comprises the following steps: a. determining the HLA haplotypes for HLA-B, and HLA-DR loci of the subject,b. comparing the HLA haplotypes determined at step a) with the HLA haplotypes of the cells of the cellular banks, and c. selecting at least one cellular bank based on said comparison, wherein the subject has (i) at least one allele in common with the cells of the selected cellular bank for at least one of the HLA-B and HLA-DR loci or (ii) a HLA-B leader sequence in common with the cells of the selected biobank.

[0011] In one embodiment, the in vitro method comprises the following steps: a. determining the HLA haplotypes for HLA-A, HLA-B and HLA-DR loci of the subject, b. comparing the HLA haplotypes determined at step a) with the HLA haplotypes of the cells of the cellular banks, and c. selecting at least one cellular bank based on said comparison, wherein the subject has (i) at least one allele in common with the cells of the selected cellular bank for at least two of the HLA-A, HLA-B and HLA-DR loci or (ii) a HLA-B leader sequence in common with the cells of the selected biobank and at least one allele in common with the cells of the selected cellular bank for at least one of the HLA-A, and HLA-DR loci.

[0012] In one embodiment, step a) of the in vitro method further comprises determining the HLA haplotype of the subject for the HLA-C locus, and at step c) at least one cellular bank is selected, wherein the subject has (i) at least one allele in common with the cells of the selected cellular bank for at least two of the HLA-B, HLA-C and HLA-DR loci or (ii) a HLA-B leader sequence in common with the cells of the selected biobank and at least one allele in common with the cells of the selected cellular bank for at least one of the HLA-C, and HLA-DR loci.

[0013] In one embodiment, step a) of the in vitro method further comprises determining the HLA haplotype of the subject for the HLA-C locus, and at step c) at least one cellular bank is selected, wherein the subject has at least one allele in common with the cells of the selected cellular bank for at least three of the HLA-A, HLA-B, HLA-C and HLA- DR loci or (ii) a HLA-B leader sequence in common with the cells of the selected biobankand at least one allele in common with the cells of the selected cellular bank for at least two of the HL A- A, HLA-C, and HLA-DR loci.

[0014] In one embodiment, the cells of the biobank are genetically modified to reduce or abolish the expression of HLA-A at the cell surface.

[0015] In one embodiment, at step c) of the in vitro method, a cellular bank is selected based on the comparison of HLA haplotypes of step b), and the subject has at least one allele in common with the cells of the selected cellular bank for each of the HLA loci determined at step a).

[0016] In one embodiment, at step c) of the in vitro method, a cellular bank is selected based on the comparison of HLA haplotypes of step b), and the subject has a HLA-B leader sequence in common with the cells of the selected biobank and has at least one allele in common with the cells of the selected cellular bank for each of the other HLA loci determined at step a).

[0017] In one embodiment, the cells of the selected cellular bank and the subject have zero, one, two, three, four or five HLA mismatches.

[0018] In one embodiment, the HLA-DR is HLA-DRA, HLA-DRB1, HLA-DRB3, HLA-DRB4 or HLA-DRB5, preferably HLA-DRB1.

[0019] The present invention further relates to a selected cellular bank comprising T cell progenitors, for use as a medicament, preferably for use in the treatment of immunodeficiency, immune disorders and / or diseases, lymphopenia or cancer in a subject in need thereof.

[0020] In one embodiment, the medicament is to be administrated to the subject in combination with: a. at least one other cellular bank, wherein said another cellular bank has the same homozygous HLA haplotype than the selected cellular bank, b. at least one other therapeutic substance, and / or c. at least one umbilical cord blood transplant or at least one mPB transplant.

[0021] The present invention also relates to a computer implemented method for selecting homozygous HLA haplotypes to prepare a biobank of at least two different cellular banks, wherein the selection of homozygous HLA haplotypes is estimated using the following formula: variable X = (HL A l, HLA 2, HLA n) corresponds to a choice of n HLA haplotypes; argmax stands for argument of the maxima and is well known from the skilled artisan;Coverage(X) corresponds to the coverage achieved by that choice and is obtained empirically on the database sample of patients;Frequency(X) corresponds to the product of the frequencies of each n donor’ s HLA, as obtained empirically on the database sample of donors.

[0022] The present invention also relates to a biobank comprising at least two different cellular banks, wherein said at least two cellular banks do not comprise alpha-beta T cells, wherein each cellular bank comprises cells from at least one donor and wherein the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HLA haplotypes:A*01-B*08-DRBl*03_A*01-B*08-DRBl*03,A*01-B*13-DRBl*07_A*01-B*13-DRBl*07,A*01-B*35-DRBl*l l_A*01-B*35-DRBl*l l,A*02-B*07-DRBl*01_A*02-B*07-DRBl*01,A*02-B*07-DRBl*04_A*02-B*07-DRBl*04,A*02-B*07-DRB 1 * 15_A*02-B*07-DRB 1*15,A*02-B* 15-DRB 1 *04_A*02-B* 15-DRB 1 *04,A*02-B* 18-DRB 1 *03_A*02-B* 18-DRB 1*03,A*02-B* 18- DRB 1 * 1 l_A*02-B* 18-DRB 1*11,A*02-B*35-DRBl*04_A*02-B*35-DRBl*04,A*02-B*35-DRB 1 * 1 l_A*02-B*35-DRB 1 * 11,A*02-B*44-DRBl*04_A*02-B*44-DRBl*04,A*02-B*44-DRBl*07_A*02-B*44-DRBl*07,A*02-B*44-DRB 1 * 13_A*02-B*44-DRB 1*13,A*02-B*51-DRB 1 *04_A*02-B*51-DRB 1 *04, A* 02-B * 51 -DRB 1 * 11 _A * 02-B * 51 -DRB 1 * 11 , A*02-B*51-DRBl*13_A*02-B*51-DRBl*13, A*03-B*07-DRBl*15_A*03-B*07-DRBl*15,A*03-B*14-DRBl*01_ A*03-B*14-DRBl*01,A*03-B*35-DRBl*01_ A*03-B*35-DRBl*01,A*03-B*35-DRBl*04_A*03-B*35-DRBl*04,A*l l-B*35-DRBl*01_ A*ll-B*35-DRBl*01,A*24-B*35-DRB1*11_A*24-B*35-DRB1*11, A*24-B*44-DRB 1 * 13_A*24-B*44-DRB 1*13, A* 24-B * 51 -DRB 1 * 11 _A * 24-B * 51 -DRB 1 * 11 , A*29-B*44-DRB 1 *07_A*29-B *44-DRB 1 *07, or A*68-B*53-DRB1*13_A*68-B*53-DRB1*13.

[0023] In one embodiment, the cells of at least one cellular bank have one of the following homozygous HL A haplotypes:A*01-B*13-DRBl*07_A*01-B*13-DRBl*07,A*01-B*35-DRBl*l l_ A*01-B*35-DRBl*l l,A*02-B*07-DRBl*04_A*02-B*07-DRBl*04, A*02-B* 18-DRB 1 *03_A*02-B* 18-DRB 1*03, A*02-B* 18- DRB 1 * 1 l_A*02-B* 18-DRB 1*11, A*03-B*14-DRBl*01_A*03-B*14-DRBl*01, A*03-B*35-DRBl*04_A*03-B*35-DRBl*04, A*24-B*44-DRB 1 * 13_A*24-B*44-DRB 1*13,A*24-B*51-DRB1*11_A*24-B*51-DRB1*11, orA*68-B*53-DRB1*13_A*68-B*53-DRB1*13.

[0024] In one embodiment, the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HL A haplotypes:A*01-B*08-C*07-DRBl*03_A*01-B*08-C*07-DRBl*03, A*01-B*35-C*04-DRBl*04_A*01-B*35-C*04-DRBl*04, A*01-B*35-C*04-DRBl*l l_ A*01-B*35-C*04-DRBl*l l,A*03-B*35-C*04-DRB 1 * 1 l_A*03-B*35-C*04-DRB 1*11, A*03-B*52-C* 12-DRB 1 * 15_A*03-B*52-C* 12-DRB 1*15, A*l l-B*35-C*04-DRBl*01_A*l l-B*35-C*04-DRBl*01, A*l l-B*35-C*04-DRBl*04_A*l l-B*35-C*04-DRBl*04, A*23-B*44-C*04-DRBl*07_A*23-B*44-C*04-DRBl*07, A*24-B*35-C*O4-DRB1*O4_A*24-B*35-C*O4-DRB1*O4, A*24-B*35-C*04-DRB 1 * 1 l_A*24-B*35-C*04-DRB 1*11, A*24-B*44-C*07-DRB 1 * 15_A*24-B*44-C*07-DRB 1*15, A*24-B*51-C*15-DRB1*11_A*24-B*51-C*15-DRB1*11, A*24-B*51-C*15-DRB1*13_A*24-B*51-C*15-DRB1*13, A*25-B* 18-C* 12-DRB 1 * 15_A*25-B* 18-C* 12-DRB 1*15, A*29-B*44-C* 16-DRB 1 *07_A*29-B*44-C* 16-DRB 1 *07, A*29-B*44-C* 16-DRB 1 * 11_A*29-B*44-C* 16-DRB 1*11, A*30-B* 13-C*06-DRB 1 *07_A*30-B* 13-C*06-DRB 1 *07, A*30-B* 18-C*05-DRB 1 *03_A*30-B* 18-C*05-DRB 1 *03, or A*68-B*53-C*04-DRB 1 * 13_ A*68-B*53-C*04-DRB 1*13.

[0025] In one embodiment, the cells comprised in the cellular bank comprise or consist of immune cells, preferably comprises or consists of cells enriched in lymphoid progenitor cells, and more preferably comprises or consists of T cell progenitors.

[0026] In one embodiment, the cells comprised in the cellular bank are in vitro generated T cell progenitors obtained by culturing CD34+ cells in a medium comprising fibronectin, an immobilized Notch ligand, TNF-alpha and / or an antagonist of the Arylhydrocarbon / Dioxin receptor, in particular StemRegenin 1 (SRI), and at least 3, preferably 4 cytokines selected from the group consisting of human SCF, human Flt3-L, human TPO and human IL-7.

[0027] In one embodiment, the cells comprised in the cellular bank contain a sequence of encoding a Chimeric Antigen Receptor (CAR) and / or an exogenous T cells receptor (TCR).

[0028] In one embodiment, the cells comprised in the cellular bank are genetically modified by a viral vector, a nucleic acid fragment, a plasmid or plasmidic RNA or DNA sequences, a system of gene editing, a system of base editing, a system of prime- editing and / or wherein the cells comprised in the cellular bank are epigenetically modified.

[0029] In one embodiment, the biobank of the in vitro method for selecting at least one cellular bank to be administered to a subject is the biobank described in the present invention.

[0030] The present invention relates to a biobank comprising at least two cellular banks, wherein said cellular banks do not comprise alpha-beta T cells, wherein each cellular bank comprises cells from at least one donor and wherein the cells of each cellular bank have one of the following homozygous HLA haplotypes:A*01-B*08-DRBl*03_A*01-B*08-DRBl*03, A*01-B*13-DRBl*07_A*01-B*13-DRBl*07, A*01-B*35-DRBl*l l_A*01-B*35-DRBl*l l, A*02-B*07-DRBl*01_ A*02-B*07-DRBl*01, A*02-B*07-DRB 1 *04_A*02-B*07-DRB 1 *04, A*02-B *07-DRB 1 * 15_A*02-B*07-DRB 1*15, A*02-B * 15-DRB 1 *04_A*02-B* 15-DRB 1 *04, A*02-B * 18-DRB 1 *03_A*02-B* 18-DRB 1*03, A*02-B *18- DRB1*11_A*O2-B*18-DRB 1*11, A*02-B *35-DRB l*04_A*02-B *35-DRB 1*04, A*02-B*35-DRBl*l l_A*02-B*35-DRBl*l l, A*02-B*44-DRB 1 *04_A*02-B*44-DRB 1 *04, A*02-B*44-DRB 1 *07_A*02-B*44-DRB 1 *07, A*02-B *44-DRB 1 * 13_A*02-B *44-DRB 1*13, A*02-B*51-DRB 1 *04_A*02-B*51-DRB 1 *04, A*O2-B*51-DRB1*11_ A*O2-B*51-DRB1*11, A*02-B*51-DRBl*13_A*02-B*51-DRBl*13, A*03-B*07-DRB 1 * 15_A*03-B*07-DRB 1*15, A*03-B*14-DRBl*01_A*03-B*14-DRBl*01,A*03-B*35-DRBl*01_A*03-B*35-DRBl*01,A*03-B*35-DRBl*04_A*03-B*35-DRBl*04, A*1 l-B*35-DRBl*01_A*l l-B*35-DRBl*01, A*24-B*35-DRB1*11_A*24-B*35-DRB1*11, A*24-B *44-DRB 1 * 13_A*24-B *44-DRB 1*13, A*24-B*51-DRB1*11_A*24-B*51-DRB1*11, A*29-B *44-DRB 1 *07_A*29-B*44-DRB 1 *07, A*68-B*53-DRB1*13_A*68-B*53-DRB1*13.

[0031] In one embodiment, the cells of each cellular bank further have one of the following homozygous HL A haplotypes:A*01-B*08-C*07-DRBl*03_A*01-B*08-C*07-DRBl*03, A*01-B*35-C*04-DRBl*04_A*01-B*35-C*04-DRBl*04, A*01-B*35-C*04-DRBl*l l_A*01-B*35-C*04-DRBl*l 1, A*01-B*57-C*06-DRBl*07_A*01-B*57-C*06-DRBl*07, A*02-B*07-C*07-DRBl*01_ A*02-B*07-C*07-DRBl*01, A*02-B*07-C*07-DRBl*04_A*02-B*07-C*07-DRBl*04, A*02-B*07-C*07-DRBl-ll_ A*02-B*07-C*07-DRBl-ll, A*02-B*07-C*07-DRB 1 * 13_A*02-B*07-C*07-DRB 1*13, A-02-B*07-C*07-DRB 1 * 15_A-02-B*07-C*07-DRB 1*15, A*02-B*08-C*07-DRBl*03_A*02-B*08-C*07-DRBl*03, A*02-B* 13-C*06-DRB 1 *07_A*02-B* 13-C*06-DRB 1 *07, A*02-B*14-C*08-DRBl*01_A*02-B*14-C*08-DRBl*01, A*02-B*15-C*03-DRBl*04_A*02-B*15-C*03-DRBl*04, A*02-B*15-C*03-DRBl*13_A*02-B*15-C*03-DRBl*13, A*02-B*18-C*05-DRBl*03_A*02-B*18-C*05-DRBl*03, A*02-B * 18-C*07-DRB 1 * 1 l_A*02-B* 18-C*07-DRB 1*11, A*02-B*27-C*01-DRBl*01_A*02-B*27-C*01-DRBl*01, A*02-B*27-C*02-DRBl*04_A*02-B*27-C*02-DRBl*04, A*02-B*35-C*04-DRBl*04_A*02-B*35-C*04-DRBl*04, A*O2-B*35-C*O4-DRB1*O7_A*O2-B*35-C*O4-DRB1*O7, A*O2-B*35-C*O4-DRB1*11_A*O2-B*35-C*O4-DRB1*11,

[0032] In one embodiment, the cells comprised in the at least one cellular bank are immune cells.

[0033] In one embodiment, the cells comprised in at least one cellular bank are cells enriched in lymphoid progenitor cells.

[0034] In one embodiment, the cells comprised in the at least one cellular bank are T cell progenitors.

[0035] In one embodiment, the cells comprised in the at least one cellular bank are:(a) progenitors of natural killers (NK) cells and / or NK cells, or(b) progenitors of innate lymphoid cells (ILCs) and / or ILCs, or(c) progenitors of dendritic cells (DCs) and / or DCs.

[0036] In one embodiment, the cells comprised in the at least one cellular bank are in vitro generated cells obtained by the following culture protocol; culturing CD34+ cells in a medium comprising an immobilized Notch ligand, TNF-alpha and / or an antagonist of the Aryl hydrocarbon / Dioxin receptor, in particular StemRegenin 1 (SRI).

[0037] In one embodiment, the cells comprised in the at least one cellular bank are Hematopoietic Stem / Progenitor cells (HSPCs), preferably CD34+ or CD133+ HSPCs.

[0038] In one embodiment, the cells comprised in the at least one cellular bank contain the sequence of a Chimeric Antigen Receptor (CAR) and / or a genetically modified T cells receptor (TCR).

[0039] In one embodiment, the cells comprised in the at least one cellular bank are genetically modified by a viral vector, a nucleic acid fragment, a plasmid or plasmidic RNA or DNA sequences, a system of gene editing, a system of base editing, a system of prime- editing and / or wherein the cells comprised in the at least one cellular bank are epigenetically modified.

[0040] In one embodiment, the cells comprised in the at least one cellular bank are genetically modified to:a) promote their drugs resistance, preferably to anti-inflammatory drugs and more preferably to glucocorticoid, and / or b) decrease their sensitivity to some antibodies, and / or c) escape the alloreactivity of at least one mature cell population from the recipient.

[0041] In one embodiment, the cells comprised in the at least one cellular bank are obtained from:(a) UCB (umbilical cord blood) HSPCs, or(b) mPB (mobilized peripheral blood from adult donors) HSPCs, or(c) iPSC- derived HSPCs (induced pluripotent stem cells), or(d) bone marrow HSPCs.

[0042] In one embodiment, the cells comprised in the at least one cellular bank are a mix of at least two UCB HSPC samples from different donors.

[0043] The present invention further relates to a method for selecting at least one cellular bank to be administered to a subject, preferably to a subject in need of a treatment, comprising selecting at least one cellular bank of interest among the cellular banks of the biobank, wherein the cells of the cellular bank of interest contain:(a) only HLA alleles that are found in the subject (i.e., 0 mismatch), or(b) one, two, three or four HLA alleles that are not found in the subject (i.e., 1, 2,3 or 4 mismatches), preferably mismatches for a class 1 HLA alleles.

[0044] In one embodiment, the at least one cellular bank of interest presents a genetic polymorphism associated to better thymic engraftment and / or better lymphoid differentiation.

[0045] In one embodiment, the method is a computer implemented method.

[0046] The present invention also relates to a selected cellular bank, for use as a medicament in the treatment of immunodeficiency, immune disorders, lymphopenia or cancer for a subject in need thereof.

[0047] In one embodiment, the medicament is to be administrated to the subject in combination with at least one another cellular bank, wherein said another cellular bank has the same homozygous HLA haplotype than the selected cellular bank.

[0048] In one embodiment, the medicament is to be administrated to the subject further in combination with at least one another therapeutic substance.

[0049] In one embodiment, the medicament is to be administrated to the subject in combination with at least one umbilical cord blood transplant or at least one mPB transplant.DEFINITIONS

[0050] In the present invention, the following terms have the following meanings:

[0051] The term “About” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or in some instances ±10%, or in some instances ±5%, or in some instances ±1%, or in some instances ±0.1% from the specified value, as such variations are appropriate to perform the disclose method.

[0052] The term “Allele” refers to a variant form of one gene. Said variant form are located at the same locus on a chromosome. Each human subject possesses two identical alleles (homozygous) of one gene or two different alleles of one gene (heterozygous) at each genetic locus (one per chromosome).

