Biological sample bank with cell banks of specific homozygous HLA haplotypes and their use in treatment of patients

Abstract

The present invention relates to a biological sample bank comprising at least two cell biological sample banks wherein the cells of the cell biological sample bank may be immune cells or hematopoietic stem and progenitor cells (HSPC) or in vitro produced T cell progenitor cells wherein the cells of each cell bank have a specific homozygous human leukocyte antigen (HLA) haplotype. The invention also relates to a method for selecting at least one cell bank, and to the use of the selected cell bank as an agent, in particular for the treatment of immunodeficiencies, immune disorders and / or diseases, lymphopenia or cancer, and covering a large number of patients.

Description

Technical Field

[0001] This invention relates to a biobank comprising cell banks, preferably at least two different cell banks, wherein the cells in each cell bank have a specific homozygous HLA haplotype. The invention also relates to a method for selecting cell banks from the biobank of the invention for use in treating subjects, and the use of the selected cell banks as pharmaceutical agents, particularly for treating immunodeficiency, immune disorders, lymphopenia, or cancer, and covering a large number of patients. Background Technology

[0002] The human leukocyte antigen (HLA) system refers to the major histocompatibility complex (MHC) in the human body. HLA molecules are cell surface glycoproteins encoded by genes located on the short arm of chromosome 6 (6p21). HLA genes are highly polymorphic, with each individual possessing a specific combination of two haplotypes at each HLA locus. The proteins encoded by HLA genes are also known as antigens. The HLA system is crucial for immune function, presenting endogenous and exogenous antigens to lymphocytes. Therefore, HLA molecules play an important role in defending against diseases, pathogens, or tumor cells, for example, through cell-mediated cytotoxic processes or by regulating humoral immune responses. They may also mediate autoimmune diseases by presenting self-antigens (e.g., disruption of immune tolerance) and may trigger transplant rejection.

[0003] HLA molecules are divided into three classes: HLA class I (HLA-A, HLA-B, and HLA-C), HLA class II (HLA-DP, HLA-DQ, and HLA-DR), and class III (which do not participate in adaptive immune responses).

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

[0005] HLA class II molecules are present on the surface of antigen-presenting cells (APCs). These molecules display exogenous antigenic peptides to CD4+ helper T cell receptors, inducing T cell stimulation. The activated CD4+ helper T cells then stimulate the production of specific antigen antibodies 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 among the most polymorphic genes in the human genome (more than 30,000 alleles have been identified to date). In the context of allogeneic transplantation, even though diversity is significantly reduced due to the widespread presence and sharing of alleles among different populations, the probability of two individuals having a strict allele match remains extremely low. This can contribute to recipient rejection of donor tissues or cells or, in the case of hematopoietic stem cell transplantation, to graft-versus-host disease (GvHD). Despite improvements in haploidentical transplantation over the years, the procedure remains associated with early and late complications, including infection, graft-versus-host disease, and organ toxicity.

[0008] Future directions focus on innovative research into the fundamental biology of umbilical cord blood (UCB) cells, enabling more patients to access UCB units through promising therapeutic strategies. Optimal selection of UCB units requires consideration of unit quality, total nucleated cell (TNC) dose per kilogram of recipient body weight, and HLA matching. Numerous clinical trials are underway using cells derived from cryopreserved UCB units, including diverse subtypes such as T lymphocytes, mesenchymal stromal cells, NK (natural killer) cells, expanded CD34+ cells, and cells derived from induced pluripotent stem cells, which collectively promote engraftment, immune reconstitution, or antitumor activity. The infusion of in vitro derived human progenitor T cells (ProTcells) has been described as a promising therapeutic strategy for delivering a new wave of T cell progenitors to patients, which can accelerate the generation of mature lymphoid grafts and a polyclonal T cell spectrum, thereby preventing severe viral and fungal infections and relapse of malignant diseases. Studies have shown that infusion of off-the-shelf expanded umbilical cord blood (UCB) cell products is safe and produces sustained bone marrow recovery, in addition to traditional grafts. Based on these encouraging results, prospective, multicenter, randomized trials using such products have been conducted. In this context, cryopreserved UCB cells, along with mobilized peripheral blood cells and iPS cells, provide ideal samples for the development of potential off-the-shelf cell therapy products. HLA-based sample selection criteria have not yet been described. While the current trend in using “off-the-shelf” cells is to circumvent tissue compatibility barriers, this invention aims to reduce HLA differential levels to improve further outcomes of allogeneic cell transplantation and allogeneic cell therapy.

[0009] Therefore, in this context, the present invention relates to a biobank comprising a cell bank (“off-the-shelf” cell bank) having a specific homozygous HLA haplotype to suit a large number / proportion of patients and improve the outcomes of allogeneic cell transplantation or allogeneic cell therapy. Summary of the Invention

[0010] This invention relates to an in vitro method for selecting at least one cell bank from a biobank for administration to a subject, the biobank comprising at least two different cell banks, each of the at least two cell banks being distinct from each other and containing T cell progenitor cells, wherein the T cell progenitor cells of the cell banks have the same HLA homozygous haplotype, wherein the method comprises the following steps: a. Determine the HLA haplotypes of the subject's HLA-B and HLA-DR loci. b. Compare the HLA haplotypes determined in step a) with the HLA haplotypes of cells in the cell bank, and c. Based on the comparison, select at least one cell bank, wherein the subject (i) shares at least one allele with cells of the selected cell bank at at least one of the HLA-B or HLA-DR loci or (ii) shares an HLA-B leader sequence with cells of the selected biosample bank.

[0011] In one embodiment, the in vitro method includes the following steps: a. Determine the HLA haplotypes of the subjects at the HLA-A, HLA-B, and HLA-DR loci. b. Compare the HLA haplotypes determined in step a) with the HLA haplotypes of cells in the cell bank, and c. Based on the comparison, select at least one cell bank, wherein the subject (i) shares at least one allele with cells of the selected cell bank at at least two of the HLA-A, HLA-B, and HLA-DR loci, or (ii) shares an HLA-B leader sequence with cells of the selected biosample bank and shares at least one allele with cells of the selected cell bank at at least one of the HLA-A and HLA-DR loci.

[0012] In one embodiment, step a) of the in vitro method further includes determining the subject's HLA haplotype at the HLA-C locus, and step c) selecting at least one cell bank, wherein the subject (i) shares at least one allele with cells of the selected cell bank at at least two of the HLA-B, HLA-C, and HLA-DR loci, or (ii) shares an HLA-B leader sequence with cells of the selected biosample bank and shares at least one allele with cells of the selected cell bank at at least one of the HLA-C and HLA-DR loci.

[0013] In one embodiment, step a) of the in vitro method further includes determining the subject's HLA haplotype at the HLA-C locus, and step c) selecting at least one cell bank, wherein the subject shares at least one allele with cells of the selected cell bank at at least three of the HLA-A, HLA-B, HLA-C, and HLA-DR loci, or (ii) shares an HLA-B leader sequence with cells of the selected biosample bank and shares at least one allele with cells of the selected cell bank at at least two of the HLA-A, HLA-C, and HLA-DR loci.

[0014] In one implementation, the cells of the biobank are genetically modified to reduce or eliminate the expression of HLA-A on the cell surface.

[0015] In one embodiment, in step c) of the in vitro method, a cell bank is selected based on the comparison of HLA haplotypes in step b), and the subject shares at least one allele with cells from the selected cell bank at each of the HLA loci identified in step a).

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

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

[0018] In one embodiment, HLA-DR is HLA-DRA, HLA-DRB1, HLA-DRB3, HLA-DRB4 or HLA-DRB5, with HLA-DRB1 being preferred.

[0019] The present invention also relates to a selected cell bank containing T cell progenitor cells, said selected cell bank being used as a pharmaceutical agent, preferably for treating immunodeficiency, immune disorders and / or diseases, lymphopenia or cancer in subjects in need.

[0020] In one implementation scheme, the drug is to be administered to the subject in combination with the following: a. At least another cell bank, wherein the other cell bank has the same homozygous HLA haplotype as the selected cell bank. b. At least another therapeutic substance, and / or c. At least one umbilical cord blood transplant or at least one mPB transplant.

[0021] This invention also relates to a computer-implemented method for selecting homozygous HLA haplotypes to prepare a biobank having at least two different cell banks, wherein the selection of homozygous HLA haplotypes is evaluated using the following formula: The variable X = (HLA_1, HLA_2, ..., HLA_n) corresponds to the selection of n HLA haplotypes; argmax represents the independent variable corresponding to the maximum value, and it is familiar to skilled technicians; The coverage (X) corresponds to the coverage achieved by this selection and is obtained empirically based on a sample of the patient database; Frequency (X) corresponds to the product of the frequencies of HLA for each of the n donors, obtained empirically from a database sample based on the donors.

[0022] The present invention also relates to a biobank comprising at least two different cell banks, wherein the at least two cell banks do not contain α-β T cells, wherein each cell bank contains cells from at least one donor, and wherein at least one of the at least two different cell banks, preferably each of the cell banks, has cells with one of the following homozygous HLA haplotypes: A*01-B*08-DRB1*03__A*01-B*08-DRB1*03、 A*01-B*13-DRB1*07__A*01-B*13-DRB1*07、 A*01-B*35-DRB1*11__A*01-B*35-DRB1*11、 A*02-B*07-DRB1*01__A*02-B*07-DRB1*01、 A*02-B*07-DRB1*04__A*02-B*07-DRB1*04、 A*02-B*07-DRB1*15__A*02-B*07-DRB1*15、 A*02-B*15-DRB1*04__A*02-B*15-DRB1*04、 A*02-B*18-DRB1*03__A*02-B*18-DRB1*03、 A*02-B*18-DRB1*11__A*02-B*18-DRB1*11、 A*02-B*35-DRB1*04__A*02-B*35-DRB1*04、 A*02-B*35-DRB1*11__A*02-B*35-DRB1*11、 A*02-B*44-DRB1*04__A*02-B*44-DRB1*04、 A*02-B*44-DRB1*07__A*02-B*44-DRB1*07、 A*02-B*44-DRB1*13__A*02-B*44-DRB1*13、 A*02-B*51-DRB1*04__A*02-B*51-DRB1*04、 A*02-B*51-DRB1*11__A*02-B*51-DRB1*11、 A*02-B*51-DRB1*13__A*02-B*51-DRB1*13、 A*03-B*07-DRB1*15__A*03-B*07-DRB1*15、 A*03-B*14-DRB1*01__A*03-B*14-DRB1*01、 A*03-B*35-DRB1*01__A*03-B*35-DRB1*01、 A*03-B*35-DRB1*04__A*03-B*35-DRB1*04、 A*11-B*35-DRB1*01__A*11-B*35-DRB1*01、 A*24-B*35-DRB1*11__A*24-B*35-DRB1*11、 A*24-B*44-DRB1*13__A*24-B*44-DRB1*13、 A*24-B*51-DRB1*11__A*24-B*51-DRB1*11、 A*29-B*44-DRB1*07__A*29-B*44-DRB1*07 or A*68-B*53-DRB1*13__A*68-B*53-DRB1*13.