[0053] The term “biobank” refers to a collection of biological data, cell samples or tissue samples. In the present invention the term “biobank” refers to a collection of at least two cellular banks, that do not comprise alpha-beta T cells and possess a specific homozygous HLA haplotype, as described herein. Preferably, a biobank comprises at least two different cellular banks, physically isolated from each other.

[0054] The term “cellular bank” refers to a pool of cells, wherein all the cells of the pool have the same haplotype for defined HLA loci. A cellular bank comprises several doses of injectable cells. In one embodiment, all the cells of a cellular bank are of the same type (e.g., T cell progenitors) and / or of the same origin.

[0055] The term “Haplotype” refers to a set of loci (e.g. HLA- A, B, DRB1) with a group of alleles per chromatid which are inherited together from a single parent. As used herein, the term “haplotype” refers to a group of HLA alleles. Each individual has thus two haplotypes for each group of alleles.

[0056] The term “Mismatch” refers to an allele that differs between a cell of a cellular bank of the invention and a patient or subject to be treated. In one embodiment, mismatches are counted according to an asymmetric count, wherein only HLA alleles of the cells of the cellular bank that are not found in the patient or subject are taken into account

[0057] The term “derived from” refers to a cell obtained by the differentiation of another cell, resulting from the capacity of a cell to differentiate in at least one lineage.

[0058] The term “hematopoietic stem cell (HSC)” refers to stem cells giving rise to all types of differentiated blood cells. HSCs have the capacity of self-renewal or the capacity of differentiation into committed progenitor cells, such as, for example, myeloid progenitor cells or lymphoid progenitor cells. HSCs used in transplantation may be derived from bone marrow, peripheral blood, or umbilical cord blood, and may be used for treating a subject in need thereof, such as, for example, a subject with blood or bone marrow cancer (including, without limitation, multiple myeloma or leukemia).

[0059] The term “Hematopoietic Stem / Progenitor cell (HSPC)” refers to a pool of stem cells and committed progenitor cells having the capacity to differentiate into blood and immune cells. HSCs or HSPCs can be positive for at least one specific marker, including, without limitation, CD34, CD45, CD43, CD45RO, CD45RA, CD59, CD90, CD190, CD117, CD133, CD166, HLA DR, or a combination thereof. Preferably, HSPCs are CD34+ cells or CD133+ cells.

[0060] The term “homozygous” refers to a cell or a subject having, for a specific gene or group of genes, the same allelic versions on both chromosomes (from each biological parent). In the context of the invention, a cell or subject is defined as having a homozygous haplotype when said cell or subject has two identical alleles of specific HLA genes, such as, for example, identical alleles for HLA- A, B and DRB1 or identical alleles for HLA- A, B, C and DRB 1.

[0061] The term “Subject” (or individual) refers to an animal, including a human. In the sense of the present invention, a subject may be a patient, ie., a person receiving medical attention, undergoing or having underwent a medical treatment, or monitored for the development of a disease. In the context of the present invention, the subject may be a transplanted subject, preferably that received a hematopoietic stem cell transplantation.

[0062] The term “Therapeutically effective amount” refers to an amount or number of cells or of the composition as described herein, effective to achieve a particular biological result. For example, the terms “therapeutically effective amount” may refer to a level or amount of a composition or a number of cells that is aimed at, without causing significant negative or adverse side effects to the target, (1) delaying or preventing the onset of the targeted disease or condition; (2) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of the targeted disease or condition; (3) bringing about ameliorations of the symptoms of the targeted disease or condition; (4) reducing the severity or incidence of the targeted disease or condition; or (5) curing the targeted disease or condition. A therapeutically effective amount may be administered prior to the onset of the targeted disease or condition, for a prophylactic or preventive action. Alternatively, or additionally, the therapeutically effective amount may be administered after initiation of the targeted disease or condition, for a therapeutic action.

[0063] The term “Treating” refers to therapeutic treatment, to prophylactic or preventative measures (wherein the object is to prevent or slow down (lessen) the targeted disease or condition) or to both therapeutic treatment and prophylactic or preventive measures. Those in need of treatment include those already with the condition as well as those prone to have the condition or those in whom the condition is to be prevented. A subject is successfully “treated” for a disease or condition if, after receiving atherapeutically effective amount of cells or compositions as described herein, the subject shows observable and / or measurable improvement in one or more of the following: reduction in the number of pathogenic cells; reduction in the percent of total cells that are pathogenic; relief to some extent of one or more of the symptoms associated with the specific condition; reduced morbidity and mortality, and / or improvement in quality of life issues. The above parameters for assessing successful treatment and improvement in the condition are readily measurable by routine procedures familiar to a physician.

[0064] The term Transfection” or “transduction” refers to a process by which an exogenous nucleic acid is transferred or introduced into the host cell. A “transfected” or “transduced” cell is one which has been transfected, transformed or transduced with an exogenous nucleic acid, and includes the primary cell and its progeny.DETAILED DESCRIPTION

[0065] The invention relates to an in vitro method for selecting at least one cellular bank to be administered to a subject from a biobank, preferably wherein the subject is in need of a treatment. The selection of the cellular bank of interest is based on HLA haplotypes typing, as described herein. Without willing to be bound to any theory, the Applicant suggests that using the method of selection described in the invention allows the treatment of a large number of patients. In addition, the Applicant suggests that using the method of selection described in the invention allows to reduce immunosuppressive treatment of patients, in particular immunosuppressive treatment to prevent GVHD or graft rejection.

[0066] In one embodiment, the patient is a transplanted patient, for example a patient that received a hematopoietic stem cell transplantation, and may thus be referred to as “the recipient”. In one embodiment, the patient is not a transplanted patient, in particular the patient did not receive a hematopoietic stem cell transplantation. The patient may have an immunodeficiency, an immune disorder or disease, a lymphopenia or a cancer. The patient may be immunocompromised by exposure to radiations or to compounds, such as, for example, chemotherapies.

[0067] In one embodiment, the biobank comprises at least two different cellular banks, each of the at least two cellular banks being different from each other, wherein the cells of a cellular bank have the same HLA homozygous haplotype.

[0068] In one embodiment, the biobank comprises at least two different cellular banks, each of the at least two cellular banks being different from each other and comprising T cell progenitors, wherein the T cell progenitors of a cellular bank have the same HLA homozygous haplotype.

[0069] In one embodiment, the in vitro method comprises the following steps: a. determining the HLA haplotypes for HLA-B, and HLA-DR loci of the subject, b. comparing the HLA haplotypes determined at step a) with the HLA haplotypes of the cells of the cellular banks, and c. selecting at least one cellular bank based on said comparison, wherein the subject has at least one allele in common with the cells of the selected cellular bank for at least one of the HLA-B and HLA-DR loci, preferably wherein the subject has at least one allele in common with the cells of the selected cellular bank for each of the HLA-B and HLA-DR loci.

[0070] In one embodiment, the in vitro method comprises the following steps: a. determining the HLA haplotypes for HLA-A, HLA-B and HLA-DR loci of the subject, b. comparing the HLA haplotypes determined at step a) with the HLA haplotypes of the cells of the cellular banks, and c. selecting at least one cellular bank based on said comparison, wherein the subject has at least one allele in common with the cells of the selected cellular bank for at least two of the HLA-A, HLA-B and HLA-DR loci, preferably wherein the subject has at least one allele in common with the cells of the selected cellular bank for each of the HLA-A, HLA-B and HLA-DR loci.

[0071] In one embodiment, step a) of the in vitro method for selecting at least one cellular bank further comprises determining the HLA haplotype of the subject for the HLA-C locus.

[0072] In one embodiment, the in vitro method comprises the following steps: a. determining the HLA haplotypes for HLA-B, HLA-C and HLA-DR loci of the subject, b. comparing the HLA haplotypes determined at step a) with the HLA haplotypes of the cells of the cellular banks, and c. selecting at least one cellular bank based on said comparison, wherein the subject has at least one allele in common with the cells of the selected cellular bank for at least two of the HLA-B, HLA-C and HLA-DR loci, preferably wherein the subject has at least one allele in common with the cells of the selected cellular bank for each of the HLA-B, HLA-C and HLA-DR loci.

[0073] In one embodiment, the in vitro method comprises the following steps: a. determining the HLA haplotypes for HLA-A, HLA-B, HLA-C and HLA- DR loci of the subject, b. comparing the HLA haplotypes determined at step a) with the HLA haplotypes of the cells of the cellular banks, and c. selecting at least one cellular bank based on said comparison, wherein the subject has at least one allele in common with the cells of the selected cellular bank for at least three of the HLA-A, HLA-B, HLA-C and HLA- DR loci, preferably wherein the subject has at least one allele in common with the cells of the selected cellular bank for each of the HLA-A, HLA- B, HLA-C and HLA-DR loci.

[0074] In one embodiment, at step c), a cellular bank is selected based on the comparison of HLA haplotypes of step b), wherein the subject has at least one allele in common with the cells of the selected cellular bank for each of the HLA loci determined at step a).

[0075] In one embodiment, the method comprises a first step of determining the HLA haplotype of the subject for at least two HLA loci including HLA-B, and a cellular bank is selected based on the comparison of said HLA haplotypes determined in the subject, wherein the subject has a HLA-B leader sequence in common with the cells of the selected biobank. The term “HLA-B leader” refers to a HLA-B leader sequence encoding methionine (M) or threonine (T) at position 2 and resulting to different genotypes, named TT, MT, or MM genotypes.

[0076] In one embodiment, the in vitro method comprises the following steps: a. determining the HLA haplotypes for HLA-B, and HL A-DR loci of the subj ect, b. comparing the HLA haplotypes determined at step a) with the HLA haplotypes of the cells of the cellular banks, and c. selecting at least one cellular bank based on said comparison, wherein the subject has a HLA-B leader sequence in common with the cells of the selected biobank, preferably wherein the subject has a HLA-B leader sequence and at least one allele of the HLA-DR locus in common with the cells of the selected biobank.

[0077] In one embodiment, the in vitro method comprises the following steps: a. determining the HLA haplotypes for HLA-A, HLA-B and HLA-DR loci of the subject, b. comparing the HLA haplotypes determined at step a) with the HLA haplotypes of the cells of the cellular banks, and c. selecting at least one cellular bank based on said comparison, wherein the subject has a HLA-B leader sequence in common with the cells of the selected biobank and at least one allele in common with the cells of the selected cellular bank for at least one of the HLA-A, and HLA-DR loci, preferably wherein the subject has a HLA-B leader sequence and at least one allele of each of the HLA-A and HLA-DR loci in common with the cells of the selected biobank.

[0078] In one embodiment, the in vitro method comprises the following steps: a. determining the HLA haplotypes for HLA-B, HLA-C, and HLA-DR loci of the subject,b. comparing the HL A haplotypes determined at step a) with the HL A haplotypes of the cells of the cellular banks, and c. selecting at least one cellular bank based on said comparison, wherein the subject has a HLA-B leader sequence in common with the cells of the selected biobank and at least one allele in common with the cells of the selected cellular bank for at least one of the HLA-C, and HLA-DR loci, preferably wherein the subject has a HLA-B leader sequence and at least one allele of each of the HLA-C and HLA-DR loci in common with the cells of the selected biobank.

[0079] In one embodiment, the in vitro method comprises the following steps: a. determining the HLA haplotypes for HLA-A, HLA-B, HLA-C and HLA-DR loci of the subject, b. comparing the HLA haplotypes determined at step a) with the HLA haplotypes of the cells of the cellular banks, and c. selecting at least one cellular bank based on said comparison, wherein the subject has a HLA-B leader sequence in common with the cells of the selected biobank and at least one allele in common with the cells of the selected cellular bank for at least two of the HLA-A, HLA-C, and HLA-DR loci, preferably wherein the subject has a HLA-B leader sequence and at least one allele of each of the HLA-A, HLA-C and HLA-DR loci in common with the cells of the selected biobank.

[0080] In one embodiment, the cells of the biobank are genetically modified to reduce or abolish (for example through knock out) the expression of HLA-A at the cell surface. Techniques to reduce or abolish (for example through knock out) the expression of markers or a receptor at the cell surface are well known and described in the art and may be based, for example, on a system of gene editing as described herein.

[0081] In one embodiment, the HLA-DR is HLA-DRA, HLA-DRB1, HLA-DRB3, HLA-DRB4 or HLA-DRB5 locus, preferably HLA-DRB1.

[0082] In one embodiment, the biobank is the biobank as described herein. In one embodiment, the cells of the cellular banks have a HLA haplotype selected in the lists described herein.

[0083] The present invention further relates to a method for selecting at least one cellular bank to be administered to a subject, preferably to a subject in need of a treatment, comprising selecting at least one cellular bank of interest among the cellular banks of the biobank as described herein, wherein the cells of the cellular bank of interest contain:(a) only HLA alleles that are found in the subject (i.e., 0 mismatch), or(b) one, two, three or four HLA alleles that are not found in the subject (i.e., 1, 2, 3 or 4 mismatches).

[0084] In one embodiment, the cells of the selected cellular bank and the subject have zero, one, two, three, four or five mismatches.

[0085] In one embodiment, the method used to count mismatches is an Asymmetric count. With the asymmetric count, the term “mismatch” refers to the number of HLA alleles of the donor that are not found in the patient. For example, a homozygous donor A1-B1-DRB1 A1-B1-DRB1 would be considered as fully compatible with a patient Al- B1-DRB1 A2-B2-DRB2 when an asymmetric count is used, because all HLA alleles of the donor are present in the patient. On the contrary, a heterozygous A1-B3-DRB1 A2- B1-DRB4 donor would be considered as having 1 mismatch with a patient A1-B3- DRB1 A2-B1-DRB1 using an asymmetric count, because the allele DRB4 is not present in the patient.

[0086] In one embodiment, the cells of the selected cellular bank have a homozygous HLA haplotype identical to the homozygous HLA haplotype of the subject to be treated.

[0087] In one embodiment, the cells of the selected cellular bank have a homozygous HLA haplotype that is not identical to the HLA haplotypes of the subject to be treated, but all HLA alleles of the donor are found in the patient. In this case, the subject may have at least one allele in common with the cells of the selected cellular bank for each of the HLA-A, HLA-B and HLA-DR loci, or with each of the HLA-A, HLA-B, HLA-C and HLA-DR loci.

[0088] In one embodiment, the subject may have at least one allele in common with the cells of the selected cellular bank for at least one of the HLA-B and HLA-DR loci, preferably with at least two of the HLA-B, HLA-C and HLA-DR loci.

[0089] In one embodiment, the subject may have at least one allele in common with the cells of the selected cellular bank for at least two of the HLA-A, HLA-B and HLA-DR loci, preferably with at least three of the HLA-A, HLA-B, HLA-C and HLA-DR loci.

[0090] In one embodiment, the cells of the cellular bank are T cell progenitors. T cell progenitors will be subjected to positive and negative selections in the thymus after transplantation.

[0091] In one embodiment, the cells of the selected cellular bank and the subject have one HLA mismatch. In one embodiment, the cells of the selected cellular bank and the subject have two HLA mismatches. In one embodiment, the cells of the selected cellular bank and the subject have three HLA mismatches. In one embodiment, the cells of the selected cellular bank and the subject have four HLA mismatches. In one embodiment, the cells of the selected cellular bank and the subject have five HLA mismatches. The mismatches may be on one haplotype or on both.

[0092] In one embodiment, the selected cellular bank is further selected because cells present a genetic polymorphism associated to better thymic engraftment in comparison with another polymorphism. In one embodiment, the at least one cellular bank of interest is selected because cells present a genetic polymorphism associated to better lymphoid differentiation in comparison with another polymorphism. In one embodiment, the at least one cellular bank of interest is selected because cells present a genetic polymorphism associated to better thymic engraftment in comparison with another polymorphism and / or better lymphoid differentiation.

[0093] The present invention further relates to a method for preparing a biobank comprising at least two different cellular banks, each of the at least two cellular banks being different from each other, wherein the cells of a cellular bank have the same HLA homozygous haplotype.

[0094] In one embodiment, the cells of the at least two cellular banks are T cell progenitors.

[0095] In one embodiment, the HLA homozygous haplotypes of the cellular bank to be included in the biobank are selected based on the coverage and frequency of each homozygous haplotypes in a population of subjects.

[0096] In one embodiment, the homozygous HLA haplotypes are chosen among all haplotypes taking into account two criteria: the coverage and the frequency. The term “coverage” refers to the percentage of patients in a population of subject that are able to receive cells comprised in at least one cellular bank with a sufficient level of HLA compatibility. The term ‘sufficient level of HLA compatibility” refers to an evaluation of the degree of compatibility between a patient and a donor based on the number of mismatches (in particular determined using an asymmetric count) between the HLA haplotype of the cells of a cellular bank and the patient’s HLA haplotype. The term “frequency” refers to the percentage of each haplotype found in a natural population and / or in any cellular bank. Without willing to be bound to any theory, the Applicants hypothesized that the fact of taking into account both the coverage and the frequency of HLA haplotypes makes it possible to treat a large number of patients and to found enough donors or cells for the transplantation of allogeneic T cells, such as, for example, for allogeneic CAR-T cells therapy.

[0097] In one embodiment, the invention also relates to a computer implemented method for selecting homozygous HLA haplotypes to prepare a biobank of at least two different cellular banks, wherein the selection of homozygous HLA haplotypes is based on the use of the following formula:X* = argmax_(X in {all possible choices}) Coverage(X) x Frequency(X), wherein variable X = (HL A l, HLA 2, ..., HLA n) corresponds to a choice of n HLA haplotypes (e.g., cord blood haplotypes); argmax stands for argument of the maxima and is well known from the skilled artisan;Coverage(X) corresponds to the coverage achieved by that choice and is obtained empirically on the database sample of patients;Frequency(X) corresponds to the product of the frequencies of each n donor’ s HLA, as obtained empirically on the database sample of donors.