[0023] In one embodiment, the cells of at least one cell bank have one of the following homozygous HLA haplotypes: A*01-B*13-DRB1*07__A*01-B*13-DRB1*07、 A*01-B*35-DRB1*11__A*01-B*35-DRB1*11、 A*02-B*07-DRB1*04__A*02-B*07-DRB1*04、 A*02-B*18-DRB1*03__A*02-B*18-DRB1*03、 A*02-B*18-DRB1*11__A*02-B*18-DRB1*11、 A*03-B*14-DRB1*01__A*03-B*14-DRB1*01、 A*03-B*35-DRB1*04__A*03-B*35-DRB1*04、 A*24-B*44-DRB1*13__A*24-B*44-DRB1*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.

[0024] In one embodiment, at least one of at least two different cell banks, preferably each of which has cells with one of the following homozygous HLA haplotypes: A*01-B*08-C*07-DRB1*03__A*01-B*08-C*07-DRB1*03, A*01-B*35-C*04-DRB1*04__A*01-B*35-C*04-DRB1*04、 A*01-B*35-C*04-DRB1*11__A*01-B*35-C*04-DRB1*11、 A*01-B*57-C*06-DRB1*07__A*01-B*57-C*06-DRB1*07、 A*02-B*07-C*07-DRB1*01__A*02-B*07-C*07-DRB1*01、 A*02-B*07-C*07-DRB1*04__A*02-B*07-C*07-DRB1*04、 A*02-B*07-C*07-DRB1-11__A*02-B*07-C*07-DRB1-11、 A*02-B*07-C*07-DRB1*13__A*02-B*07-C*07-DRB1*13、 A-02-B*07-C*07-DRB1*15__A-02-B*07-C*07-DRB1*15、 A*02-B*08-C*07-DRB1*03__A*02-B*08-C*07-DRB1*03、 A*02-B*13-C*06-DRB1*07__A*02-B*13-C*06-DRB1*07、 A*02-B*14-C*08-DRB1*01__A*02-B*14-C*08-DRB1*01、 A*02-B*15-C*03-DRB1*04__A*02-B*15-C*03-DRB1*04、 A*02-B*15-C*03-DRB1*13__A*02-B*15-C*03-DRB1*13、 A*02-B*18-C*05-DRB1*03__A*02-B*18-C*05-DRB1*03、 A*02-B*18-C*07-DRB1*11__A*02-B*18-C*07-DRB1*11、 A*02-B*27-C*01-DRB1*01__A*02-B*27-C*01-DRB1*01、 A*02-B*27-C*02-DRB1*04__A*02-B*27-C*02-DRB1*04、 A*02-B*35-C*04-DRB1*04__A*02-B*35-C*04-DRB1*04、 A*02-B*35-C*04-DRB1*07__A*02-B*35-C*04-DRB1*07、 A*02-B*35-C*04-DRB1*11__A*02-B*35-C*04-DRB1*11、 A*02-B*35-C*04-DRB1*13__A*02-B*35-C*04-DRB1*13、 A*02-B*40-C*03-DRB1*04__A*02-B*40-C*03-DRB1*04、 A*02-B*44-C*05-DRB1*01__A*02-B*44-C*05-DRB1*01、 A*02-B*44-C*05-DRB1*04__A*02-B*44-C*05-DRB1*04、 A*02-B*44-C*05-DRB1*13__A*02-B*44-C*05-DRB1*13、 A*02-B*44-C*07-DRB1*07__A*02-B*44-C*07-DRB1*07、 A*02-B*49-C*07-DRB1*11__A*02-B*49-C*07-DRB1*11、 A*02-B*50-C*06-DRB1*07__A*02-B*50-C*06-DRB1*07、 A*02-B*51-C*15-DRB1*11__A*02-B*51-C*15-DRB1*11、 A*03-B*07-C*07-DRB1*04__A*03-B*07-C*07-DRB1*04、 A*03-B*07-C*07-DRB1*11__A*03-B*07-C*07-DRB1*11、 A*03-B*07-C*07-DRB1*15__A*03-B*07-C*07-DRB1*15、 A*03-B*35-C*04-DRB1*01__A*03-B*35-C*04-DRB1*01、 A*03-B*35-C*04-DRB1*04__A*03-B*35-C*04-DRB1*04、 A*03-B*35-C*04-DRB1*11__A*03-B*35-C*04-DRB1*11、 A*03-B*52-C*12-DRB1*15__A*03-B*52-C*12-DRB1*15、 A*11-B*35-C*04-DRB1*01__A*11-B*35-C*04-DRB1*01、 A*11-B*35-C*04-DRB1*04__A*11-B*35-C*04-DRB1*04、 A*23-B*44-C*04-DRB1*07__A*23-B*44-C*04-DRB1*07、 A*24-B*35-C*04-DRB1*04__A*24-B*35-C*04-DRB1*04、 A*24-B*35-C*04-DRB1*11__A*24-B*35-C*04-DRB1*11、 A*24-B*44-C*07-DRB1*15__A*24-B*44-C*07-DRB1*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-DRB1*15__A*25-B*18-C*12-DRB1*15、 A*29-B*44-C*16-DRB1*07__A*29-B*44-C*16-DRB1*07、 A*29-B*44-C*16-DRB1*11__A*29-B*44-C*16-DRB1*11、 A*30-B*13-C*06-DRB1*07__A*30-B*13-C*06-DRB1*07、 A*30-B*18-C*05-DRB1*03__A*30-B*18-C*05-DRB1*03 or A*68-B*53-C*04-DRB1*13__A*68-B*53-C*04-DRB1*13.

[0025] In one embodiment, the cells contained in the cell bank comprise or consist of immune cells, preferably comprise or consist of cells rich in lymphoid progenitor cells, and more preferably comprise or consist of T cell progenitor cells.

[0026] In one embodiment, the cells contained in the cell bank are in vitro-generated T cell progenitor cells obtained by culturing CD34+ cells in a culture medium containing fibronectin, immobilized Notch ligand, TNF-α and / or aryl hydrocarbon / dioxin receptor antagonists, particularly StemRegenin 1 (SR1), and at least three, preferably four, cytokines selected from the group consisting of: human SCF, human Flt3-L, human TPO, and human IL-7.

[0027] In one implementation, the cells contained in the cell bank contain sequences encoding chimeric antigen receptors (CARs) and / or exogenous T-cell receptors (TCRs).

[0028] In one implementation, the cells contained in the cell bank are genetically modified using viral vectors, nucleic acid fragments, plasmids or plasmid RNA or DNA sequences, gene editing systems, base editing systems, lead editing systems, and / or the cells contained in the cell bank are epigenetically modified.

[0029] In one embodiment, the biobank for selecting at least one cell bank to be administered to a subject via in vitro methods is the biobank described in this invention.

[0030] This invention relates to a biobank comprising at least two cell banks, wherein the cell banks do not contain α-β T cells, wherein each cell bank contains cells from at least one donor, and wherein the cells of each cell bank have one of the following homozygous HLA haplotypes: A*01-B*08-DRB1*03__A*01-B*08-DRB1*03、 A*01-B*13-DRB1*07__A*01-B*13-DRB1*07、 A*01-B*35-DRB1*11__A*01-B*35-DRB1*11、 A*02-B*07-DRB1*01__A*02-B*07-DRB1*01、 A*02-B*07-DRB1*04__A*02-B*07-DRB1*04、 A*02-B*07-DRB1*15__A*02-B*07-DRB1*15、 A*02-B*15-DRB1*04__A*02-B*15-DRB1*04、 A*02-B*18-DRB1*03__A*02-B*18-DRB1*03、 A*02-B*18-DRB1*11__A*02-B*18-DRB1*11、 A*02-B*35-DRB1*04__A*02-B*35-DRB1*04、 A*02-B*35-DRB1*11__A*02-B*35-DRB1*11、 A*02-B*44-DRB1*04__A*02-B*44-DRB1*04、 A*02-B*44-DRB1*07__A*02-B*44-DRB1*07、 A*02-B*44-DRB1*13__A*02-B*44-DRB1*13、 A*02-B*51-DRB1*04__A*02-B*51-DRB1*04、 A*02-B*51-DRB1*11__A*02-B*51-DRB1*11、 A*02-B*51-DRB1*13__A*02-B*51-DRB1*13、 A*03-B*07-DRB1*15__A*03-B*07-DRB1*15、 A*03-B*14-DRB1*01__A*03-B*14-DRB1*01、 A*03-B*35-DRB1*01__A*03-B*35-DRB1*01、 A*03-B*35-DRB1*04__A*03-B*35-DRB1*04、 A*11-B*35-DRB1*01__A*11-B*35-DRB1*01、 A*24-B*35-DRB1*11__A*24-B*35-DRB1*11、 A*24-B*44-DRB1*13__A*24-B*44-DRB1*13、 A*24-B*51-DRB1*11__A*24-B*51-DRB1*11、 A*29-B*44-DRB1*07__A*29-B*44-DRB1*07、 A*68-B*53-DRB1*13__A*68-B*53-DRB1*13.