[0098] The present invention also relates to a biobank comprising or consisting of at least two cellular banks (preferably at least two different cellular banks), preferably wherein said at least two cellular banks do not comprise alpha-beta T cells, wherein each cellular bank comprises cells from at least one donor and wherein the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HLA haplotypes:A*01-B*08-DRBl*03_A*01-B*08-DRBl*03, A*01-B*13-DRBl*07_A*01-B*13-DRBl*07, A*01-B*35-DRBl*l l_A*01-B*35-DRBl*l l, A*02-B*07-DRBl*01_A*02-B*07-DRBl*01, A*02-B*07-DRBl*04_A*02-B*07-DRBl*04, A*02-B*07-DRB 1 * 15_A*02-B*07-DRB 1*15, A*02-B* 15-DRB 1 *04_A*02-B* 15-DRB 1 *04, A*02-B* 18-DRB 1 *03_A*02-B* 18-DRB 1*03, A*02-B* 18- DRB 1 * 1 l_A*02-B* 18-DRB 1*11, A*02-B*35-DRBl*04_A*02-B*35-DRBl*04, A*02-B*35-DRB 1 * 1 l_A*02-B*35-DRB 1 * 11, A*02-B*44-DRBl*04_A*02-B*44-DRBl*04, A*02-B*44-DRBl*07_A*02-B*44-DRBl*07, A*02-B*44-DRB 1 * 13_A*02-B*44-DRB 1*13, A*02-B*51-DRB 1 *04_A*02-B*51-DRB 1 *04, A* 02-B * 51 -DRB 1 * 11 _A * 02-B * 51 -DRB 1 * 11 , A*02-B*51-DRBl*13_A*02-B*51-DRBl*13, A*03-B*07-DRBl*15_A*03-B*07-DRBl*15, A*03-B*14-DRBl*01_A*03-B*14-DRBl*01,A*03-B*35-DRBl*01_ A*03-B*35-DRBl*01, A*03-B*35-DRBl*04_A*03-B*35-DRBl*04,A*l l-B*35-DRBl*01_A*l l-B*35-DRBl*01, A*24-B*35-DRB1*11_A*24-B*35-DRB1*11, A*24-B*44-DRB 1 * 13_A*24-B*44-DRB 1*13, A* 24-B * 51 -DRB 1 * 11 _A * 24-B * 51 -DRB 1 * 11 , A*29-B*44-DRB 1 *07_A*29-B *44-DRB 1 *07, or A*68-B*53-DRB1*13_A*68-B*53-DRB1*13

[0099] In one embodiment, the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HL A haplotypes:A*01-B*08-DRBl*03_A*01-B*08-DRBl*03, A*02-B *44-DRB 1 *04_A*02-B*44-DRB 1 *04, A*02-B *44-DRB 1 *07_A*02-B*44-DRB 1 *07, A*02-B * 18-DRB 1 * 1 l_A*02-B* 18-DRB 1 * 11 , A*O2-B*51-DRB1*11_A*O2-B*51-DRB1*11, A*02-B *35-DRB l*04_A*02-B *35-DRB 1*04, A*24-B*35-DRB1*11_A*24-B*35-DRB1*11, A*02-B *07-DRB 1 * 15_A*02-B*07-DRB 1*15, A*02-B*35-DRBl*l l_A*02-B*35-DRBl*l l, A*02-B * 15-DRB 1 *04_A*02-B* 15-DRB 1 *04, A*29-B *44-DRB 1 *07_A*29-B*44-DRB 1 *07, A*02-B*51-DRBl*13_A*02-B*51-DRBl*13, A*02-B *07-DRB 1 *04_A*02-B*07-DRB 1 *04, A*03-B*35-DRBl*01_A*03-B*35-DRBl*01, A*24-B*51-DRB1*11_A*24-B*51-DRB1*11, A*24-B *44-DRB 1 * 13_A*24-B *44-DRB 1*13, A*l l-B*35-DRBl*01_ A*l l-B*35-DRBl*01, A*02-B*07-DRBl*01_ A*02-B*07-DRBl*01, A*03-B*35-DRBl*04_A*03-B*35-DRBl*04, A*03-B *07-DRB 1 * 15_A*03-B*07-DRB 1*15, A*24-B*51-DRB1*11_A*24-B*51-DRB1*11, A*24-B *44-DRB 1 * 13_ A*24-B *44-DRB 1 * 13 , or A*02-B * 18-DRB 1 *03_A*02-B* 18-DRB 1*03.

[0100] In one embodiment, the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HL A haplotypes:A*01-B*08-DRBl*03_A*01-B*08-DRBl*03, A*02-B *44-DRB 1 *04_A*02-B*44-DRB 1 *04, A*02-B *44-DRB 1 *07_A*02-B*44-DRB 1 *07, A*02-B * 18-DRB 1 * 1 l_A*02-B* 18-DRB 1 * 11 , A*O2-B*51-DRB1*11_A*O2-B*51-DRB1*11, A*02-B *35-DRB l*04_A*02-B *35-DRB 1*04, A*24-B*35-DRB1*11_A*24-B*35-DRB1*11, A*02-B *07-DRB 1 * 15_A*02-B*07-DRB 1*15, A*02-B*35-DRBl*l l_A*02-B*35-DRBl*l l, A*02-B * 15-DRB 1 *04_A*02-B* 15-DRB 1 *04, A*02-B*07-DRBl*01_ A*02-B*07-DRBl*01, A*03-B*35-DRBl*04_A*03-B*35-DRBl*04, A*02-B*51-DRBl*13_A*02-B*51-DRBl*13, or A*03-B *07-DRB 1 * 15_A*03-B*07-DRB 1*15.

[0101] In one embodiment, the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HL A haplotypes:A*01-B*08-DRBl*03_A*01-B*08-DRBl*03, A*02-B *44-DRB 1 *04_A*02-B*44-DRB 1 *04, A*02-B *44-DRB 1 *07_A*02-B*44-DRB 1 *07, A*02-B * 18-DRB 1 * 1 l_A*02-B* 18-DRB 1 * 11 , A*O2-B*51-DRB1*11_A*O2-B*51-DRB1*11, A*02-B*35-DRBl*l l_A*02-B*35-DRBl*l l, or A*02-B*07-DRBl*01_A*02-B*07-DRBl*01.

[0102] In one embodiment, the cells of at least one, preferably of each of the different cellular bank have one of the following homozygous HLA haplotypes:A*01-B*13-DRBl*07_A*01-B*13-DRBl*07,A*01-B*35-DRBl*l l_ A*01-B*35-DRBl*l l,A*02-B*07-DRBl*04_A*02-B*07-DRBl*04,A*02-B* 18-DRB 1 *03_A*02-B* 18-DRB 1*03, A*02-B* 18- DRB 1 * 1 l_A*02-B* 18-DRB 1*11, A*03-B*14-DRBl*01_A*03-B*14-DRBl*01, A*03-B*35-DRBl*04_A*03-B*35-DRBl*04, A*24-B*44-DRB 1 * 13_A*24-B*44-DRB 1*13, A*24-B*51-DRB1*11_A*24-B*51-DRB1*11, or A*68-B*53-DRB1*13_A*68-B*53-DRB1*13.

[0103] In one embodiment, the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HL A haplotypes:A*01-B*08-C*07-DRBl*03_A*01-B*08-C*07-DRBl*03, A*01-B*35-C*04-DRBl*04_A*01-B*35-C*04-DRBl*04, A*01-B*35-C*04-DRBl*l l_ A*01-B*35-C*04-DRBl*l l, A*01-B*57-C*06-DRBl*07_A*01-B*57-C*06-DRBl*07, A*02-B*07-C*07-DRBl*01_ A*02-B*07-C*07-DRBl*01, A*02-B*07-C*07-DRBl*04_A*02-B*07-C*07-DRBl*04, A*02-B*07-C*07-DRB 1-1 l_A*02-B*07-C*07-DRB 1-11, A*02-B*07-C*07-DRB 1 * 13_A*02-B*07-C*07-DRB 1*13, A-02-B *07-C*07-DRB 1 * 15_A-02-B*07-C*07-DRB 1*15, A*02-B*08-C*07-DRBl*03_A*02-B*08-C*07-DRBl*03, A*02-B* 13-C*06-DRB 1 *07_A*02-B* 13-C*06-DRB 1 *07, A*02-B* 14-C*08-DRB 1 *01_A*02-B* 14-C*08-DRB 1*01, A*02-B*15-C*03-DRBl*04_A*02-B*15-C*03-DRBl*04, A*02-B* 15-C*03-DRB 1 * 13_A*02-B* 15-C*03-DRB 1*13, A*02-B*18-C*05-DRBl*03_A*02-B*18-C*05-DRBl*03, A*02-B* 18-C*07-DRB 1 * 1 l_A*02-B* 18-C*07-DRB 1*11, A*02-B*27-C*01-DRBl*01_A*02-B*27-C*01-DRBl*01, A*02-B*27-C*02-DRBl*04_A*02-B*27-C*02-DRBl*04, A*02-B*35-C*04-DRBl*04_A*02-B*35-C*04-DRBl*04, A*02-B*35-C*04-DRBl*07_A*02-B*35-C*04-DRBl*07, A*02-B*35-C*04-DRB 1 * 1 l_A*02-B*35-C*04-DRB 1*11, A*02-B*35-C*04-DRBl*13_A*02-B*35-C*04-DRBl*13,A*02-B*40-C*03-DRBl*04_A*02-B*40-C*03-DRBl*04, A*02-B*44-C*05-DRBl*01_A*02-B*44-C*05-DRBl*01, A*02-B*44-C*05-DRBl*04_A*02-B*44-C*05-DRBl*04, A*02-B*44-C*05-DRB 1 * 13_A*02-B*44-C*05-DRB 1*13, A*02-B*44-C*07-DRBl*07_A*02-B*44-C*07-DRBl*07, A*02-B*49-C*07-DRB 1 * 1 l_A*02-B*49-C*07-DRB 1*11, A*02-B*50-C*06-DRBl*07_A*02-B*50-C*06-DRBl*07, A*02-B*51-C* 15-DRB 1 * 1 l_A*02-B*51-C* 15-DRB 1*11, A*03-B*07-C*07-DRBl*04_A*03-B*07-C*07-DRBl*04, A*03-B*07-C*07-DRB 1 * 1 l_A*03-B*07-C*07-DRB 1*11, A*03-B*07-C*07-DRBl*15_A*03-B*07-C*07-DRBl*15, A*03-B*35-C*04-DRBl*01_ A*03-B*35-C*04-DRBl*01, A*03-B*35-C*04-DRBl*04_A*03-B*35-C*04-DRBl*04, A*03-B*35-C*04-DRB 1 * 1 l_A*03-B*35-C*04-DRB 1*11, A*03-B*52-C* 12-DRB 1 * 15_A*03-B*52-C* 12-DRB 1*15, A*l l-B*35-C*04-DRBl*01_A*l l-B*35-C*04-DRBl*01, A*l l-B*35-C*04-DRBl*04_A*l l-B*35-C*04-DRBl*04, A*23-B*44-C*04-DRBl*07_A*23-B*44-C*04-DRBl*07, A*24-B*35-C*O4-DRB1*O4_A*24-B*35-C*O4-DRB1*O4, A*24-B*35-C*04-DRB 1 * 1 l_A*24-B*35-C*04-DRB 1*11, A*24-B*44-C*07-DRB 1 * 15_A*24-B*44-C*07-DRB 1*15, A*24-B*51-C*15-DRB1*11_A*24-B*51-C*15-DRB1*11, A*24-B*51-C*15-DRB1*13_A*24-B*51-C*15-DRB1*13, A*25-B* 18-C* 12-DRB 1 * 15_A*25-B* 18-C* 12-DRB 1*15, A*29-B*44-C* 16-DRB 1 *07_A*29-B*44-C* 16-DRB 1 *07, A*29-B*44-C* 16-DRB 1 * 11_A*29-B*44-C* 16-DRB 1*11, A*30-B* 13-C*06-DRB 1 *07_A*30-B* 13-C*06-DRB 1 *07, A*30-B* 18-C*05-DRB 1 *03_A*30-B* 18-C*05-DRB 1 *03, or A*68-B*53-C*04-DRB 1*13 A*68-B*53-C*04-DRB 1*13.

[0104] In one embodiment, the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HL A haplotypes:A*24-B*35-C*04-DRB 1 * 1 l_A*24-B*35-C*04-DRB 1*11, A*24-B*44-C*07-DRB 1 * 15_A*24-B*44-C*07-DRB 1*15, A*24-B*51-C*15-DRB1*11_A*24-B*51-C*15-DRB1*11, A*24-B*51-C*15-DRB1*13_A*24-B*51-C*15-DRB1*13, A*25-B* 18-C* 12-DRB 1 * 15_A*25-B* 18-C* 12-DRB 1*15, A*29-B*44-C* 16-DRB 1 * 11_A*29-B*44-C* 16-DRB 1*11, A*30-B* 13-C*06-DRB 1 *07_A*30-B* 13-C*06-DRB 1 *07, A*30-B* 18-C*05-DRB 1 *03_A*30-B* 18-C*05-DRB 1 *03, or A*68-B*53-C*04-DRB 1 * 13_ A*68-B*53-C*04-DRB 1*13.

[0105] In one embodiment, the cells of the biobank are genetically modified to reduce or abolish (for example through knock out) the expression of HLA-A at the cell surface. The technique to reduce or abolish (for example through knock out) the expression of markers or a receptor (such as for example HLA-A) at the cell surface are well known and described in the art and are based on such as for example a system of gene editing as described herein.

[0106] In one embodiment, the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HL A haplotypes:B*08-DRB 1 *03_B*08-DRB 1 *03,B * 13 -DRB 1 * 07_B * 13 -DRB 1 * 07,B*35-DRB1*11_B*35-DRB1*11,B*07-DRBl*01_ B*07-DRBl*01,B*07-DRB 1 *04_B*07-DRB 1 *04,B*07-DRB 1 * 15_B*07-DRB 1*15,B* 15-DRB 1 *04_B* 15-DRB 1 *04,B*18-DRBl*03_B*18-DRBl*03,B*18- DRB1*11_ B*18-DRB1*11,B*35-DRB 1 *04_B*35-DRB 1 *04,B*35-DRB1*11_B*35-DRB1*11,B*44-DRB 1 *04_B*44-DRB 1 *04,B*44-DRB 1 *07_B*44-DRB 1 *07,B *44-DRB 1 * 13_B *44-DRB 1 * 13 ,B*51-DRB 1 *04_B*51-DRB 1 *04,B*51-DRB1*11_B*51-DRB1*11,B*51-DRB1*13_B*51-DRB1*13,B*07-DRB 1 * 15_B*07-DRB 1*15,B*14-DRB1*O1_ B*14-DRB1*O1,B*35-DRBl*01_ B*35-DRBl*01,B*35-DRB 1 *04_B*35-DRB 1 *04,B*35-DRBl*01_B*35-DRBl*01,B*35-DRB1*11_B*35-DRB1*11,B *44-DRB 1 * 13_B *44-DRB 1 * 13 ,B*51-DRB1*11_B*51-DRB1*11,B*44-DRBl*07_B*44-DRBl*07, orB*53-DRB1*13_B*53-DRB1*13

[0107] In one embodiment, the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HL A haplotypes:B*08-DRBl*03_B*08-DRBl*03,B*44-DRB 1 *04_B *44-DRB 1 *04,B*44-DRB 1 *07_B *44-DRB 1 *07,B*18-DRB1*11_ B*18-DRB1*11,B*51-DRB1*11_B*51-DRB1*11,B*35-DRBl*04_B*35-DRBl*04,B*35-DRB1*11_B*35-DRB1*11,B*07-DRB 1 * 15_B *07-DRB 1*15,B*35-DRB1*11_B*35-DRB1*11,B* 15-DRB 1 *04_B * 15-DRB 1 *04,B*44-DRB 1 *07_B *44-DRB 1 *07,B*51-DRB1*13_B*51-DRB1*13,B*07-DRB 1 *04_B *07-DRB 1 *04,B*35-DRBl*01_ B*35-DRBl*01,B*51-DRB1*11_B*51-DRB1*11,B *44-DRB 1 * 13_B *44-DRB 1 * 13 , B*35-DRBl*01_ B*35-DRBl*01, B*07-DRBl*01_ B*07-DRBl*01, B*35-DRBl*04_B*35-DRBl*04, B*07-DRB 1 * 15_B *07-DRB 1*15, B*51-DRB1*11_B*51-DRB1*11, B*44-DRB1*13_B*44-DRB1*13, or B* 18-DRB 1 *03_B * 18-DRB 1 *03.

[0108] In one embodiment, the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HL A haplotypes:B*08-DRBl*03_B*08-DRBl*03, B*44-DRB 1 *04_B *44-DRB 1 *04, B*44-DRB 1 *07_B *44-DRB 1 *07, B*18-DRB1*11_ B*18-DRB1*11, B*51-DRB1*11_B*51-DRB1*11, B*35-DRBl*04_B*35-DRBl*04, B*35-DRB1*11_B*35-DRB1*11, B*07-DRB 1 * 15_B *07-DRB 1*15, B*35-DRB1*11_B*35-DRB1*11, B* 15-DRB 1 *04_B * 15-DRB 1 *04, B*07-DRBl*01_ B*07-DRBl*01, B*35-DRBl*04_B*35-DRBl*04, B*51-DRB1*13_B*51-DRB1*13 B *07-DRB 1 * 15_B *07-DRB 1 * 15.

[0109] In one embodiment, the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HL A haplotypes:B*08-DRBl*03_B*08-DRBl*03, B*44-DRB 1 *04_B *44-DRB 1 *04, B*44-DRB 1 *07_B *44-DRB 1 *07, B*18-DRB1*11_ B*18-DRB1*11,B*51-DRB1*11_B*51-DRB1*11,B*35-DRB1*11_B*35-DRB1*11, orB*07-DRBl*01_ B*07-DRBl*01.

[0110] In one embodiment, the cells of at least one, preferably of each of the different cellular bank have one of the following homozygous HLA haplotypes:B * 13 -DRB 1 * 07_B * 13 -DRB 1 * 07, B*35-DRB1*11_B*35-DRB1*11, B*07-DRB 1 *04_B*07-DRB 1 *04, B*18-DRBl*03_B*18-DRBl*03, B*18- DRB1*11_ B*18-DRB1*11, B*14-DRB1*O1_B*14-DRB1*O1, B*35-DRB 1 *04_B*35-DRB 1 *04, B *44-DRB 1 * 13_B *44-DRB 1 * 13 , B*51-DRB1*11_B*51-DRB1*11, or B*53-DRB1*13_B*53-DRB1*13.

[0111] In one embodiment, the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HLA haplotypes:B*08-C*07-DRB 1 *03_B*08-C*07-DRB 1 *03, B*35-C*04-DRB 1 *04_B*35-C*04-DRB 1 *04, B*35-C*O4-DRB1*11_B*35-C*O4-DRB1*11, B*57-C*06-DRB 1 *07_B*57-C*06-DRB 1 *07, B*07-C*07-DRBl*01_B*07-C*07-DRBl*01, B*07-C*07-DRB 1 *04_B*07-C*07-DRB 1 *04, B*07-C*07-DRBl-l l_B*07-C*07-DRBl-l 1, B*07-C*07-DRB 1 * 13_B*07-C*07-DRB 1*13, B*07-C*07-DRB 1 * 15_B*07-C*07-DRB 1*15, B*08-C*07-DRB 1 *03_B*08-C*07-DRB 1 *03, B* 13-C*06-DRB 1 *07_B* 13-C*06-DRB 1 *07, B*14-C*08-DRBl*01_B*14-C*08-DRBl*01, B* 15-C*03-DRB 1 *04_B* 15-C*03-DRB 1 *04,B*18-C*12-DRB1*15_B*18-C*12-DRB1*15,B*44-C* 16-DRB 1 *07_B*44-C* 16-DRB 1 *07,B*44-C*16-DRB1*11_B*44-C*16-DRB1*11,B* 13-C*06-DRB 1 *07_B* 13-C*06-DRB 1 *07,B* 18-C*05-DRB 1 *03_B* 18-C*05-DRB 1 *03, orB*53-C*04-DRBl*13_ *53-C*04-DRBl*13.

[0112] In one embodiment, the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HL A haplotypes:B*35-C*04-DRB 1 *04_B*35-C*04-DRB 1 *04,B*35-C*O4-DRB1*11_B*35-C*O4-DRB1*11,B*07-C*07-DRBl*01_B*07-C*07-DRBl*01,B*07-C*07-DRB 1 *04_B*07-C*07-DRB 1 *04,B*07-C*07-DRBl-l l_B*07-C*07-DRBl-l 1,B*07-C*07-DRB 1 * 13_B*07-C*07-DRB 1*13,B*14-C*08-DRBl*01_B*14-C*08-DRBl*01,B*15-C*03-DRBl*13_B*15-C*03-DRBl*13,B*18-C*05-DRBl*03_B*18-C*05-DRBl*03,B* 18-C*07-DRB 1 * 11_B* 18-C*07-DRB 1*11,B*27-C*01-DRBl*01_B*27-C*01-DRBl*01,B*27-C*02-DRB 1 *04_B*27-C*02-DRB 1 *04,B*35-C*04-DRB 1 *04_B*35-C*04-DRB 1 *04,B*35-C*04-DRB 1 *07_B*35-C*04-DRB 1 *07,B*35-C*O4-DRB1*11_B*35-C*O4-DRB1*11,B*35-C*04-DRBl*13_B*35-C*04-DRBl*13,B*40-C*03-DRB 1 *04_B*40-C*03-DRB 1 *04,B*44-C*05-DRBl*01_B*44-C*05-DRBl*01,B*44-C*05-DRB 1 * 13_B*44-C*05-DRB 1*13,B*44-C*07-DRB 1 *07_B*44-C*07-DRB 1 *07,B*49-C*07-DRB 1 * 1 l_B*49-C*07-DRB 1*11,B*50-C*06-DRB 1 *07_B*50-C*06-DRB 1 *07,B*51-C*15-DRB1*11_B*51-C*15-DRB1*11,B*07-C*07-DRB 1 *04_B*07-C*07-DRB 1 *04, B*07-C*07-DRB 1 * 1 l_B*07-C*07-DRB 1*11, B*35-C*04-DRB 1 *04_B*35-C*04-DRB 1 *04, B*35-C*04-DRBl*l l_B*35-C*04-DRBl*l l, B*52-C* 12-DRB 1 * 15_B*52-C* 12-DRB 1*15, B*35-C*04-DRBl*01_ B*35-C*04-DRBl*01, B*35-C*04-DRB 1 *04_B*35-C*04-DRB 1 *04, B*44-C*04-DRB 1 *07_B*44-C*04-DRB 1 *07, B*35-C*04-DRB 1 *04_B*35-C*04-DRB 1 *04, B*35-C*O4-DRB1*11_B*35-C*O4-DRB1*11, B*44-C*07-DRB 1 * 15_B*44-C*07-DRB 1*15, B*51-C*15-DRB1*11_B*51-C*15-DRB1*11, B*51-C*15-DRB1*13_B*51-C*15-DRB1*13, B*18-C* 12-DRB 1*15_B*18-C*12-DRB1* 15, B*44-C*16-DRB1*11_B*44-C*16-DRB1*11, B* 13-C*06-DRB 1 *07_B* 13-C*06-DRB 1 *07, B* 18-C*05-DRB 1 *03_B* 18-C*05-DRB 1 *03, or B*53-C*04-DRBl*13_ B*53-C*04-DRBl*13.

[0113] In one embodiment, the at least two cellular banks are at least two different cellular banks, wherein each cell bank is physically isolated from the other(s).

[0114] In one embodiment, a biobank of the present invention may comprise a first pool of cells having a specific haplotype (z.e., a first cellular bank) and a second distinct pool of cells having another specific haplotype (z.e., a second cellular bank); wherein the cell type (e.g., T cell progenitors, immune cells) and / or origin e.g., cord blood, peripheral blood, bone marrow) of the cells are the same in the two cellular banks.

[0115] In one embodiment, a biobank of the present invention may comprise a first pool of cells having a specific haplotype (z.e., a first cellular bank) and a second distinct pool of cells having the same specific haplotype (z.e., a second cellular bank); wherein the cell type and / or origin of the cells are different between the two cellular banks.

[0116] In one embodiment, the biobank of the invention would make possible to treat at least about 20, 25, 30, 35, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 % of the subjects in need thereof.

[0117] In one embodiment, the biobank comprises or consist of at least two cellular banks (preferably different cellular banks, based on their haplotypes, origin and / or cell types). In one embodiment, the biobank contains at least two cellular banks. In one embodiment, the biobank comprises at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 cellular banks (preferably different cellular banks, based on their haplotypes, origin and / or cell types). In one embodiment, the biobank comprises or consists of less than 20 different cellular banks, preferably less than 15 different cellular banks and more preferably 10 or less than 10 different cellular banks (preferably different cellular banks, based on their haplotypes, origin and / or cell types).

[0118] In one embodiment, the biobank comprises more than 20 cellular banks. In one embodiment, the biobank contains more than 20 cellular banks. In one embodiment, the biobank comprises at least about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39 or 40 cellular banks (preferably different cellular banks, based on their haplotypes, origin and / or cell types). In one embodiment, the biobank comprises or consists of less than 100 cellular banks.

[0119] In one embodiment, the biobank is not a biobank of tissues or of blood samples comprising cells.

[0120] In one embodiment, the cells of the cellular banks do not comprise alpha-beta T cells. In one embodiment, the cells of the cellular banks comprise less than 1% of alphabeta T cells. In one embodiment, the cells of the cellular banks comprise less than 0.1; 0.2; 0.3; 0.4; 0.5; 0.6; 0.7; 0.8; 0.9 or 1 % of alpha-beta T cells. “Alpha-beta T cells” refer here to a population of lymphocyte T cells that expresses a T-cell receptor comprising an alpha and a beta chain.

[0121] In one embodiment, the cells of the cellular banks do not comprise initially alphabeta T cells. In one embodiment, the cells of the cellular banks are depleted of alpha-beta T cells. Methods for depleting a cell sample of alpha-beta T cells are well-known by theskilled artisan, and include, without limitation, magnetic separation, fluorescence activated cell sorting (FACS) or affinity chromatography.

[0122] In one embodiment, each cellular bank comprised in the biobank, comprises cells from one donor, or for more than one donor. In one embodiment, each cellular bank comprised in the biobank, comprises cells from at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 donors.

[0123] In one embodiment, each cellular bank comprises several batches of cells (that may for example be packaged in different containers), wherein each batch comprises several doses of injectable cells. In the context of the invention, a batch of cells is extracted from the cellular bank, or produced, after exhaustion of the previous one.

[0124] In one embodiment, each dose of injectable cells is cryopreserved. In one embodiment, each batch of cells is cryopreserved. In one embodiment, each cellular bank comprises cryopreserved cells.

[0125] In one embodiment, each cellular bank comprises several batches of cells, wherein each batch comprises several doses of injectable cells and wherein each batch comprises cells from 1 donor or from more than 1 donor. The donors may differ between different batches in one cellular bank but all the cells of all batches have the same homologous HLA haplotype.

[0126] In one embodiment, each cellular bank comprises several batches of cells, wherein each batch comprises several doses of injectable cells and wherein each batch comprises cells from at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 donors.

[0127] In one embodiment, each batch of cells comprised in a cellular bank, comprises at least about 10 doses of injectable cells. In one embodiment, each batch of cells comprised in a cellular bank, comprises at least about 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24 or 25 doses of injectable cells, preferably between 10 and 20 doses. In one embodiment, each batch of cells comprised in a cellular bank, comprises more than 10 doses of injectable cells.

[0128] The term “dose of injectable cells” refers here to the total nucleated cell (TNC) dose per kilogram (kg) of recipient body weight. In one embodiment, the optimal dose of TNC ranges from 0.1 x 105 / kg to 1 x 107 / kg recipient body weight, preferably from 0.5 x 105 / kg to 5 x 106 / kg recipient body weight and more preferably from lx 106 / kg to 3 x 106 / kg recipient body weight. In one embodiment, the optimal dose of TNC ranges from 0.3 x 105cells to 1,5 x 109cells, preferably from 1.5 x 105cells to 7.5 x 108cells and more preferably from 3x 106cells to 4.5 x 108cells. In one embodiment, the optimal dose ranges from 5 x 105cells to 5 x 108cells, preferably from 2.5 x 106cells to 2.5 x 108cells and more preferably from 5x 107cells to 1.5 x 108cells. In one embodiment, the optimal dose of TNC for cord blood cells ranges from 0.5 x 105 / kg to 1 x 106 / kg recipient body weight, preferably from 0.5 x 105 / kg to 5 x 105 / kg recipient body weight and more preferably from 0.5 x 105 / kg to 1.5 x 105 / kg recipient body weight. In one embodiment, the optimal dose of TNC for cord blood cells ranges from 1.5 x 105cells to 7.5 x 108cells, preferably from 1.5 x 105cells to 7.5 x 107cells and more preferably from 1.5 x 105cells to 2.25 x 107cells. In one embodiment, the optimal dose of TNC for cord blood cells ranges from 2.5 x 106cells to 5 x 107cells, preferably from 2.5 x 106cells to 2.5 x 107cells and more preferably from 2.5 x 106cells to 7.5 x 106cells. In one embodiment, one dose of injectable cells may be administered to the subject. In one embodiment, several doses of cells may be administered to the subject over a period time.

[0129] In one embodiment, the optimal dose of CD7+ TNC ranges from 0.1 x 105 / kg to 1 x 107 / kg recipient body weight, preferably from 0.5 x 105 / kg to 5 x 106 / kg recipient body weight and more preferably from lx 106 / kg to 3 x 106 / kg recipient body weight. In one embodiment, the optimal dose of CD7+ TNC ranges from 0.3 x 105cells to 1,5 x 109cells, preferably from 1.5 x 105cells to 7.5 x 108cells and more preferably from 3x 106cells to 4.5 x 108cells. In one embodiment, the optimal dose of CD7+ TNC ranges from 5 x 105cells to 5 x 108cells, preferably from 2.5 x 106cells to 2.5 x 108cells and more preferably from 5 x 107cells to 1.5 x 108cells. In one embodiment, the optimal dose of CD7+ TCN for cord blood cells ranges from 0.5 x 105 / kg to 1 x 106 / kg recipient body weight, preferably from 0.5 x 105 / kg to 5 x 105 / kg recipient body weight and more preferably from 0.5 x 105 / kg to 1.5 x 105 / kg recipient body weight. In one embodiment, the optimal dose of CD7+ TNC for cord blood cells ranges from 1.5 x 105cells to 1,5 x108cells, preferably from 1.5 x 105to 7.5 x 107cells and more preferably from 1.5 x 105to 2.25 x 107cells. In one embodiment, the optimal dose of CD7+ TNC for cord blood cells ranges from 2.5 x 106cells to 5 x 107cells, preferably from 2.5 x 106to 2.5 x 107cells and more preferably from 2.5 x 106to 7.5 x 107cells. In one embodiment, one dose of injectable cells may be administered to the subject. In one embodiment, several doses of cells may be administered to the subject over a period time.

[0130] In one embodiment, each cellular bank comprised in the biobank may comprise cells from at least about two donors, wherein said donors have:(i) the same combination of two HLA-A, -B -DRB1 haplotypes, and(ii) one of the following homozygous HLA haplotypes: A*01-B*08-DRBl*03_A*01-B*08-DRBl*03, A*01-B*13-DRBl*07_A*01-B*13-DRBl*07, A*01-B*35-DRBl*l l_A*01-B*35-DRBl*l l, A*02-B*07-DRBl*01_A*02-B*07-DRBl*01, A*02-B*07-DRBl*04_A*02-B*07-DRBl*04, A*02-B*07-DRB 1 * 15_A*02-B*07-DRB 1*15, A*02-B* 15-DRB 1 *04_A*02-B* 15-DRB 1 *04, A*02-B* 18-DRB 1 *03_A*02-B* 18-DRB 1*03, A*02-B* 18- DRB 1 * 1 l_A*02-B* 18-DRB 1*11, A*02-B*35-DRBl*04_A*02-B*35-DRBl*04, A*02-B*35-DRB 1 * 1 l_A*02-B*35-DRB 1 * 11, A*02-B*44-DRBl*04_A*02-B*44-DRBl*04, A*O2-B*44-DRB1*O7_A*O2-B*44-DRB1*O7, A*02-B*44-DRB 1 * 13_A*02-B*44-DRB 1*13, A*02-B*51-DRB 1 *04_A*02-B*51-DRB 1 *04, A* 02-B * 51 -DRB 1 * 11 _A * 02-B * 51 -DRB 1 * 11 , A*02-B*51-DRBl*13_A*02-B*51-DRBl*13, A*03-B*07-DRBl*15_A*03-B*07-DRBl*15, A*03-B*14-DRBl*01_A*03-B*14-DRBl*01, A*03-B*35-DRBl*01_ A*03-B*35-DRBl*01, A*03-B*35-DRBl*04_A*03-B*35-DRBl*04,A*ll-B*35-DRBl*01_A*ll-B*35-DRBl*01, A*24-B*35-DRB1*11_A*24-B*35-DRB1*11, A*24-B*44-DRB 1 * 13_A*24-B*44-DRB 1*13, A* 24-B * 51 -DRB 1 * 11 _A * 24-B * 51 -DRB 1 * 11 , A*29-B*44-DRB 1 *07_A*29-B *44-DRB 1 *07, or A*68-B*53-DRB1*13_A*68-B*53-DRB1*13.

[0131] In one embodiment, each cellular bank comprised in the biobank may comprise cells from at least about two donors, wherein said donors have:(i) the same combination of two HLA-A, -B, -C and -DRB 1 haplotypes, and(ii) one of the following homozygous HLA haplotypes:A*01-B*08-C*07-DRBl*03_A*01-B*08-C*07-DRBl*03, A*01-B*35-C*04-DRBl*04_A*01-B*35-C*04-DRBl*04, A*01-B*35-C*04-DRBl*ll_ A*01-B*35-C*04-DRBl*ll, A*01-B*57-C*06-DRBl*07_A*01-B*57-C*06-DRBl*07, A*02-B*07-C*07-DRBl*01_ A*02-B*07-C*07-DRBl*01, A*02-B*07-C*07-DRBl*04_A*02-B*07-C*07-DRBl*04, A*02-B*07-C*07-DRB 1-1 l_A*02-B*07-C*07-DRB 1-11, A*02-B*07-C*07-DRB 1 * 13_A*02-B*07-C*07-DRB 1*13, A-02-B *07-C*07-DRB 1 * 15_A-02-B*07-C*07-DRB 1*15, A*02-B*08-C*07-DRBl*03_A*02-B*08-C*07-DRBl*03, A*02-B* 13-C*06-DRB 1 *07_A*02-B* 13-C*06-DRB 1 *07, A*02-B* 14-C*08-DRB 1 *01_A*02-B* 14-C*08-DRB 1*01, A*02-B*15-C*03-DRBl*04_A*02-B*15-C*03-DRBl*04, A*02-B* 15-C*03-DRB 1 * 13_A*02-B* 15-C*03-DRB 1*13, A*02-B*18-C*05-DRBl*03_A*02-B*18-C*05-DRBl*03, A*02-B* 18-C*07-DRB 1 * 1 l_A*02-B* 18-C*07-DRB 1*11, A*02-B*27-C*01-DRBl*01_A*02-B*27-C*01-DRBl*01, A*02-B*27-C*02-DRBl*04_A*02-B*27-C*02-DRBl*04, A*02-B*35-C*04-DRBl*04_A*02-B*35-C*04-DRBl*04, A*02-B*35-C*04-DRBl*07_A*02-B*35-C*04-DRBl*07, A*02-B*35-C*04-DRB 1 * 1 l_A*02-B*35-C*04-DRB 1*11,

[0132] In one embodiment, each cellular bank comprised in the biobank may comprise cells from at least about two donors, wherein said donors have:(i) the same combination of two HLA -B and DRB 1 haplotypes, and(ii) one of the following homozygous HLA haplotypes: B*08-DRBl*03_B*08-DRBl*03, B*13-DRB1*O7_B*13-DRB1*O7, B*35-DRB1*11_B*35-DRB1*11, B*07-DRBl*01_ B*07-DRBl*01, B*07-DRB 1 *04_B *07-DRB 1 *04, B*07-DRB 1 * 15_B *07-DRB 1*15,B* 15-DRB 1 *04_B * 15-DRB 1 *04, B*18-DRBl*03_B*18-DRBl*03, B*18- DRB1*11_B*18-DRB1*11, B*35-DRBl*04_B*35-DRBl*04, B*35-DRB1*11_B*35-DRB1*11, B*44-DRB 1 *04_B *44-DRB 1 *04, B*44-DRB 1 *07_B *44-DRB 1 *07, B *44-DRB 1 * 13_B *44-DRB 1 * 13 , B*51-DRB1*O4_B*51-DRB1*O4, B*51-DRB1*11_B*51-DRB1*11, B*51-DRB1*13_B*51-DRB1*13, B*07-DRB 1 * 15_B *07-DRB 1*15, B*14-DRB1*O1_ B*14-DRB1*O1, B*35-DRBl*01_ B*35-DRBl*01, B*35-DRBl*04_B*35-DRBl*04, B*35-DRBl*01_B*35-DRBl*01, B*35-DRB1*11_B*35-DRB1*11, B *44-DRB 1 * 13_B *44-DRB 1 * 13 , B*51-DRB1*11_B*51-DRB1*11, B*44-DRBl*07_B*44-DRBl*07, or B*53-DRB1*13_B*53-DRB1*13.

[0133] In one embodiment, each cellular bank comprised in the biobank may comprise cells from at least about two donors, wherein said donors have:(i) the same combination of two HLA-B, -C and -DRB1 haplotypes, and(ii) one of the following homozygous HLA haplotypes:A B*08-C*07-DRBl*03 > B*08-C*07-DRBl*03, B*35-C*04-DRB 1 *04_B*35-C*04-DRB 1 *04, B*35-C*04-DRBl*ll_B*35-C*04-DRBl*ll, B*57-C*06-DRB 1 *07_B*57-C*06-DRB 1 *07, B*07-C*07-DRBl*01_B*07-C*07-DRBl*01, B*07-C*07-DRB 1 *04_B*07-C*07-DRB 1 *04, B*07-C*07-DRBl-l l_B*07-C*07-DRBl-l 1, B*07-C*07-DRB 1 * 13_B*07-C*07-DRB 1*13, B*07-C*07-DRB 1 * 15_B*07-C*07-DRB 1*15, B*08-C*07-DRB 1 *03_B*08-C*07-DRB 1 *03, B* 13-C*06-DRB 1 *07_B* 13-C*06-DRB 1 *07, B*14-C*08-DRBl*01_B*14-C*08-DRBl*01, B* 15-C*03-DRB 1 *04_B* 15-C*03-DRB 1 *04, B*15-C*03-DRBl*13_B*15-C*03-DRBl*13, B*18-C*05-DRBl*03_B*18-C*05-DRBl*03, B* 18-C*07-DRB 1 * 11_B* 18-C*07-DRB 1*11, B*27-C*01-DRBl*01_B*27-C*01-DRBl*01, B*27-C*02-DRB 1 *04_B*27-C*02-DRB 1 *04, B*35-C*04-DRB 1 *04_B*35-C*04-DRB 1 *04, B*35-C*04-DRB 1 *07_B*35-C*04-DRB 1 *07, B*35-C*O4-DRB1*11_B*35-C*O4-DRB1*11, B*35-C*04-DRBl*13_B*35-C*04-DRBl*13, B*40-C*03-DRB 1 *04_B*40-C*03-DRB 1 *04, B*44-C*05-DRBl*01_B*44-C*05-DRBl*01, B*44-C*05-DRB 1 *04_B*44-C*05-DRB 1 *04, B*44-C*05-DRB 1 * 13_B*44-C*05-DRB 1*13, B*44-C*07-DRB 1 *07_B*44-C*07-DRB 1 *07,B*49-C*07-DRB 1 * 1 l_B*49-C*07-DRB 1*11, B*50-C*06-DRB 1 *07_B*50-C*06-DRB 1 *07, B*51-C*15-DRB1*11_B*51-C*15-DRB1*11, B*07-C*07-DRB 1 *04_B*07-C*07-DRB 1 *04, B*07-C*07-DRB 1 * 1 l_B*07-C*07-DRB 1*11, B*07-C*07-DRB 1 * 15_B*07-C*07-DRB 1*15, B*35-C*04-DRBl*01_ B*35-C*04-DRBl*01, B*35-C*04-DRB 1 *04_B*35-C*04-DRB 1 *04, B*35-C*04-DRBl*ll_B*35-C*04-DRBl*ll, B*52-C* 12-DRB 1 * 15_B*52-C* 12-DRB 1*15, B*35-C*04-DRBl*01_ B*35-C*04-DRBl*01, B*35-C*04-DRB 1 *04_B*35-C*04-DRB 1 *04, B*44-C*04-DRB 1 *07_B*44-C*04-DRB 1 *07, B*35-C*04-DRB 1 *04_B*35-C*04-DRB 1 *04, B*35-C*04-DRBl*ll_B*35-C*04-DRBl*ll, B*44-C*07-DRB 1 * 15_B*44-C*07-DRB 1*15, B*51-C*15-DRB1*11_B*51-C*15-DRB1*11, B*51-C*15-DRB1*13_B*51-C*15-DRB1*13, B*18-C* 12-DRB 1*15_B*18-C*12-DRB1* 15, B*44-C* 16-DRB 1 *07_B*44-C* 16-DRB 1 *07, B*44-C*16-DRB1*11_B*44-C*16-DRB1*11, B* 13-C*06-DRB 1 *07_B* 13-C*06-DRB 1 *07, B* 18-C*05-DRB 1 *03_B* 18-C*05-DRB 1 *03, or B*53-C*04-DRBl*13_B*53-C*04-DRBl*13.