[0031] In one implementation, the cells in each cell bank also possess one of the following homozygous HLA haplotypes: A*01-B*08-C*07-DRB1*03__A*01-B*08-C*07-DRB1*03, A*01-B*35-C*04-DRB1*04__A*01-B*35-C*04-DRB1*04、 A*01-B*35-C*04-DRB1*11__A*01-B*35-C*04-DRB1*11、 A*01-B*57-C*06-DRB1*07__A*01-B*57-C*06-DRB1*07、 A*02-B*07-C*07-DRB1*01__A*02-B*07-C*07-DRB1*01、 A*02-B*07-C*07-DRB1*04__A*02-B*07-C*07-DRB1*04、 A*02-B*07-C*07-DRB1-11__A*02-B*07-C*07-DRB1-11、 A*02-B*07-C*07-DRB1*13__A*02-B*07-C*07-DRB1*13、 A-02-B*07-C*07-DRB1*15__A-02-B*07-C*07-DRB1*15、 A*02-B*08-C*07-DRB1*03__A*02-B*08-C*07-DRB1*03、 A*02-B*13-C*06-DRB1*07__A*02-B*13-C*06-DRB1*07、 A*02-B*14-C*08-DRB1*01__A*02-B*14-C*08-DRB1*01、 A*02-B*15-C*03-DRB1*04__A*02-B*15-C*03-DRB1*04、 A*02-B*15-C*03-DRB1*13__A*02-B*15-C*03-DRB1*13、 A*02-B*18-C*05-DRB1*03__A*02-B*18-C*05-DRB1*03、 A*02-B*18-C*07-DRB1*11__A*02-B*18-C*07-DRB1*11、 A*02-B*27-C*01-DRB1*01__A*02-B*27-C*01-DRB1*01、 A*02-B*27-C*02-DRB1*04__A*02-B*27-C*02-DRB1*04、 A*02-B*35-C*04-DRB1*04__A*02-B*35-C*04-DRB1*04、 A*02-B*35-C*04-DRB1*07__A*02-B*35-C*04-DRB1*07、 A*02-B*35-C*04-DRB1*11__A*02-B*35-C*04-DRB1*11、 A*02-B*35-C*04-DRB1*13__A*02-B*35-C*04-DRB1*13、 A*02-B*40-C*03-DRB1*04__A*02-B*40-C*03-DRB1*04、 A*02-B*44-C*05-DRB1*01__A*02-B*44-C*05-DRB1*01、 A*02-B*44-C*05-DRB1*04__A*02-B*44-C*05-DRB1*04、 A*02-B*44-C*05-DRB1*13__A*02-B*44-C*05-DRB1*13、 A*02-B*44-C*07-DRB1*07__A*02-B*44-C*07-DRB1*07、 A*02-B*49-C*07-DRB1*11__A*02-B*49-C*07-DRB1*11、 A*02-B*50-C*06-DRB1*07__A*02-B*50-C*06-DRB1*07、 A*02-B*51-C*15-DRB1*11__A*02-B*51-C*15-DRB1*11、 A*03-B*07-C*07-DRB1*04__A*03-B*07-C*07-DRB1*04、 A*03-B*07-C*07-DRB1*11__A*03-B*07-C*07-DRB1*11、 A*03-B*07-C*07-DRB1*15__A*03-B*07-C*07-DRB1*15、 A*03-B*35-C*04-DRB1*01__A*03-B*35-C*04-DRB1*01、 A*03-B*35-C*04-DRB1*04__A*03-B*35-C*04-DRB1*04、 A*03-B*35-C*04-DRB1*11__A*03-B*35-C*04-DRB1*11、 A*03-B*52-C*12-DRB1*15__A*03-B*52-C*12-DRB1*15、 A*11-B*35-C*04-DRB1*01__A*11-B*35-C*04-DRB1*01、 A*11-B*35-C*04-DRB1*04__A*11-B*35-C*04-DRB1*04、 A*23-B*44-C*04-DRB1*07__A*23-B*44-C*04-DRB1*07、 A*24-B*35-C*04-DRB1*04__A*24-B*35-C*04-DRB1*04、 A*24-B*35-C*04-DRB1*11__A*24-B*35-C*04-DRB1*11、 A*24-B*44-C*07-DRB1*15__A*24-B*44-C*07-DRB1*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-DRB1*15__A*25-B*18-C*12-DRB1*15、 A*29-B*44-C*16-DRB1*07__A*29-B*44-C*16-DRB1*07、 A*29-B*44-C*16-DRB1*11__A*29-B*44-C*16-DRB1*11、 A*30-B*13-C*06-DRB1*07__A*30-B*13-C*06-DRB1*07、 A*30-B*18-C*05-DRB1*03__A*30-B*18-C*05-DRB1*03、 A*68-B*53-C*04-DRB1*13__A*68-B*53-C*04-DRB1*13.

[0032] In one embodiment, at least one cell bank contains immune cells.

[0033] In one embodiment, at least one cell bank contains cells rich in lymphoid progenitor cells.

[0034] In one embodiment, at least one cell bank contains T cell progenitor cells.

[0035] In one implementation, at least one cell bank contains the following cells: (a) Progenitor cells of natural killer (NK) cells and / or NK cells, or (b) Progenitor cells and / or ILCs of congenital lymphoid cells (ILCs), or (c) Progenitor cells and / or dendritic cells (DCs).

[0036] In one embodiment, the cells contained in at least one cell bank are cells generated in vitro by a culture protocol of culturing CD34+ cells in a medium containing a fixed Notch ligand, TNF-α and / or an aryl hydrocarbon / dioxin receptor antagonist, particularly StemRegenin 1 (SR1).

[0037] In one embodiment, at least one cell bank contains hematopoietic stem / progenitor cells (HSPCs), preferably CD34+ or CD133+ HSPCs.

[0038] In one embodiment, at least one cell bank contains cells containing sequences of chimeric antigen receptors (CARs) and / or genetically modified T-cell receptors (TCRs).

[0039] In one embodiment, the cells contained in at least one cell bank are genetically modified using a viral vector, nucleic acid fragment, plasmid or plasmid RNA or DNA sequence, gene editing system, base editing system, leader editing system, and / or the cells contained in at least one of the cell banks are epigenetically modified.

[0040] In one implementation, at least one cell bank contains cells that are genetically modified to: a) Promotes drug resistance, preferably to anti-inflammatory drugs and more preferably to glucocorticoids, and / or b) Reduce their sensitivity to some antibodies, and / or c) Escape from alloreactivity of at least one mature cell population from the recipient.