[0134] In one embodiment, the cells of each cellular bank have one specific and defined combination of two HLA haplotypes, wherein said combination of two HLA haplotypes are homozygous. In one embodiment, the cells of each cellular bank have one specific and defined homozygous HLA haplotype, wherein said HLA haplotypes are defined by HLA- A, HLA-B and HLA-DRB 1 loci or wherein said HLA haplotypes are defined by HLA- A, HLA-B, HLA-C and HLA-DRB 1 loci. In one embodiment, the cells of each cellular bank have one specific and defined homozygous HLA haplotype, wherein saidHLA haplotypes are defined by HLA-B and HLA-DRB1 loci or wherein said HLA haplotypes are defined by HLA-B, HLA-C and HLA-DRB1 loci.

[0135] In one embodiment, the cellular bank comprises or consist of hematopoietic cells. In one embodiment, the cells comprised in the cellular bank are hematopoietic cells.

[0136] In one embodiment, the cellular bank comprises or consists of immune cells. In one embodiment, the cellular bank comprises or consists of cells enriched in lymphoid progenitor cells. In one embodiment, the cellular bank comprises or consists of T cell progenitors.

[0137] In one embodiment, the cells comprised in the cellular bank are immune cells. In one embodiment, the cells comprised in the cellular bank are cells enriched in lymphoid progenitor cells.

[0138] In one embodiment, the cellular bank comprises or consists of at least one immune cell type selected from the group comprising or consisting of T cell progenitors, gamma-delta T cells, progenitors of innate lymphoid cells (ILCs), ILCs, progenitors of NK cells, NK cells, progenitors of dendritic cells (DCs), DCs, granulocyte-monocyte progenitor cells, monocytes and macrophages.

[0139] In one embodiment, the cells comprised in the cellular bank comprises at least about, or more than about 50%, preferably at least about, or more than about 60%, 70%, 80%, 90%, 95%, of T cell progenitors and less than about 50%, 40%, 30%, 20%, 10%, 5%, of immune cells selected from the group comprising or consisting of gamma-delta T cells, progenitors of innate lymphoid cells (ILCs), ILCs, progenitors of NK cells, NK cells, progenitors of dendritic cells (DCs), DCs, granulocyte-monocyte progenitor cells, monocytes and macrophages.

[0140] In one embodiment, the immune cells are T cell progenitors. In one embodiment, T cell progenitors comprise CD34- CD7+ T cell progenitors.

[0141] In one embodiment, the immune cells are progenitors of NK cells. In one embodiment, the immune cells are NK cells. In one embodiment, the immune cells are progenitors of NK cells and NK cells.

[0142] In one embodiment, the immune cells are progenitors of innate lymphoid cells (ILCs). In one embodiment, the immune cells are ILCs, wherein said ILCs comprise ILC- 1, ILC-2 and / or ILC-3 populations. In one embodiment, the immune cells are progenitors of ILCs.

[0143] In one embodiment, the immune cells are progenitors of dendritic cells (DCs). In one embodiment, the immune cells are DCs. In one embodiment, the immune cells are progenitors of dendritic cells (DCs) and DCs.

[0144] In one embodiment, the immune cells are granulocyte-monocyte progenitor cells and / or monocyte and / or macrophage.

[0145] In one embodiment, the immune cells are immune progenitor cells. In one embodiment, the immune cells are immune progenitor cells selected from the group comprising or consisting of T cell progenitors, progenitors of innate lymphoid cells (ILCs), progenitors of NK cells, progenitors of dendritic cells (DCs) and granulocytemonocyte progenitor cells.

[0146] In one embodiment, the cells comprised in the at least one cellular bank are in vitro generated T cell progenitors.

[0147] In one embodiment, the T cell progenitors comprised in the cellular bank are in vitro generated cells obtained by the culture protocol described in WO2016 / 055396, which is incorporated herein by reference. According to the method described in WO2016 / 055396, in vitro generated T cell progenitors are obtained by culturing CD34+ cells in a medium comprising fibronectin and an immobilized Notch ligand. In one embodiment, the Notch ligand is immobilized on the inner surface of the culture vessel or on beads. in a culture vessel or on beads.

[0148] In one embodiment, the CD34+ cells are isolated from a human.

[0149] In one embodiment, the CD34+ cells are isolated from an adult donor. In one embodiment, the CD34+ cells are isolated from a bone marrow puncture or from peripheral blood from adult donors, which have been mobilized, such as, for example, using G-CSF.

[0150] In one embodiment, the CD34+ cells are isolated from umbilical cord blood.

[0151] Methods for isolating CD34+ cells are well known in the art and include, without limitation, methods using beads coated with an antibody recognizing CD34.

[0152] In one embodiment, the CD34+ cell population used in the method of the present invention is pure at least about 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99%.

[0153] In one embodiment, the CD34+ cells are seeded at a concentration ranging from about 106to about 107cells / mL of culture medium.

[0154] In one embodiment, the culture vessel is selected conventional culture vessels comprising (but not limited to) culture plates from 6 to 96 wells, petri dishes, flasks, stirrer bottles, micro titer plates, test tubes, hollow fiber devices, cell foam and bags. The quantity of cells seeded may be adapted by one skilled in the art, according to the culture vessel used.

[0155] In one embodiment, the culture medium is adapted for the culture of CD34+ cells. Examples of culture medium adapted for culture of CD34+ cells include, but are not limited to, a-MEM, DMEM, RPMI 1640, IMDM, BME, McCoy's 5 A, SFII (StemCell Technologies) media, Fischer's medium.

[0156] In one embodiment, the culture conditions are feeder cell-free.

[0157] In one embodiment, the culture medium serum free. In one embodiment, the culture medium is supplemented with fetal bovine serum (FBS) or fetal calf serum (FCS), preferably with at least 15% or 20% v / v of FBS or FCS.

[0158] Notch proteins are transmembrane receptors that regulate the cellular response to a large number of environmental signals. In mammals, four Notch receptors (Notch 1-4) and five ligands (Delta-like- 1, Delta-like-3, Delta-like-4, Jagged-1 and Jagged-2) have been described (Weinmaster Curr Opin Genet Dev 2000: 10: 363-369).

[0159] In one embodiment, the Notch ligand is Delta-like-4, preferably human Delta- like-4 (also known as DL-4, Uniprot accession number: Q9NR61, SEQ ID NO: 1), or a fragment thereof.

[0160] SEQ ID NO : 1MAAASRSASGWALLLLVALWQQRAAGSGVFQLQLQEFINERGVLASGRPCEP GCRTFFRVCLKHFQAVVSPGPCTFGTVSTPVLGTNSFAVRDDSSGGGRNPLQLP FNFTWPGTFSLIIEAWHAPGDDLRPEALPPDALISKIAIQGSLAVGQNWLLDEQT STLTRLRYSYRVICSDNYYGDNCSRLCKKRNDHFGHYVCQPDGNLSCLPGWTG EYCQQPICLSGCHEQNGYCSKPAECLCRPGWQGRLCNECIPHNGCRHGTCSTP WQCTCDEGWGGLFCDQDLNYCTHHSPCKNGATCSNSGQRSYTCTCRPGYTGV DCELELSECDSNPCRNGGSCKDQEDGYHCLCPPGYYGLHCEHSTLSCADSPCFN GGSCRERNQGANYACECPPNFTGSNCEKKVDRCTSNPCANGGQCLNRGPSRM CRCRPGFTGTYCELHVSDCARNPCAHGGTCHDLENGLMCTCPAGFSGRRCEVR TSIDACASSPCFNRATCYTDLSTDTFVCNCPYGFVGSRCEFPVGLPPSFPWVAVS LGVGLAVLLVLLGMVAVAVRQLRLRRPDDGSREAMNNLSDFQKDNLIPAAQL KNTNQKKELEVDCGLDKSNCGKQQNHTLDYNLAPGPLGRGTMPGKFPHSDKS LGEKAPLRLHSEKPECRISAICSPRDSMYQSVCLISEERNECVIATEV

[0161] In one embodiment, the Notch ligand is the soluble domain of at least one Notch ligand. In one embodiment, the soluble domain of a Notch ligand represents the extracellular portion of said ligand.

[0162] In one embodiment, the Notch ligand or fragment thereof (preferably the soluble domain of the notch ligand) is fused to a protein allowing the Notch ligand to be immobilized on a support.

[0163] In one embodiment, the Notch ligand or fragment thereof (preferably the soluble domain of the notch ligand) is fused to a Fc region of an IgG protein, such as, for example, a human IgG protein. In one embodiment, the Notch ligand or fragment thereof (preferably the soluble domain of the notch ligand) is fused to a Fc region of an IgG2 protein, such as, for example, a human IgG2 protein (NCBI accession number: 4HAF A, SEQ ID NO: 2).

[0164] SEQ ID NO: 2VECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWY VDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPA PIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK

[0165] In one embodiment, the culture medium comprises DL-4 or a fragment thereof, preferably a fragment comprising or consisting of the soluble domain of the DL-4.

[0166] In one embodiment, the soluble domain of DL-4 comprises or consists of amino acids 1-526 of SEQ ID NO: 1. In another embodiment, the soluble domain of DL-4 comprises or consists of amino acids 1-525 of SEQ ID NO: 1. In another embodiment, the soluble domain of DL-4 comprises or consists of amino acids 1-524 of SEQ ID NO: 1.

[0167] In one embodiment, DL-4 or a soluble domain thereof is fused to the Fc receptor region of an IgG protein (such as, for example, a human IgG protein), in particular an IgG2 protein and preferably a human IgG2. An example of a protein comprising a soluble domain of DL-4 fused to the Fc receptor region of a human IgG2 protein is SEQ ID NO: 3.

[0168] SEQ ID NO: 3MAAASRSASGWALLLLVALWQQRAAGSGVFQLQLQEFINERGVLASGRPCEP GCRTFFRVCLKHFQAVVSPGPCTFGTVSTPVLGTNSFAVRDDSSGGGRNPLQLPFNFTWPGTFSLIIEAWHAPGDDLRPEALPPDALISKIAIQGSLAVGQNWLLDEQT STLTRLRYSYRVICSDNYYGDNCSRLCKKRNDHFGHYVCQPDGNLSCLPGWTG EYCQQPICLSGCHEQNGYCSKPAECLCRPGWQGRLCNECIPHNGCRHGTCSTP WQCTCDEGWGGLFCDQDLNYCTHHSPCKNGATCSNSGQRSYTCTCRPGYTGVDCELELSECDSNPCRNGGSCKDQEDGYHCLCPPGYYGLHCEHSTLSCADSPCFN GGSCRERNQGANYACECPPNFTGSNCEKKVDRCTSNPCANGGQCLNRGPSRM CRCRPGFTGTYCELHVSDCARNPCAHGGTCHDLENGLMCTCPAGFSGRRCEVRTSIDACASSPCFNRATCYTDLSTDTFVCNCPYGFVGSRCEFPVGLPPSTMVRSVE CPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVD GMEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPI EKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGK

[0169] In one embodiment, the Notch ligand or fragment thereof is immobilized to the culture vessel used for the culture (z.e., bound to a solid support), although it is possible that certain elements may be found in solution. In one embodiment, the Notch ligand or fragment thereof is immobilized on the surface, preferably on the inner surface, of the culture vessel. Without willing to be bound to any theory, the Applicants suggest that immobilization of the Notch ligand or fragment thereof may stabilize it in order to facilitate interaction with the CD34+ cells and thus to allow activation of the Notch receptor of the CD34+ cells. In another embodiment, the Notch ligand or fragment thereof is immobilized on the surface of beads, preferably microbeads or such as polymer or magnetic beads (with a diameter generally comprised between 1 and 5 pm), present in the culture medium.

[0170] The binding of the Notch ligand or fragment thereof (e.g., to beads or to the surface of a culture vessel) may or may not be covalent. The binding of the Notch ligand may be carried out non-covalently by allowing the Notch ligand or fragment thereof to be adsorbed onto the surface of the culture vessel or of beads. Methods for attaching a protein or peptide to beads or culture vessels are known in the art, and include, without limitation, fragment crystallizable (Fc) region of an immunoglobulin molecule (such as, e.g., human IgG).

[0171] In one embodiment, according to WO 2016 / 055396, around 75% of the Notch ligand, in particular DL-4, will adhere to the culture vessel surface or to the beads surface when 5 pg / ml is used. In one embodiment, the composition used for coating a culture vessel or beads with a Notch ligand comprises a concentration of the Notch ligand higher or equal to 1.25 pg / ml and preferably ranging from about 2.5 and 5 pg / ml.

[0172] In one embodiment, the culture medium comprises fibronectin or a fibronectin fragment (fibronectin may have a sequence corresponding to the uniprot accession number: P02751, SEQ ID NO: 4). In one embodiment, the fibronectin fragment comprises or consists of an RGDS motif, a connecting segment 1 (CS-1) motif and / or a heparin binding domain. Preferably, the fibronectin fragment comprises or consists of an RGDS motif, a CS-1 motif and a heparin binding domain.

[0173] Fibronectin is a protein, which in its natural form is a v-shaped large dimer of 100 nm long and 460 kDa. The two monomers are connected by two disulfide bridges at their C-terminus. The term "fibronectin" or “fibronectin fragment” is understood to mean the natural fibronectin protein (z.e., any isoform produced by alternative splicing), but also a monomer of this protein, or a fragment of this protein (containing, when specified, the RGDS motif, CS-1 motif and heparin binding site).

[0174] An example of a fibronectin fragment which is particularly suitable for carrying out the process herein disclosed is Retronectin®. This protein corresponds to a fragment of a human fibronectin (CH-296 fragment, Kimizuka et al., J Biochem., 1991 Aug. 110 (2):284-91, Chono et al., J Biochem 2001 Sep 130 (3):331-4) and contains the cellbinding C domain (comprising the RGDS motif, the heparin-binding domain and the CS- 1 motif). This protein is sold in particular by the companies Takara Bio Inc. (Shiga, Japan), Clinisciences (Nanterre, France, also called NovoNectin®) and Fisher scientific (Hampton, United- States).

[0175] In one embodiment, the fibronectin fragment is immobilized on an inner surface of a culture vessel or on beads.

[0176] The term “RGDS motif’ is intended to designate any peptide or protein that contains the RGDS (SEQ ID NO: 5) pattern, so that it can bind integrin VLA-5. Such peptide or protein can be tested for its ability to bind VLA-5 integrin by methods known and reported in the art. RGDS motif binds to integrin VLA-5 (Very Late Antigen-5), which is a dimer composed of CD49e (alpha5) and CD29 (betal).

[0177] Heparin-binding domains are known in the art and present in numerous proteins that bind to heparin. Their sequence is generally XBBXBX or XBBBXXBX (B = basicamino acid; X = hydropathic amino acid; Cardin and Weintraub, Arterioscler Thromb Vase Biol. 1989;9:21-32). Presence of such a heparin-binding domain is particularly favorable when the CD34+ cells are exposed to a viral (especially a retroviral) vector in order to transduce them and obtain T cell progenitors expressing a transgene.

[0178] A CS-1 motif is a 25 amino acids peptide (DELPQLVTLPHPNLHGPEILDVPST, SEQ ID NO: 6), as described by Wayner et al., 1989, J. Cell Biol. 109: 1321). The CS-1 motif binds to the VLA-4 (Very Late Antigen- 4) receptor. VLA-4 is a dimer integrin, composed of CD49d (alpha 4) and CD29 (beta 1).

[0179] In one embodiment, the fibronectin or fibronectin fragment is immobilized (i.e., bound to a solid support). The binding of the fibronectin or fibronectin fragment (e.g., to beads or to the surface of a culture vessel) may or may not be covalent. In one embodiment, the fibronectin or fibronectin fragment is immobilized to the inner surface of the culture vessel (although it is possible that certain elements may be found in solution). In another embodiment, the fibronectin or fibronectin fragment is immobilized on the surface of beads, preferably microbeads or such as polymer or magnetic beads (with a diameter generally comprised between 1 and 5 pm). In one embodiment, the Notch ligand or fragment thereof and the fibronectin or fragment thereof are immobilized on the same beads. In another embodiment, the Notch ligand or fragment thereof and the fibronectin or fragment thereof are immobilized on the distinct beads.

[0180] In one embodiment, immobilization of the fibronectin or fibronectin fragment is carried out non-covalently by allowing the fibronectin or fragment thereof to be adsorbed onto the inner surface of the culture vessel or onto the surface of beads. Methods for attaching a protein or peptide to beads or to the surface of a culture vessel are known in the art and are listed hereinabove.

[0181] A method to coat a culture vessel or beads with fibronectin or a fragment thereof is disclosed in WO2016 / 055396. In one embodiment, the composition used for coating a culture vessel or beads with fibronectin or a fragment thereof comprises a concentration of fibronectin or a fragment thereof ranging from 10 and 100 pg / ml, preferably of about 25 pg / ml.

[0182] In one embodiment, the culture medium may comprise cytokines and growth factors. These cytokines and growth factors are selected from the group comprising or consisting of SCF (stem cell factor), thrombopoietin (TPO, also called megakaryocyte growth and development factor, 20 MGDF), Flt3-Ligand (which is a growth factor Hematopoietic), interleukin 3 (IL-3), interleukin 7 (IL-7) and SCF (stem cell factor).

[0183] In one embodiment, the culture medium comprises at least 1, 2, 3 or 4 (such as, for example, 1, 2, 3, or 4) cytokines selected from the group comprising or consisting of human SCF, human Flt3-L, human TPO and human IL-7.

[0184] In one embodiment, the concentration of SCF, preferably of hSCF ranges from about 2 to about 300 ng / mL, preferably from about 40 to about 300 ng / mL or from about 40 ng / mL to about 200 ng / mL and more preferably is of about 100 ng / mL.

[0185] In one embodiment, the concentration of Flt3-L, preferably of hFlt3-L ranges from about 2 to about 300 ng / mL, preferably from about 40 to about 300 ng / mL or from about 40 ng / mL to about 200 ng / mL and more preferably is of about 100 ng / mL.

[0186] In one embodiment, the concentration of TPO, preferably of hTPO ranges from about 2 to about 300 ng / mL, preferably from about 40 to about 300 ng / mL or from about 40 ng / mL to about 200 ng / mL and more preferably is of about 100 ng / mL.

[0187] In one embodiment, the concentration of IL-7, preferably of hIL-7 ranges from about 2 to about 300 ng / mL, preferably from about 40 to about 300 ng / mL or from about 40 ng / mL to about 200 ng / mL and more preferably is of about 100 ng / mL.

[0188] In one embodiment, the medium comprises IL-3, preferably human IL-3. In one embodiment, the medium does not comprise IL-3.

[0189] In one embodiment, the culture medium contains at least three, preferably at least four of these cytokines or growth factors, in addition to TNF-alpha.

[0190] In one embodiment, CD34+ cells are cultured in a culture medium comprising TNF-a and / or an antagonist of the Aryl hydrocarbon / Dioxin receptor,

[0191] In one embodiment, TNF-a is human TNF-a, having for example the sequence of SEQ ID NO: 7 (Uniprot accession number: P01375).

[0192] SEQ ID NO: 7MSTESMIRDVELAEEALPKKTGGPQGSRRCLFLSLFSFLIVAGATTLFCLLHFGV IGPQREEFPRDLSLISPLAQAVRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRA NALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSY QTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDY LDFAESGQVYFGIIAL

[0193] TNF-a is primarily produced as a type II transmembrane protein arranged in stable homodimers, each monomer comprising 233 amino acids in human. In human, the soluble part of human TNF-a is composed of amino acid 77 to 233 of SEQ ID NO: 7.

[0194] In one embodiment, culture medium comprises full-length TNF-a or a soluble fragment thereof.

[0195] In one embodiment, TNF-a or the fragment thereof is added from day 0 of culture. In one embodiment, TNF-a or the fragment thereof is present in the culture medium since day 0 and during at least about 1, 2, 3, 4, 5, 6 or 7 days. In one embodiment, TNF-a or the fragment thereof is present in the culture medium from day 0 to the end of the culture.

[0196] In one embodiment, TNF-a or the fragment thereof is used at a concentration ranging from about 10 to about 300 ng / mL, such as, for example, of at least about 10, 20, 30, 40, 50, 100, 200 or 300 ng / mL. In one embodiment, TNF-a or the fragment thereof is used at a concentration of about 10 ng / mL. However, other concentrations such as about 5, 10, 20 or 50 ng / mL are also suitable.

[0197] In one embodiment, the antagonist of the Aryl hydrocarbon / Dioxin receptor is StemRegenin 1 (SRI, 4-(2-(2-(Benzo[b]thi ophen-3 -yl)-9-isopropyl-9H-purin-6- ylamino)ethyl)phenol, CAS 1227633-49-10).

[0198] In one embodiment, the antagonist of the Aryl hydrocarbon / Dioxin receptor is present in the culture medium from day 0 of the culture.

[0199] In one embodiment, the antagonist of the Aryl hydrocarbon / Dioxin receptor is added to the medium culture at a concentration ranging from about 1 ng / ml to about 300 ng / ml and preferably higher or equal to 1 ng / ml, or higher or equal to 3 ng / ml, or higher or equal to 10 ng / ml, and preferably lower than 200 ng / ml, or 150 ng / ml and generally between 3 ng / ml and 100 ng / ml.

[0200] In one embodiment, CD34+ are cultured for at most 10 days, preferably for 3 to 7 days.

[0201] In one embodiment, CD34+ cells from human CB or mobilized peripheral blood, bone marrow, ESC (embryonic stem cell) or iPSC samples are cultured with recombinant human fibronectin and DL-4 and the recombinant human cytokines interleukin-7 (IL-7), Flt3 -ligand (Flt-3L), stem cell factor (SCF) and thrombopoietin (TPO) with or without TNF-a.

[0202] The term “embryonic stem cells (ESCs)” refers here to a type of pluripotent stem cell derived from the blastocyst stage of early mammalian embryos and that have the ability to differentiate into an unlimited number of distinct cell types (i.e., all somatic cell types in the embryo). In one embodiment, ESCs are not obtained by carrying out a step of destruction of a human embryo.

[0203] In one embodiment, the cells comprised in the cellular bank are stem cells. The stem cells may be HSPCs. In one embodiment, the HSPCs are CD34 ( / .c., they express the CD34 marker). In one embodiment, the HSPCs are CD133+(i.e., they express the CD133 marker). HSPC may for example be selected from the group comprising or consisting of UCB (umbilical cord blood) HSPCs (Hematopoietic Stem / Progenitor cells), mPB (mobilized peripheral blood from adult donors) HSCPs, bone marrow HSPCs, ESC- derived HSPCs (embryonic stem cell derived - HSPCs), iPSC-derived HSPCs (induced pluripotent stem cells derived - HSPCs).

[0204] In one embodiment, the cells comprised in the cellular bank are a mix of at least two UCB HSPC samples obtained from different donors. The selection of the different donors is based on HLA haplotypes as described in the invention. In one embodiment, the cells comprised in the cellular bank are a mix of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 UCB HSPC samples from different donors.

[0205] In one embodiment, the cells comprised in the cellular bank are a mix of at least two mPB HSPC samples from different donors. The selection of the different donors is based on HLA haplotypes as described in the invention. In one embodiment, the cells comprised in the cellular bank are a mix of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 mPB HSPC samples from different donors.

[0206] In one embodiment, the cells comprised in the cellular bank are a mix of at least two iPSC-derived HSPC samples from different donors. The selection of the different donors is based on HLA haplotypes as described in the invention. In one embodiment, the cells comprised in the cellular bank are a mix of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 iPSC-derived HSPC samples from different donors.

[0207] In one embodiment, the cells comprised in the cellular bank are a mix of at least two ESC-derived HSPC samples from different donors. The selection of the different donors is based on HLA haplotypes as described in the invention. In one embodiment, the cells comprised in the cellular bank are a mix of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 ESC-derived HSPC samples from different donors.

[0208] In one embodiment, the cells comprised in the cellular bank are a mix of at least two bone marrow HSPCs from different donors. The selection of the different donors is based on HLA haplotypes as described in the invention. In one embodiment, the cells comprised in the at least one cellular bank are a mix of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 bone marrow HSPC samples from different donors.

[0209] In one embodiment, the cells comprised in the cellular bank contain a sequence encoding a Chimeric Antigen Receptor (CAR). In one embodiment, the cells comprised in the at least one cellular bank express a CAR at the cell surface. CARs are widely known and described in the art and are generally composed of an extracellular binding domain,a hinge region, a transmembrane domain and an intracellular signaling domain. CARs provide the cell with specificity for a specific target / antigen.

[0210] In one embodiment, the cells comprised in the cellular bank are genetically modified T cells, and contain a sequence encoding an exogenous T cell receptor (TCR). In one embodiment, the cells comprised in the cellular bank express a TCR, preferably an exogenous TCR. A TCR recognizes an antigen presented by a major histocompatibility complex (MHC) molecule and confers antigenic specificity to T cells. Genetically modified T cells modified for expressing an exogenous TCR are widely known and described in the art and are based on alteration / modification of T-cell specificity through the expression of an exogenous antigen-specific TCR, as example a tumor specific antigen.

[0211] In one embodiment, the cells comprised in the cellular bank contain a sequence encoding a CAR and / or an exogenous TCR. In one embodiment, the cells comprised in the cellular bank express at the cell surface a CAR and / or an exogenous TCR.

[0212] In one embodiment, the cells comprised in the cellular bank are genetically modified by a viral vector, a nucleic acid fragment, a plasmid or plasmidic RNA or DNA sequences, such as for example in order to introduce a gene of interest or to silence a gene of interest in these cells.

[0213] In one embodiment, the cells comprised in the cellular bank are transfected or transduced with an exogenous nucleic acid, wherein said exogenous nucleic acid may for example encode an exogenous protein.

[0214] In one embodiment, the cells comprised in the cellular bank are transfected or transduced with an exogenous nucleic acid encoding a Chimeric Antigen Receptor (CAR) or an exogenous TCR.

[0215] In one embodiment, the cells comprised in the cellular bank are genetically modified using a system of gene editing, base editing or a system of prime- editing. In one embodiment, the cells are exposed to a system making it possible to perform gene editing, base editing or prime editing. Such systems are widely known and described inthe art and are essentially based on nucleic acid double-break repair. Such systems may use a nuclease selected from the group consisting of meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALEN), and CRISPR-Cas nucleases. Such systems may use natural or synthetic transposon systems e.g., the Sleeping Beauty (SB) transposon system, based on transposase activity.

[0216] In one embodiment, the cells comprised in the cellular bank are epigenetically modified at a specific site. Such modifications are widely known and described in the art and are essentially based on DNA-associated modifications (e.g., nucleotide methylation or hydroxymethylation), histone-associated modifications (e.g., acetylation, methylation, phosphorylation) and non-coding RNA (ncRNA)-associated modifications, without modified amino-acid sequences. In one embodiment, the cells are exposed to a system making it possible to perform epigenetic modifications at a specific site. Such systems are widely known and described in the art. Such systems may use a nuclease selected from the group consisting of meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALEN), and CRISPR-Cas nucleases. Such systems may use natural or synthetic transposon systems e.g., the Sleeping Beauty (SB) transposon system, based on transposase activity. In one embodiment, the cells comprised in the cellular bank are genetically modified and epigenetically modified as indicated above.

[0217] In one embodiment, genetic modifications and / or epigenetic modifications as described herein are performed on immune cells or HSPCs or on the cells that are in vitro generated as described herein.

[0218] In one embodiment, the cells comprised in the cellular bank are genetically modified to promote their drugs resistance, preferably to anti-inflammatory drugs and more preferably to glucocorticoid. In one embodiment, the cells comprised in the cellular bank are genetically modified to promote resistance to chemicals that may be used for cell selection, such as, for example, neomycin or ganciclovir. In one embodiment, the cells comprised in the cellular bank are genetically modified to promote resistance to antibodies that may be used for conditioning, such as, for example an anti-CD45 antibody or an anti-CD3 antibody. In one embodiment, decreasing or abolishing (for examplethrough knock out) the expression of receptors that are specifically targeted by drugs, promotes drugs resistance. Without willing to be bound to any theory, the Applicant suggests that promoting drugs resistance to at least one cellular bank increases the viability and / or the efficiency of cells one of the cellular bank after transplantation.

[0219] In one embodiment, the cells comprised in the cellular bank are genetically modified to decrease or abolish (for example through knock out) the expression of receptors that are specifically targeted by drugs, such for as examples anti-inflammatory or immunomodulatory drugs. In one embodiment, the cells comprised in the cellular bank are genetically modified to decrease or abolish (for example through knock out) the expression of glucocorticoid receptor. Such modifications are widely known and described in the art and may for example be performed using a system of gene editing, base editing or a system of prime-editing, targeted epigenetic modification or all systems described herein.

[0220] In one embodiment, the cells comprised in the at least one cellular bank are genetically or epigenetically modified to decrease their sensitivity to a therapeutic agent, including, without limitation, some antibodies (such as, for example, antibodies targeting clusters of differentiation (CD) expressed in mature immune cells or targeting T-cells like anti-CD3, CD4, CD8, CD2 or CD45 antibodies), or some T cell engagers. In one embodiment, the cells comprised in the at least one cellular bank are genetically modified to decrease or abolish (for example through knock out) the expression of clusters of differentiation (CD) expressed in mature immune cells, such as, for example, CD3, CD4, CD8, CD2 or CD45. Such modifications are widely known and described in the art and may for example be performed using a system of gene editing, base editing or a system of prime- editing or all system describe hereinabove. Without willing to be bound to any theory, the Applicant suggest that decreasing or abolishing (for example through knock out) the expression of clusters of differentiation (CD) expressed in the cells comprised in the cellular bank allows to decrease the sensitivity of said cells to some antibodies such as for example antibodies targeting clusters of differentiation (CD) expressed in mature immune cells or targeting T-cells like anti-CD3, CD4, CD8, CD2 or CD45 antibodies.

[0221] In one embodiment, the cells comprised in the cellular bank are genetically or epigenetically modified to escape the alloreactivity of at least one mature cell population from the recipient. Examples of mature cell population from the recipient include, but are not limited to, a T cell population, a B cell population, a NK cell population, a dendritic cells population, a macrophage population or a ILC population. Escaping the alloreactivity of at least one mature cell population from the recipient may allow to decrease the rejection of the transplant, in particular if there is a mismatch between the donor and the recipient. Escaping the alloreactivity of at least one mature cell population from the recipient may in addition increase the viability and / or the efficiency of cells of the cellular bank after transplantation. To promote escape of the cells of the cellular bank from alloreactivity, cells from the recipient that express mature cell receptors (such as, for example, CD2, CD3 or CD45) may be depleted or removed using for example specific antibodies targeting said receptors. Transplanted cells from the cellular bank that are genetically or epigenetically modified as described herein to present reduced sensitivity for specific antibodies will thus not be depleted. The term “sensitivity” refers here to poor antibody recognition for a binding site (e.g., antigen, receptors, cluster of differentiation).

[0222] In one embodiment, the cells comprised in the cellular bank are derived or obtained from UCB (umbilical cord blood) HSPCs (Hematopoietic Stem / Progenitor cells). Said cells may be derived or obtained from UCB HSPCs from one donor or a mix of UCB HSPCs from different donors as described in the invention. In one embodiment, the cells comprised in the cellular bank are derived or obtained from UCB HSPCs from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different donors as described in the invention.

[0223] In one embodiment, the cells comprised in the cellular bank are derived or obtained from mPB (mobilized peripheral blood from adult donors) HSPCs. Said cells may be derived or obtained from mPB HSPCs from one donor or a mix of mPB HSPCs from different donors as described in the invention. In one embodiment, the cells comprised in the cellular bank are derived or obtained from mPB HSPCs from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different donors as described in the invention.

[0224] In one embodiment, the cells comprised in cellular bank are derived or obtained from iPSC-derived HSPCs (induced pluripotent stem cells-derived HSPCs). Said cellsmay be derived or obtained from iPSC-derived HSPCs from one donor or a mix of iPSC- derived HSPCs from different donors as described in the invention. In one embodiment, the cells comprised in the cellular bank are derived or obtained from iPSC-derived HSPCs from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different donors as described in the invention.

[0225] In one embodiment, the cells comprised in cellular bank are derived or obtained from ESC-derived HSPCs (embryonic stem cells-derived HSPCs). Said cells may be derived or obtained from ESC-derived HSPCs from one donor or a mix of ESC-derived HSPCs from different donors as described in the invention. In one embodiment, the cells comprised in the cellular bank are derived or obtained from ESC-derived HSPCs from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different donors as described in the invention.

[0226] In one embodiment, the cells comprised in the cellular bank are derived or obtained from bone marrow HSPCs. Said cells may be derived or obtained from bone marrow HSPCs from one donor or a mix of bone marrow HSPCs from different donors as described in the invention. In one embodiment, the cells comprised in the cellular bank are derived or obtained from bone marrow HSPCs from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different donors as described in the invention.

[0227] In one embodiment, the cells comprised in the cellular bank may be derived or obtained from UCB HSPCs, mPB HSPCs, ESC- derived HSPCs, iPSC-derived HSPCs or bone marrow HSPCs with different methods known in the art, including, without limitation, cell differentiation, cell culture, cell isolation, cell enrichment or cell depletion.

[0228] In one embodiment, HSPCs are isolated and / or enriched from human cord blood, bone marrow, mPB, ESC or iPSC samples. Isolation or enrichment refers here to an increase of the percentage of HSPCs, in particular of CD34+ or CD133+ HSPCs. Isolation or enrichment may be performed with magnetic separation, fluorescence activated cell sorting (FACS) or affinity chromatography. Isolation or enrichment of HSPCs may also result on alpha / beta T cell depletion.

[0229] In one embodiment, the UCB, bone marrow, mPB, ESC and iPSC samples are obtained from donors having different ethnicity such as for example: African- American,Caucasian, Asian, Hispanic, Native-American, Australian Aboriginal, Inuit, Pacific Islander, Irish, Italian, Indian, Japanese, Chinese, Russian, etc.

[0230] In one embodiment, the UCB, bone marrow, mPB, ESC and iPSC samples are obtained from Caucasian donors. In one embodiment, the UCB, bone marrow, mPB, ESC and iPSC samples are obtained from African-American donors. In one embodiment, the UCB, bone marrow, mPB, ESC and iPSC samples are obtained from Native-American donors. In one embodiment, the UCB, bone marrow, mPB, ESC and iPSC samples are obtained from Asian donors. In one embodiment, the UCB, bone marrow, mPB, ESC and iPSC samples are obtained from African donors. In one embodiment, the UCB, bone marrow, mPB, ESC and iPSC samples are obtained from Australian donors. In one embodiment, the UCB, bone marrow, mPB, ESC and iPSC samples are obtained from Inuit donors. In one embodiment, the UCB, bone marrow, mPB, ESC and iPSC samples are obtained from Pacific Islander donors.

[0231] In one embodiment, at least one cellular bank is dedicated to Caucasian recipients. In one embodiment, at least one cellular bank is dedicated to African- American recipients. In one embodiment, at least one cellular bank is dedicated to Native - American recipients. In one embodiment, at least one cellular bank is dedicated to Asian recipients. In one embodiment, at least one cellular bank is dedicated to African recipients. In one embodiment, at least one cellular bank is dedicated to Australian Aboriginal recipients. In one embodiment, at least one cellular bank is dedicated to Pacific Islander recipients. In one embodiment, at least one cellular bank is dedicated to Hispanic recipients. In one embodiment, at least one cellular bank is dedicated to Inuit recipients.

[0232] In one embodiment, the in vitro method for selecting at least one cellular bank to be administered to a subject from a biobank is a computer implemented method.

[0233] Some of the methods described above may be implemented with a device comprising a computer, this computer comprising a memory to store program instructions loadable into a circuit and adapted to cause the circuit to carry out steps of those methods when the program instructions are run by the circuit. The memory may also store data and useful information for carrying steps of those methods as described above.

[0234] The circuit may be for instance:- a processor or a processing unit adapted to interpret instructions in a computer language, the processor or the processing unit may comprise, may be associated with or be attached to a memory comprising the instructions, or- the association of a processor / processing unit and a memory, the processor or the processing unit adapted to interpret instructions in a computer language, the memory comprising said instructions, or- an electronic card wherein the steps of the invention are described within silicon, or a programmable electronic chip such as a FPGA chip (for « Field-Programmable Gate Array »).

[0235] The computer may also comprise an input interface for the reception of data and an output interface.

[0236] To ease the interaction with the computer, a screen and a keyboard may be provided and connected to the computer circuit.