[0041] In one embodiment, at least one cell bank contains cells obtained from: (a) UCB (umbilical cord blood) HSPC, or (b) mPB (mobilized peripheral blood from an adult donor) HSPC, or (c) iPSC-derived HSPCs (induced pluripotent stem cells), or (d) Bone marrow HSPC.

[0042] In one embodiment, at least one cell bank contains cells that are a mixture of at least two UCB HSPC samples from different donors.

[0043] The present invention also relates to a method for selecting at least one cell bank to be administered to a subject, preferably to a subject requiring treatment, the method comprising selecting at least one cell bank of interest from cell banks in a biobank, wherein the cells of the cell bank of interest contain: (a) HLA alleles found only in the subjects (i.e., 0 mismatches), or (b) One, two, three or four HLA alleles not found in the subjects (i.e., 1, 2, 3 or 4 mismatches), preferably a mismatch of type 1 HLA alleles.

[0044] In one implementation, at least one cell bank of interest exhibits genetic polymorphisms associated with better thymus implantation and / or better lymphoid differentiation.

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

[0046] The present invention also relates to a selected cell bank, which is used as a pharmaceutical agent in treating immunodeficiency, immune disorders, lymphopenia or cancer in subjects in need.

[0047] In one implementation, the agent is administered to the subject in combination with at least one other cell bank, wherein the other cell bank has the same homozygous HLA haplotype as the selected cell bank.

[0048] In one implementation, the agent is further administered to the subject in combination with at least one other therapeutic substance.

[0049] In one implementation, the agent is administered to the subject in combination with at least one umbilical cord blood transplant or at least one mPB transplant.

[0050] definition In this invention, the following terms have the following meanings: The term “about” when referring to measurable values, such as quantity, duration, etc., is intended to cover variations of ±20%, or in some cases ±10%, or in some cases ±5%, or in some cases ±1%, or in some cases ±0.1%, as such variations are appropriate for performing the disclosed method.

[0051] The term "allelic" refers to a variant form of a gene. This variant form is located at the same locus on a chromosome. Each individual subject has two identical alleles (homozygous) or two different alleles (heterozygous) of a gene at each locus (one per chromosome).

[0052] The term "biobank" refers to a collection of biological data, cell samples, or tissue samples. In this invention, the term "biobank" refers to a collection of at least two cell banks that do not contain α-β T cells and have a specific homozygous HLA haplotype as described herein. Preferably, the biobank comprises at least two distinct cell banks that are physically separated from each other.

[0053] The term "cell bank" refers to an aggregate of cells in which all cells in the aggregate have the same haplotype at a defined HLA locus. A cell bank contains a number of doses of injectable cells. In one embodiment, all cells in the cell bank are of the same type (e.g., T cell progenitor cells) and / or of the same origin.

[0054] The term "haplotype" refers to a set of loci (e.g., HLA-A, B, DRB1) on each chromatid, which together are inherited from a single parent. As used herein, the term "haplotype" refers to a set of HLA alleles. Therefore, each individual has two haplotypes for each set of alleles.

[0055] The term "mismatch" refers to an allele difference between the cells of the cell bank of the present invention and the patient or subject to be treated. In one embodiment, mismatches are counted based on asymmetric counting, wherein only HLA alleles of the cell bank cells not found in the patient or subject are considered.

[0056] The term "derived from" refers to the acquisition of a cell through the differentiation of another cell, which is generated by the cell's ability to differentiate in at least one lineage.

[0057] The term "hematopoietic stem cells (HSCs)" refers to stem cells that produce all types of differentiated blood cells. HSCs have the ability to self-renew or differentiate into directed progenitor cells (such as bone marrow progenitor cells or lymphoid progenitor cells). HSCs used in transplantation can be derived from bone marrow, peripheral blood, or umbilical cord blood and can be used to treat subjects in need, such as those with blood cancers or bone marrow cancers (including but not limited to multiple myeloma or leukemia).

[0058] The term "hematopoietic stem / progenitor cells (HSPCs)" refers to a collection of stem cells and directed progenitor cells capable of differentiating into blood cells and immune cells. HSCs or HSPCs may be positive for at least one specific marker, including but not limited to CD34, CD45, CD43, CD45RO, CD45RA, CD59, CD90, CD190, CD117, CD133, CD166, HLA DR, or combinations thereof. Preferably, HSPCs are CD34+ cells or CD133+ cells.

[0059] The term "homozygous" refers to a cell or subject having the same allele pattern on two chromosomes (from each biological parent) for a specific gene or genome. In the context of this invention, a cell or subject is defined as having a homozygous haplotype when it possesses two identical alleles of a specific HLA gene, such as identical alleles of HLA-A, B, and DRB1, or identical alleles of HLA-A, B, C, and DRB1.

[0060] The term "subject" (or individual) refers to an animal, including humans. In the context of this invention, a subject can be a patient, i.e., a person receiving medical care, undergoing or having undergone medical treatment, or being monitored for disease progression. In the context of this invention, a subject can be a transplant recipient, preferably a recipient of a hematopoietic stem cell transplant.

[0061] The term “therapeutic effective dose” refers to the amount or number of cells or compositions as described herein that are effective in achieving a specific biological outcome. For example, the term “therapeutic effective dose” may refer to the level or amount of a composition or the number of cells intended to, without producing significant negative or adverse side effects on the target, (1) delay or prevent the onset of a target disease or disorder; (2) slow or prevent the progression, aggravation, or worsening of one or more symptoms of a target disease or disorder; (3) induce improvement in the symptoms of a target disease or disorder; (4) reduce the severity or incidence of a target disease or disorder; or (5) cure a target disease or disorder. Therapeutic effective doses may be administered before the onset of a target disease or disorder for preventative or preventative purposes. Alternatively, therapeutic effective doses may be administered after the onset of a target disease or disorder for therapeutic purposes.