[0237] This invention also relates to at least one cellular bank selected according to the method defined herein for use as a medicament, in particular for use in the treatment of immunodeficiency, immune disorders and / or diseases (such as, for example, inflammatory diseases or autoimmune diseases), lymphopenia or cancer in a subject in need thereof.

[0238] In one embodiment, the at least one selected cellular bank is for use as a medicament in the treatment of an immunodeficiency that may be caused by exposure to radiations or compounds like chemotherapies.

[0239] In one embodiment, the at least one selected cellular bank is for use as a medicament in the treatment of an inflammatory disease, such as for example inflammatory bowel disease, psoriasis and arthritis.

[0240] In one embodiment, the at least one selected cellular bank is for use as a medicament in the treatment of an autoimmune disease, such as for example, rheumatoidarthritis, diabetes type I, chronic hepatitis, multiple sclerosis and systemic lupus erythematosus.

[0241] The present invention further relates to a method for treating immunodeficiency, immune disorders and / or diseases (such as, for example, inflammatory diseases or autoimmune diseases), lymphopenia or cancer in a subject in need thereof, comprising administering the selected cellular bank to the subject. In one embodiment, the method of treatment comprises a step of selecting the cellular bank to be administered to the subject according to the method described herein.

[0242] In one embodiment, a therapeutically effective amount of cells is administered to the subject.

[0243] In one embodiment, the selected cellular bank is administered alone.

[0244] In one embodiment, the selected cellular bank is combined with another therapeutic substance for the treatment of immunodeficiency, immune disorders and / or diseases (such as, for example, inflammatory diseases or autoimmune diseases), lymphopenia or cancer. Thus, according to this embodiment, the subject is administered with the selected cellular bank, and with another therapeutic substance, such as, for example, a immunosuppressor or a therapeutic agent that prevents GVHD and / or rejection. Administration may be concomitant or subsequent.

[0245] In one embodiment, the selected cellular bank is combined with another cellular bank of the biobank. Thus, according to this embodiment, the subject is administered with two cellular banks. Administration may be concomitant or subsequent.

[0246] In one embodiment, the selected cellular bank is combined with at least one umbilical cord blood transplant or at least one mPB transplant. Thus, according to this embodiment, the subject is administered with the selected cellular bank and with at least one umbilical cord blood transplant or at least one mPB transplant. Administration may be concomitant or subsequent.

[0247] The present invention further relates to the at least one cellular bank selected using the method as described herein for the manufacture of a medicament for thetreatment of immunodeficiency, immune disorders and / or diseases (such as, for example, inflammatory diseases or autoimmune diseases), lymphopenia or cancer for a subject in need thereof. In one embodiment, at least one selected cellular bank is used for the manufacture of a medicament for the treatment of immunodeficiency, immune disorders and / or diseases (such as, for example, inflammatory diseases or autoimmune diseases),, lymphopenia or cancer for a subject in need thereof in combination with at least one another cellular bank. In one embodiment, at least one selected cellular bank is used for the manufacture of a medicament for the treatment of immunodeficiency, immune disorders and / or diseases (such as, for example, inflammatory diseases or autoimmune diseases), lymphopenia or cancer for a subject in need thereof in combination with another therapeutic substance. In one embodiment, at least one selected cellular bank is used for the manufacture of a medicament for the treatment of immunodeficiency, immune disorders and / or diseases (such as, for example, inflammatory diseases or autoimmune diseases), lymphopenia or cancer for a subject in need thereof in combination with at least one umbilical cord blood transplant or at least one mPB transplant.

[0248] In one embodiment, the at least one selected cellular bank is for use as a medicament in the treatment of genetic disorders, such as for example; anemias, familial aplastic, Fanconi's syndrome, Bloom's syndrome, pure red cell aplasia (PRCA), dyskeratosis congenital, Blackfan-Diamond syndrome, congenital dyserythropoietic syndromes I-IV, Chwachmann-Diamond syndrome, dihydrofolate reductase deficiencies, formamino transferase deficiency, Lesch-Nyhan syndrome, congenital spherocytosis, congenital elliptocytosis, congenital stomatocytosis, congenital Rh null disease, paroxysmal nocturnal hemoglobinuria, G6PD (glucose-6-phosphate dehydrogenase) variants 1, 2, 3, pyruvate kinase deficiency, congenital erythropoietin sensitivity deficiency, sickle cell disease and trait, thalassemia alpha, beta, gamma, methemoglobinemia, congenital disorders of immunity, severe combined immunodeficiency disease (SCID), bare lymphocyte syndrome, ionophore-responsive combined immunodeficiency, combined immunodeficiency with a capping abnormality, nucleoside phosphorylase deficiency.

[0249] In one embodiment, the at least one selected cellular bank is for use as a medicament in the treatment of osteopetrosis, myelosclerosis, acquired hemolytic anemias, acquired immunodeficiencies, infectious disorders causing primary or secondary; bacterial infections (e.g., Brucellosis, Listerosis, tuberculosis, leprosy), parasitic infections (e.g., malaria, Leishmaniasis), fungal infections, disorders involving disproportions in lymphoid cell sets and impaired immune functions due to aging, phagocyte disorders, Kostmann's agranulocytosis, chronic granulomatous disease, Chediak-Higachi syndrome, neutrophil actin deficiency, neutrophil membrane GP-180 deficiency, metabolic storage diseases, mucopolysaccharidoses, mucolipidoses, miscellaneous disorders involving immune mechanisms, Wiskott-Aldrich Syndrome granulocyte actin deficiency, infantile agranulocytosis, Gaucher's disease, adenosine deaminase deficiency, Kostmann's syndrome, reticular dysgenesis and congenital leukocyte dysfunction syndrome.

[0250] In one embodiment, the reasons for the lymphopenia, may be a particular medical condition, such as for example cancer, human immunodeficiency virus (HIV) infection, partial thymectomy, autoimmune disease, and / or organ transplant.

[0251] In one embodiment, the reasons for the immunodeficiency may be multiple: hereditary immune deficiency, chemotherapy such as for example for leukemia, conditioning, graft containing only stem cells, ionizing radiation, postgraft treatment for prophylaxis of GVHD (graft-versus-host disease), age of patient, and complications such as infections. In particular, the immunodeficiency may be due to the depletion of its immune cells following therapy before hematopoietic stem cell transplantation.

[0252] In one embodiment, the cancer is selected from the group comprising but not limited to leukemia (e.g., acute myeloid leukemia, B cell acute lymphoblastic leukemia (B-ALL), T cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia), lymphoma (e.g., B lymphomas, peripheral T cell lymphoma), non-Hodgkin lymphoma, glioblastoma, neuroblastoma, multiple myeloma, cervical cancer, breast cancer (e.g., Triple-negative breast cancer), ovarian cancer, bladder cancer, prostate cancer, pancreatic cancer, gastric cancer, thyroid cancer, melanoma, uterine cancer, kidney cancer, liver cancer (e.g., hepatocellularcancer), sarcoma, carcinoma (e.g., renal cell carcinoma, breast carcinoma), small cell lung cancer, non-small cell lung cancer, pediatric solid tumor, CD133+ cancer stem cells, NKGDL+ cancer cells, PD-L1+ cancer cells, oral and oropharyngeal cancer (e.g., tongue cancer, esophageal cancer, laryngeal cancer, pharyngeal cancer) methylcholanthrene- induced sarcomas and colorectal cancer.

[0253] The invention also relates to a method for treating a subject in need thereof, comprising administering to the subject at least one selected cellular bank. In one embodiment the subject is to be treated for a disease as described hereabove.

[0254] In one embodiment, the subject receiving at least one selected cellular bank does not receive an immunosuppressive treatment or therapeutic agents to prevent GVHD and / or rejection. In one embodiment, the subject receiving at least one selected cellular bank receives an immunosuppressive treatment or therapeutic agents to prevent GVHD and / or rejection.

[0255] In one embodiment, the method for treating a subject in need thereof, comprises or consists of the following step: a) selecting at least one cellular bank from a biobank comprising or consisting of at least two different cellular banks as described herein, and b) administrating to the subject the at least one cellular bank selected at step (a).

[0256] In one embodiment, the method for treating a subject in need thereof comprising administering to the subject at least one selected cellular bank with another selected cellular bank. In one embodiment, the method for treating a subject in need thereof comprising administering to the subject at least one selected cellular bank with an umbilical cord blood transplant or a mPB transplant. In one embodiment, the method for treating a subject in need thereof comprising administering to the subject at least one selected cellular bank with another therapeutic substance.

[0257] In one embodiment, the cellular banks are cryopreserved and thawed prior to be administered to the subject.

[0258] In one embodiment, a therapeutically effective amount of the cell of at least one selected cellular bank is administered (or is for administration) to a subject in need thereof.

[0259] In one embodiment, a therapeutically effective amount of the cell of at least one selected cellular bank is administered (or is for administration) to a subject in need thereof for, or for use for treating immunodeficiency, immune disorders and / or diseases such as inflammatory diseases or autoimmune diseases, lymphopenia or cancer for a subject in need thereof as described herein.

[0260] A therapeutically effective amount of the cell of at least one selected cellular bank may range from about 0. IxlO5to about IxlO7cells / kg body weight, preferably, from about 0.5xl05to about 5xl06cells / kg body weight, and more preferably from about IxlO6to about 3xl06cells / kg body weight. A therapeutically effective amount of the cell of at least one selected cellular bank may range from about 0.3 x 105cells and 1,5 x 109cells, from about 1.5 x 105and 7.5 x 108cells and more preferably to about 3 x 106and 4.5 x 108cells. A therapeutically effective amount of the cell of at least one selected cellular bank may range from about 5 x 105cells and 5 x 108cells, from about 2.5 x 106and 2.5 x 108cells and more preferably to about 5 x 107and 1.5 x 108cells.

[0261] In one embodiment, a selected cellular bank may be co-administrated with at least one another cellular bank as described herein, wherein said another cellular bank has the same homozygous HLA haplotype than the selected cellular bank. Said cellular banks are selected based on homozygous HLA haplotype as disclosed in the present invention, wherein the cells of said cellular banks may be different types of cells, such as for example, the first cellular bank to be administered comprises immune cells and the second cellular bank to be administered comprises HSPCs; or the first cellular bank to be administered comprises T cell progenitors and the second cellular bank to be administered comprises dendritic cells (DC). In one embodiment, the first cellular bank to be administrated and the second cellular bank to be administered have the same homozygous HLA haplotype. In one embodiment, the medicament administered to the subject further comprises at least one other cellular bank, wherein said at least one other cellular bank have the same homozygous HLA haplotype than the selected cellular bank. In oneembodiment, the administration of the cells of at least one of selected cellular bank is performed just prior to, just after or concomitantly with at least one another cellular bank.

[0262] In one embodiment, the cells of at least one of selected cellular bank, as described herein, are administrated to the subject combined with HSPCs, wherein said HSPCs comprise CD34+ or CD133+ cells. Such as for example, in vitro generated cells, T cell progenitors, gamma-delta T cells, progenitors of innate lymphoid cells (ILCs), ILCs, progenitors of NK cells, NK cells, progenitors of dendritic cells (DCs), DCs, granulocyte-monocyte progenitor cells, monocytes or macrophages may be administrated with HSPCs, wherein said HSPCs comprise CD34+ or CD133+ cells. In one embodiment, the administration of the cells of at least one of selected cellular bank is performed just prior to, just after or concomitantly with a HSPC transplant in the subject.

[0263] In one embodiment, the cells of at least one of selected cellular bank is for use as a medicament. Said medicament is to be administrated to the subject in combination with at least one umbilical cord blood transplant or at least one mPB transplant.

[0264] In one embodiment, the cells of at least one selected cellular bank are coadministrated with at least one umbilical cord blood transplant. In one embodiment, the cells of at least one of selected cellular bank is administrated just prior to, just after or concomitantly with an umbilical cord blood transplant in the subject.

[0265] In one embodiment, the cells of at least one selected cellular bank are coadministrated with at least mPB transplant. In one embodiment, the cells of at least one of selected cellular bank is administrated just prior to, just after or concomitantly with an mPB transplant in the subject.

[0266] In one embodiment, the cells of at least one of selected cellular bank is for use as a medicament. Said the medicament is to be administrated to the subject in combination with at least one another therapeutic substance. In one embodiment, the cells of at least one of selected cellular bank is administrated just prior to, just after or concomitantly with at least one another therapeutic substance.

[0267] In one embodiment, the method comprises administering to the subject at least one selected cellular bank combined with another therapeutic substance. In one embodiment, the medicament is to be administrated to the subject further comprises at least one another therapeutic agent. In one embodiment, the other therapeutic substance comprises cytokines, chemokines, growth factors, antibodies such as anti-PDl (programmed cell death protein 1) or PD-L1 (programmed cell death-ligand 1), chemotherapy molecules, hormones, immunosuppressive drugs, cell populations, cell engagers or recombinant proteins. In one embodiment, the cells of at least one of selected cellular bank is administrated just prior to, just after or concomitantly with the other therapeutic substance in the subject.

[0268] The present invention further relates to a composition comprising or consisting essentially of the cells of the at least one selected cellular bank of the invention.

[0269] In one embodiment, the composition is a pharmaceutical composition, and further comprises a pharmaceutically acceptable excipient.

[0270] Examples of pharmaceutically acceptable excipients that may be used in the pharmaceutical composition of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as, for example, human serum albumin, buffer substances such as, for example, phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as, for example, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (for example sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene- polyoxypropylene- block polymers, polyethylene glycol and wool fat.

[0271] In one embodiment, the composition is a medicament.

[0272] The present invention further relates to a composition comprising or consisting essentially of the cells of the at least one selected cellular bank of the invention, for, or for use for treating immunodeficiency, immune disorders and / or diseases (such as, forexample, inflammatory diseases or autoimmune diseases), lymphopenia or cancer for a subject in need thereof as described herein.

[0273] As used herein, the term “consisting essentially of’, with reference to a composition, pharmaceutical composition or medicament, means that the cells of at least one selected cellular bank are the only therapeutic agents or agents with a biologic activity within said composition, pharmaceutical composition or medicament.BRIEF DESCRIPTION OF THE DRAWINGS

[0274] Figure 1 is a representative illustration of mismatch count using asymmetric count method.

[0275] Figure 2A is a chart showing population coverage obtained with k optimal choices of donor’s HLA haplotypes (HLA-A, B and DRB1) when k (z.e., the size of the shelf) increases from 1 to 40. The different lines correspond to different definitions of compatibility, based on the number of mismatches 0 or 1 as determined using an asymmetric count only, z.e., wherein only HLA alleles of the cells of the donor that are not found in the patient or subject are taken into account. Figure 2B is chart showing the frequency of HLA haplotypes (HLA-A, B and DRB1) when the number of optimal haplotypes increases from 1 to 40 (z.e., the size of the shelf).

[0276] Figure 3A is chart showing population coverage obtained with k optimal choices of donor’s HLA haplotypes (HLA-A, B, C and DRB1) when k (z.e., the size of the shelf) increases from 1 to 40. The different lines correspond to different definitions of compatibility, based on the number of mismatches 0 or 1 as determined using an asymmetric count only, z.e., wherein only HLA alleles of the cells of the donor that are not found in the patient or subject are taken into account. Figure 3B is chart showing the frequency of HLA haplotypes (HLA-A, B, C and DRB1) when the number of optimal haplotypes (z.e., the size of the shelf) increases from 1 to 40.

[0277] Figure 4A is a representative illustration of preclinical mouse models (NSG mice) to asses GvHD occurrence after human CAR-ProT cells injection or human matureCAR T cells injection. Figure 4B is a chart showing the percentage of body weight loss of mice that receive human CAR-ProT cells or of mice that receive human mature CAR T cells over time. Figure 4C is a chart showing the assessment of GvHD occurrence in mice that receive human CAR-ProT cells or of mice that receive human mature CAR T cells, performed following the GvHD score based on the binary assessment (present / absent) of five clinical criteria of GvHD manifestation (body weight loss > 10%, hunching posture, skin lesions, dull fur and diarrhea).EXAMPLES

[0278] The present invention is further illustrated by the following example.Example 1 : Characterization of homozygous HLA haplotypes with the maximum probability to reach a large number of patients and frequency compatible efficient sourcing:Objective

[0279] The goal is to characterize the best HLA haplotypes for prepare cell banks with the maximum probability to reach a large number of patients, taking into account two criteria: estimating the coverage percentage of patients in a Caucasian population that are able to receive cell bank with a sufficient level of HLA compatibility; and- the frequency of occurrence HLA haplotypes in donors’ banks.Materials and MethodsDatabase

[0280] HLA haplotypes of 8298 patients undergoing UCBT from 1994 to 2022 in EBMT centers in Europe (including Russia and Turkey) were retrospectively collected and analyzed from EurocordZEBMT database. Eurocord database contains HLA types from transplanted patients and cord blood used for the transplantation. Low resolution HLA typing results were used for the analyses of HLA- A, -B, and -DRB1, considering 8092 patients corresponding to a total of 16184 alleles. A second analyses were performedseparately to take into account information on HLA-C on 6903 patients corresponding to a total of 13806 alleles. The ten most frequent haplotypes are listed on Table 1.Mismatches count

[0281] The degree of compatibility between a patient and a donor was evaluated based on counting mismatches between the donor’s HLA and the patient’s HLA. In practice, most of the cord blood HSCT (74-83%) are performed allowing 1 or 2 mismatches - indeed 6 / 6 or 5 / 6 HLA matched UCB / recipient pairs give similar results for survival, engraftment, GvHD and relapse.

[0282] In the present invention, the method used to count mismatches is an asymmetric count (Figure 1). The number of mismatches is defined by the number of HLA alleles of the donor that are not found in the patient. The asymmetric count naturally favors homozygous donors (homozygous HLA haplotypes). In Figure 2, 0 mismatch means that the patient has at least one allele in common with the cells of the donor for each of the HLA- A, HLA-B and HLA-DRB1 loci and 1 mismatch means that the patient has at least one allele in common with the cells of the selected cellular bank for only two of the HLA-A, HLA-B and HLA-DR loci. Accordingly, in Figure 3, 0 mismatch means that the patient has at least one allele in common with the cells of the donor for each of the HLA-A, HLA-B, HLA-C and HLA-DRB1 loci and 1 mismatch means that the patient has at least one allele in common with the cells of the selected cellular bank for only three of the HL A- A, HLA-B, HLA-C and HLA-DR loci.

[0283] It is assumed that there is a lower probability of antigen rejection if donor cells are homozygous for HLA antigens.Criteria

[0284] The coverage criteria alone is not sufficient to quantitatively estimate the worthiness of a choice of n cord blood HLA haplotypes. Indeed, we could well imagine a choice of n cord blood HLA haplotypes that maximize coverage, but are worthless in practice, because those HLA actually can’t be found in the natural population and / or in any donor bank. Therefore, a second criteria of choice is used, which is frequency of occurrence in donors’ banks.

[0285] The frequency of donor’s full haplotype (HLA l, HLA 2) is estimated with the following approximation:Frequency (HLA l, HLA 2) = Frequency (HLA l) x Frequency (HLA 2)

[0286] The worthiness of a choice of n cord blood HLA haplotypes is quantitatively estimated with the following criteria:Criteria = Coverage x FrequencyMathematic strategy

[0287] Given the criteria defined herein above, the objective is to determine a choice of n cord blood HLA haplotypes which is optimal with respect to the latter criteria. The latter problem can be expressed mathematically as:

[0288] X* = argmax_(X in {all possible choices}) Coverage(X) x Frequency(X) where variable X = (HLA l, HLA 2, ..., HLA n) corresponds to a choice of n cord blood HLA haplotypes; Coverage(X) corresponds to the coverage achieved by that choice and is obtained empirically on the Eurocord sample of patients; Frequency(X)corresponds to the product of the frequencies of each n donor’s HL A, as obtained empirically on the Eurocord sample of donors.