[0062] The term "treatment" refers to therapeutic treatment, preventative or preventive measures (where the goal is to prevent or slow (alleviate) a target disease or ailment), or both. Those who require treatment include those who already have the disease, those who are predisposed to having the disease, and those who wish to prevent the disease. A subject is considered to have successfully "treated" a disease or ailment if, after receiving a therapeutically effective amount of cells or a composition as described herein, the subject shows observable and / or measurable improvement in one or more of the following: a reduction in the number of pathogenic cells; a reduction in the percentage of pathogenic cells among total cells; some relief of one or more symptoms associated with the specific ailment; a reduction in morbidity and mortality; and / or an improvement in quality of life. The parameters described above used to assess successful treatment and ailment improvement can be readily measured using routine procedures familiar to a physician.

[0063] The terms “transfection” or “transduction” refer to the process of transferring or introducing exogenous nucleic acids into host cells. “Transfected” or “transduced” cells are cells that have been transfected, transformed, or transduced with exogenous nucleic acids, and include primary cells and their progeny. Detailed Implementation

[0064] This invention relates to an in vitro method for selecting at least one cell bank from a biobank for administration to a subject, preferably wherein the subject requires treatment. As described herein, the selection of the cell bank of interest is based on HLA haplotype typing. Not wishing to be bound by any theory, the applicant proposes that the selection method described herein allows for the treatment of a large number of patients. Furthermore, the applicant proposes that the selection method described herein allows for the reduction of immunosuppressive therapy for patients, particularly immunosuppressive therapy for the prevention of GVHD or transplant rejection.

[0065] In one implementation, the patient is the recipient of a transplant, such as someone who has received a hematopoietic stem cell transplant, and is therefore referred to as the "recipient." In another implementation, the patient is not the recipient of a transplant, particularly if the patient has not received a hematopoietic stem cell transplant. The patient may have an immunodeficiency, immune disorder or disease, lymphopenia, or cancer. The patient may have an compromised immune system due to exposure to radiation or compounds (such as chemotherapy).

[0066] In one embodiment, the biobank comprises at least two different cell banks, each of which is distinct from the others, wherein the cells in the cell banks have the same HLA homozygous haplotype.

[0067] In one embodiment, the biobank comprises at least two different cell banks, each of which is distinct from one another and contains T cell progenitor cells, wherein the T cell progenitor cells of the cell banks have the same HLA homozygous haplotype.

[0068] In one embodiment, the in vitro method includes the following steps: a. Determine the HLA haplotypes of the subject's HLA-B and HLA-DR loci. b. Compare the HLA haplotypes determined in step a) with the HLA haplotypes of cells in the cell bank, and c. Based on the comparison, select at least one cell bank, wherein the subject shares at least one allele with cells of the selected cell bank at at least one of the HLA-B and HLA-DR loci, preferably wherein the subject shares at least one allele with cells of the selected cell bank at each of the HLA-B and HLA-DR loci.

[0069] In one embodiment, the in vitro method includes the following steps: a. Determine the HLA haplotypes of the subjects at the HLA-A, HLA-B, and HLA-DR loci. b. Compare the HLA haplotypes determined in step a) with the HLA haplotypes of cells in the cell bank, and c. Based on the comparison, select at least one cell bank, wherein the subject shares at least one allele with cells of the selected cell bank at at least two of the HLA-A, HLA-B, and HLA-DR loci, preferably wherein the subject shares at least one allele with cells of the selected cell bank at each of the HLA-A, HLA-B, and HLA-DR loci.

[0070] In one embodiment, step a) of the in vitro method for selecting at least one cell bank further includes determining the subject's HLA haplotype at the HLA-C locus.

[0071] In one embodiment, the in vitro method includes the following steps: a. Determine the HLA haplotypes of the subjects at the HLA-B, HLA-C, and HLA-DR loci. b. Compare the HLA haplotypes determined in step a) with the HLA haplotypes of cells in the cell bank, and c. Based on the comparison, select at least one cell bank, wherein the subject shares at least one allele with cells of the selected cell bank at at least two of the HLA-B, HLA-C, and HLA-DR loci, preferably wherein the subject shares at least one allele with cells of the selected cell bank at each of the HLA-B, HLA-C, and HLA-DR loci.

[0072] In one embodiment, the in vitro method includes the following steps: a. Determine the HLA haplotypes of the subjects at the HLA-A, HLA-B, HLA-C, and HLA-DR loci. b. Compare the HLA haplotypes determined in step a) with the HLA haplotypes of cells in the cell bank, and c. Based on the comparison, select at least one cell bank, wherein the subject shares at least one allele with cells of the selected cell bank at at least three of the HLA-A, HLA-B, HLA-C, and HLA-DR loci, preferably wherein the subject shares at least one allele with cells of the selected cell bank at each of the HLA-A, HLA-B, HLA-C, and HLA-DR loci.

[0073] In one implementation, in step c), a cell bank is selected based on the comparison of HLA haplotypes in step b), wherein the subject shares at least one allele with cells in the selected cell bank at each of the HLA loci identified in step a).