[0289] The above optimization problem is not trivial, it can be solved numerically using for instance an integer linear programming (ILP) scheme. However, given the large size of the set of all possible choices for X, such an ILP approach may have a prohibitively high computational cost if applied straightforwardly. We argue that a very good approximation of the solution can be obtained for a much lower computational cost, using instead a recursive optimization algorithm described below:

[0290] Initialization:The first donour’s HLA, denoted HLA l, is obtained as:HLA l = argmax_(HLA in {all possible donours}) Coverage(HLA) x Frequency (HL A) Recurrence k to k+1 :HLA_{k+l } = argmax_(HLA in {all possible donours}) Incremental_coverage_{k}(HLA) x Frequency (HL A) where Incremental_coverage_{k}(HLA) corresponds to the coverage achieved by HLA, but computed on a sub-population which consists of the patients which are not already covered by the first k selected donors (HLA l, HLA 2, . . . , HLA k).

[0291] From an implementation standpoint, this recursive scheme can be applied easily after computing the compatibility matrix C defined by:Cij = 1 if patient i is compatible with donor j, and 0 if not which requires to first compute the mismatch matrix M defined by:Mij = count of mismatches between patient i and donor j

[0292] Both matrices C and M are rectangular of dimension N x M with N the number of patients and M the number of different donors, in the Eurocord sample.Results

[0293] Using the method described hereinabove, the best homozygous HLA haplotypes comprising HLA A, B and DRB1 were first characterized. As shown in Figure 2A, 20 HLA haplotypes coverage reaches about 35% of the population if compatibility requireszero asymmetric mismatches, but increases to about 92% if compatibility requires at most one asymmetric mismatch. These coverages are achieved with HLA haplotypes that are all among the most frequent ones (Figure 2B). Said HLA Haplotypes are listed in table 2.

[0294] In a second time, the same evaluation was performed taking into account HLA-C. As shown in Figure 3A, 20 HLA haplotypes coverage reaches approximatively 25% of the population if compatibility requires zero asymmetric mismatches, but increases to about 70% if compatibility requires at most one asymmetric mismatch. These coverages are achieved with HLA haplotypes that are all among the most frequent ones (Figure 3B). Said HLA Haplotypes are listed in table 3.

[0295] Based on Eurocord dataset, if homozygotes cord blood units (UCBs) can be sourced from very large cell banks and if one mismatch with the recipient is tolerated, less than 20 different haplotypes HLA-A, -B, -DRB1 and about 20 different haplotypes HLA-A, -B, C, -DRB1 are sufficient to cover 70% of the Caucasian population. If only fully matched haplotypes HLA-A, -B, -DRB1 or HLA-A, -B, -C, -DRB1 are accepted, then the coverage of the population will be respectively of about 35% and 25% with 20 cell banks.Example 2: Characterization of GvHD occurrence after CAR-ProT cells injection in a preclinical model.Objectif

[0193] The goal is to characterize the safety of generated human ProT cells administration using a NSG mice model.Materials and MethodsHuman ProT cells

[0296] Human CD7+ CD34- ProT cells were obtained by the culture protocol described in WO2016 / 055396. Briefly CD34+ cells were transduced with a lentiviral vector coding for a CAR anti-human CD 19. Next, modified CD34+ were cultured in a medium comprising interleukin-7 (IL-7), Flt3-ligand (Flt-3L), stem cell factor (SCF) and thrombopoietin (TPO), TNF-alpha, fibronectin and an immobilized Notch ligand for 7 days.Mice modelA group on neonate NSG mice has received 2xl06HLA-unmatched CAR-ProT cells, issued from cord blood derived CD34+ cells, via intrahepatic injection. A second group of mice received 2xl06HLA-unmatched mature CD3+ T cells from healthy donor PBMC at 6 weeks age. Both groups received sub cutaneous injection of human IL2 (three times, 2500U per dose) and IL7 (twice, 5 pg per dose) between week 6 at seek 8 of age and GvHD has been scored during these two weeks (see Figure 4A). GvHD assessment has been performed following the score proposed by Naserian et al. 2018, which is based on the binary assessment (present / absent) of five clinical criteria of GvHD manifestation (body weight loss > 10%, hunching posture, skin lesions, dull fur and diarrhea).Results

[0297] As shown in Figures 4B and 4C, mice receiving HLA-unmatched CAR-ProT cells do not lose weight nor develop GvHD in comparison of mice receiving HLA- unmatched mature CAR T cells.

[0298] Therefore, said results demonstrate that ProT cells do no induced GvHD despite the absence of HLA matching.

Claims

CLAIMS1. An in vitro method for selecting at least one cellular bank to be administered to a subject from a biobank comprising at least two different cellular banks, each of the at least two cellular banks being different from each other and comprising T cell progenitors, wherein the T cell progenitors of a cellular bank have the same HLA homozygous haplotype, wherein said method comprises the following steps: a. determining the HLA haplotypes for HLA-B, and HL A-DR loci of the subj ect, b. comparing the HLA haplotypes determined at step a) with the HLA haplotypes of the cells of the cellular banks, and c. selecting at least one cellular bank based on said comparison, wherein the subject has (i) at least one allele in common with the cells of the selected cellular bank for at least one of the HLA-B and HLA-DR loci or (ii) a HLA- B leader sequence in common with the cells of the selected biobank.

2. The in vitro method according to claim 1, wherein said method comprises the following steps: a. determining the HLA haplotypes for HLA-A, HLA-Band HLA-DR loci of the subject, b. comparing the HLA haplotypes determined at step a) with the HLA haplotypes of the cells of the cellular banks, and c. selecting at least one cellular bank based on said comparison, wherein the subject has (i) at least one allele in common with the cells of the selected cellular bank for at least two of the HLA-A, HLA-B and HLA-DR loci or (ii) a HLA-B leader sequence in common with the cells of the selected biobank and at least one allele in common with the cells of the selected cellular bank for at least one of the HLA-A, and HLA-DR loci.

3. The in vitro method according to claim 1, wherein step a) further comprises determining the HLA haplotype of the subject for the HLA-C locus, and wherein at step c) at least one cellular bank is selected, wherein the subject has (i) at least one allele in common with the cells of the selected cellular bank for at least two of the HLA-B, HLA-C and HLA-DR loci or (ii) a HLA-B leader sequence in commonwith the cells of the selected biobank and at least one allele in common with the cells of the selected cellular bank for at least one of the HLA-C, and HLA-DR loci.

4. The in vitro method according to claim 1 or 2, wherein step a) further comprises determining the HLA haplotype of the subject for the HLA-C locus, and wherein at step c) at least one cellular bank is selected, wherein the subject has at least one allele in common with the cells of the selected cellular bank for at least three of the HLA- A, HLA-B, HLA-C and HLA-DR loci or (ii) a HLA-B leader sequence in common with the cells of the selected biobank and at least one allele in common with the cells of the selected cellular bank for at least two of the HLA-A, HLA-C, and HLA-DR loci.

5. The in vitro method according to any one of claims 1 and 3, wherein the cells of the biobank are genetically modified to reduce or abolish the expression of HLA-A at the cell surface.

6. The in vitro method according to any one of claims 1 to 5, wherein at step c), a cellular bank is selected based on the comparison of HLA haplotypes of step b), and wherein the subject has at least one allele in common with the cells of the selected cellular bank for each of the HLA loci determined at step a).

7. The in vitro method according to any one of claims 1 to 5, wherein at step c), a cellular bank is selected based on the comparison of HLA haplotypes of step b), and wherein the subject has a HLA-B leader sequence in common with the cells of the selected biobank and has at least one allele in common with the cells of the selected cellular bank for each of the other HLA loci determined at step a).

8. The in vitro method according to any one of claims 1 to 7, wherein the cells of the selected cellular bank and the subject have zero, one, two, three, four or five HLA mismatches.

9. The in vitro method according to any one of claims 1 to 8, wherein the HLA-DR is HLA-DRA, HLA-DRB1, HLA-DRB3, HLA-DRB4 or HLA-DRB5, preferably HLA-DRB1.

10. A selected cellular bank comprising T cell progenitors, according to any one of claims 1 to 9, for use as a medicament, preferably for use in the treatment of immunodeficiency, immune disorders and / or diseases, lymphopenia or cancer in a subject in need thereof.

11. The selected cellular bank comprising T cell progenitors for use according to claim 10, wherein the medicament is to be administrated to the subject in combination with: a. at least one other cellular bank, wherein said another cellular bank has the same homozygous HLA haplotype than the selected cellular bank, b. at least one other therapeutic substance, and / or c. at least one umbilical cord blood transplant or at least one mobilized peripheral blood (mPB) transplant.

12. A computer implemented method for selecting homozygous HLA haplotypes to prepare a biobank of at least two different cellular banks, wherein the selection of homozygous HLA haplotypes is estimated using the following formula: variable X = (HL A l, HLA 2, ..., HLA n) corresponds to a choice of n HLA haplotypes; argmax stands for argument of the maxima and is well known from the skilled artisan;Coverage(X) corresponds to the coverage achieved by that choice and is obtained empirically on the database sample of patients;Frequency(X) corresponds to the product of the frequencies of each n donor’ s HLA, as obtained empirically on the database sample of donors.

13. A biobank comprising at least two different cellular banks, wherein said at least two cellular banks do not comprise alpha-beta T cells, wherein each cellular bank comprises cells from at least one donor and wherein the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HLA haplotypes: A*01-B*08-DRBl*03_A*01-B*08-DRBl*03, A*01-B*13-DRBl*07_A*01-B*13-DRBl*07, A*01-B*35-DRBl*l l_A*01-B*35-DRBl*l l,A*02-B*07-DRBl*01_A*02-B*07-DRBl*01, A*02-B*07-DRBl*04_A*02-B*07-DRBl*04, A*02-B*07-DRB 1 * 15_A*02-B*07-DRB 1*15, A*02-B* 15-DRB 1 *04_A*02-B* 15-DRB 1 *04, A*02-B* 18-DRB 1 *03_A*02-B* 18-DRB 1*03, A*02-B* 18- DRB 1 * 1 l_A*02-B* 18-DRB 1*11, A*02-B*35-DRBl*04_A*02-B*35-DRBl*04, A*02-B*35-DRB 1 * 1 l_A*02-B*35-DRB 1 * 11, A*02-B*44-DRBl*04_A*02-B*44-DRBl*04, A*O2-B*44-DRB1*O7_A*O2-B*44-DRB1*O7, A*02-B*44-DRB 1 * 13_A*02-B*44-DRB 1*13, A*02-B*51-DRB 1 *04_A*02-B*51-DRB 1 *04, A* 02-B * 51 -DRB 1 * 11 _A * 02-B * 51 -DRB 1 * 11 , A*02-B*51-DRBl*13_A*02-B*51-DRBl*13, A*03-B*07-DRBl*15_A*03-B*07-DRBl*15, A*03-B*14-DRBl*01_A*03-B*14-DRBl*01, A*03-B*35-DRBl*01_ A*03-B*35-DRBl*01, A*03-B*35-DRBl*04_A*03-B*35-DRBl*04, A*l l-B*35-DRBl*01_A*ll-B*35-DRBl*01, A*24-B*35-DRB1*11_A*24-B*35-DRB1*11, A*24-B*44-DRB 1 * 13_A*24-B*44-DRB 1*13, A* 24-B * 51 -DRB 1 * 11 _A * 24-B * 51 -DRB 1 * 11 , A*29-B*44-DRB 1 *07_A*29-B *44-DRB 1 *07, or A*68-B*53-DRB1*13_A*68-B*53-DRB1*13.

14. The biobank according to claim 13, wherein the cells of at least one cellular bank have one of the following homozygous HLA haplotypes: A*01-B*13-DRBl*07_A*01-B*13-DRBl*07, A*01-B*35-DRBl*ll_ A*01-B*35-DRBl*ll, A*02-B*07-DRBl*04_A*02-B*07-DRBl*04, A*02-B* 18-DRB 1 *03_A*02-B* 18-DRB 1*03, A*02-B* 18- DRB 1 * 1 l_A*02-B* 18-DRB 1*11,A*03-B*14-DRBl*01_A*03-B*14-DRBl*01, A*03-B*35-DRBl*04_A*03-B*35-DRBl*04, A*24-B*44-DRB 1 * 13_A*24-B*44-DRB 1*13, A*24-B*51-DRB1*11_A*24-B*51-DRB1*11, or A*68-B*53-DRB1*13_A*68-B*53-DRB1*13.

15. The biobank according to claim 13 or 14, wherein the cells of at least one, preferably of each of the at least two different cellular banks have one of the following homozygous HL A haplotypes: A*01-B*08-C*07-DRBl*03_A*01-B*08-C*07-DRBl*03, A*01-B*35-C*04-DRBl*04_A*01-B*35-C*04-DRBl*04, A*01-B*35-C*04-DRBl*ll_A*01-B*35-C*04-DRBl*ll, A*01-B*57-C*06-DRBl*07_A*01-B*57-C*06-DRBl*07, A*02-B*07-C*07-DRBl*01_A*02-B*07-C*07-DRBl*01, A*02-B*07-C*07-DRBl*04_A*02-B*07-C*07-DRBl*04, A*02-B*07-C*07-DRB 1-1 l_A*02-B*07-C*07-DRB 1-11, A*02-B*07-C*07-DRB 1 * 13_A*02-B*07-C*07-DRB 1*13, A-02-B *07-C*07-DRB 1 * 15_A-02-B*07-C*07-DRB 1*15, A*02-B*08-C*07-DRBl*03_A*02-B*08-C*07-DRBl*03, A*02-B* 13-C*06-DRB 1 *07_A*02-B* 13-C*06-DRB 1 *07, A*02-B* 14-C*08-DRB 1 *01_A*02-B* 14-C*08-DRB 1*01, A*02-B*15-C*03-DRBl*04_A*02-B*15-C*03-DRBl*04, A*02-B* 15-C*03-DRB 1 * 13_A*02-B* 15-C*03-DRB 1*13, A*02-B*18-C*05-DRBl*03_A*02-B*18-C*05-DRBl*03, A*02-B* 18-C*07-DRB 1 * 1 l_A*02-B* 18-C*07-DRB 1*11, A*02-B*27-C*01-DRBl*01_A*02-B*27-C*01-DRBl*01, A*02-B*27-C*02-DRBl*04_A*02-B*27-C*02-DRBl*04, A*02-B*35-C*04-DRBl*04_A*02-B*35-C*04-DRBl*04, A*02-B*35-C*04-DRBl*07_A*02-B*35-C*04-DRBl*07, A*02-B*35-C*04-DRB 1 * 1 l_A*02-B*35-C*04-DRB 1*11, A*02-B*35-C*04-DRBl*13_A*02-B*35-C*04-DRBl*13, A*02-B*40-C*03-DRBl*04_A*02-B*40-C*03-DRBl*04,A*02-B*44-C*05-DRBl*01_A*02-B*44-C*05-DRBl*01, A*02-B*44-C*05-DRBl*04_A*02-B*44-C*05-DRBl*04, A*02-B*44-C*05-DRB 1 * 13_A*02-B*44-C*05-DRB 1*13, A*02-B*44-C*07-DRBl*07_A*02-B*44-C*07-DRBl*07, A*02-B*49-C*07-DRB 1 * 1 l_A*02-B*49-C*07-DRB 1*11, A*02-B*50-C*06-DRBl*07_A*02-B*50-C*06-DRBl*07, A*02-B*51-C* 15-DRB 1 * 1 l_A*02-B*51-C* 15-DRB 1*11, A*03-B*07-C*07-DRBl*04_A*03-B*07-C*07-DRBl*04, A*03-B*07-C*07-DRB 1 * 1 l_A*03-B*07-C*07-DRB 1*11, A*03-B*07-C*07-DRBl*15_A*03-B*07-C*07-DRBl*15, A*03-B*35-C*04-DRBl*01_ A*03-B*35-C*04-DRBl*01, A*03-B*35-C*04-DRBl*04_A*03-B*35-C*04-DRBl*04, A*03-B*35-C*04-DRB 1 * 1 l_A*03-B*35-C*04-DRB 1*11, A*03-B*52-C* 12-DRB 1 * 15_A*03-B*52-C* 12-DRB 1*15, A*l l-B*35-C*04-DRBl*01_A*l l-B*35-C*04-DRBl*01, A*l l-B*35-C*04-DRBl*04_A*l l-B*35-C*04-DRBl*04, A*23-B*44-C*04-DRBl*07_A*23-B*44-C*04-DRBl*07, A*24-B*35-C*O4-DRB1*O4_A*24-B*35-C*O4-DRB1*O4, A*24-B*35-C*04-DRB 1 * 1 l_A*24-B*35-C*04-DRB 1*11, A*24-B*44-C*07-DRB 1 * 15_A*24-B*44-C*07-DRB 1*15, A*24-B*51-C*15-DRB1*11_A*24-B*51-C*15-DRB1*11, A*24-B*51-C*15-DRB1*13_A*24-B*51-C*15-DRB1*13, A*25-B* 18-C* 12-DRB 1 * 15_A*25-B* 18-C* 12-DRB 1*15, A*29-B*44-C* 16-DRB 1 *07_A*29-B*44-C* 16-DRB 1 *07, A*29-B*44-C* 16-DRB 1 * 11_A*29-B*44-C* 16-DRB 1*11, A*30-B* 13-C*06-DRB 1 *07_A*30-B* 13-C*06-DRB 1 *07, A*30-B* 18-C*05-DRB 1 *03_A*30-B* 18-C*05-DRB 1 *03, or A*68-B*53-C*04-DRB 1*13 A*68-B*53-C*04-DRB 1*13.

16. The biobank according to any one of claims 13 to 15, wherein the cells comprised in the cellular bank comprise or consist of immune cells, preferably comprises orconsists of cells enriched in lymphoid progenitor cells, and more preferably comprises or consists of T cell progenitors.

17. The biobank according to any one of claims 13 to 16, wherein the cells comprised in the cellular bank are in vitro generated T cell progenitors obtained by culturing CD34+ cells in a medium comprising fibronectin, an immobilized Notch ligand, TNF-alpha and / or an antagonist of the Arylhydrocarbon / Dioxin receptor, in particular StemRegenin 1 (SRI), and at least 3, preferably 4 cytokines selected from the group consisting of human SCF, human Flt3-L, human TPO and human IL-7.

18. The biobank according to any one of claims 13 to 17, wherein the cells comprised in the cellular bank contain a sequence of encoding a Chimeric Antigen Receptor (CAR) and / or an exogenous T cells receptor (TCR).

19. The biobank according to any one of claims 13 to 18; wherein the cells comprised in the cellular bank are genetically modified by a viral vector, a nucleic acid fragment, a plasmid or plasmidic RNA or DNA sequences, a system of gene editing, a system of base editing, a system of prime- editing and / or wherein the cells comprised in the cellular bank are epigenetically modified.

20. The in vitro method according to any one of claims 1 to 9, wherein the biobank is the biobank according to any one of claims 13 to 19.

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