[0074] In one embodiment, the method includes a first step of determining the subject's HLA haplotype at at least two HLA loci, including HLA-B, and selecting a cell bank based on a comparison of the HLA haplotypes determined in the subject, wherein the subject shares an HLA-B leader sequence with cells in the selected biobank. The term "HLA-B leader sequence" refers to an HLA-B leader sequence that encodes either methionine (M) or threonine (T) at position 2 and produces different genotypes (referred to as TT, MT, or MM genotypes).

[0075] In one embodiment, the in vitro method includes the following steps: a. Determine the HLA haplotypes of the subject's HLA-B and HLA-DR loci. b. Compare the HLA haplotypes determined in step a) with the HLA haplotypes of cells in the cell bank, and c. Based on the comparison, select at least one cell bank, wherein the subject shares the HLA-B leader sequence with the cells of the selected biobank, preferably wherein the subject shares the HLA-B leader sequence and at least one allele of the HLA-DR locus with the cells of the selected biobank.

[0076] In one embodiment, the in vitro method includes the following steps: a. Determine the HLA haplotypes of the subjects at the HLA-A, HLA-B, and HLA-DR loci. b. Compare the HLA haplotypes determined in step a) with the HLA haplotypes of cells in the cell bank, and c. Based on the comparison, select at least one cell bank, wherein the subject shares the HLA-B leader sequence with the cells of the selected biobank and shares at least one allele with the cells of the selected cell bank at at least one of the HLA-A and HLA-DR loci, preferably wherein the subject shares the HLA-B leader sequence and at least one allele of each of the HLA-A and HLA-DR loci with the cells of the selected biobank.

[0077] In one embodiment, the in vitro method includes the following steps: a. Determine the HLA haplotypes of the subjects at the HLA-B, HLA-C, and HLA-DR loci. b. Compare the HLA haplotypes determined in step a) with the HLA haplotypes of cells in the cell bank, and c. Based on the comparison, select at least one cell bank, wherein the subject shares the HLA-B leader sequence with the cells of the selected biobank and shares at least one allele with the cells of the selected cell bank at at least one of the HLA-C and HLA-DR loci, preferably wherein the subject shares the HLA-B leader sequence and at least one allele of each of the HLA-C and HLA-DR loci with the cells of the selected biobank.

[0078] In one embodiment, the in vitro method includes the following steps: a. Determine the HLA haplotypes of the subjects at the HLA-A, HLA-B, HLA-C, and HLA-DR loci. b. Compare the HLA haplotypes determined in step a) with the HLA haplotypes of cells in the cell bank, and c. Based on the comparison, select at least one cell bank, wherein the subject shares the HLA-B leader sequence with the cells of the selected biobank and shares at least one allele with the cells of the selected cell bank at at least two of the HLA-A, HLA-C, and HLA-DR loci, preferably wherein the subject shares the HLA-B leader sequence and at least one allele of each of the HLA-A, HLA-C, and HLA-DR loci with the cells of the selected biobank.

[0079] In one embodiment, cells in a biobank are genetically modified to reduce or eliminate (e.g., by knockout) the expression of HLA-A on the cell surface. Techniques for reducing or eliminating (e.g., by knockout) the expression of markers or receptors on the cell surface are well known and described in the art and can be based on, for example, gene editing systems as described herein.

[0080] In one embodiment, HLA-DR is an HLA-DRRA, HLA-DRB1, HLA-DRB3, HLA-DRB4, or HLA-DRB5 locus, with HLA-DRB1 being preferred.

[0081] In one embodiment, the biobank is a biobank as described herein. In one embodiment, the cells in the cell bank have HLA haplotypes selected from the list described herein.

[0082] The present invention also relates to a method for selecting at least one cell bank to be administered to a subject, preferably to a subject requiring treatment, the method comprising selecting at least one cell bank of interest from cell banks of a biobank as described herein, wherein the cells of the cell bank of interest contain: (a) HLA alleles found only in the subjects (i.e., 0 mismatches), or (b) One, two, three or four HLA alleles not found in the subjects (i.e., 1, 2, 3 or 4 mismatches).

[0083] In one implementation, the cells in the selected cell bank and the subject have zero, one, two, three, four, or five mismatches.

[0084] In one implementation, the method used to count mismatches is asymmetric counting. In the case of asymmetric counting, the term "mismatch" refers to the number of donor HLA alleles not found in the patient. For example, when using asymmetric counting, the homozygous donor A1-B1-DRB1_A1-B1-DRB1 would be considered perfectly compatible with the patient A1-B1-DRB1_A2-B2-DRB2 because all of the donor's HLA alleles are present in the patient. Conversely, using asymmetric counting, the heterozygous donor A1-B3-DRB1_A2-B1-DRB4 would be considered to have one mismatch with the patient A1-B3-DRB1_A2-B1-DRB1 because allele DRB4 is not present in the patient.

[0085] In one implementation, the cells in the selected cell bank have the same homozygous HLA haplotype as the subject to be treated.

[0086] In one implementation, the cells of the selected cell bank have a homozygous HLA haplotype that is not identical to the HLA haplotype of the subject to be treated, but all HLA alleles of the donor are found in the patient. In this case, the subject may share at least one allele with the cells of the selected cell bank at each of the HLA-A, HLA-B, and HLA-DR loci, or at each of the HLA-A, HLA-B, HLA-C, and HLA-DR loci.

[0087] In one implementation, the subject may share at least one allele with cells from the selected cell bank at at least one of the HLA-B and HLA-DR loci, preferably at least two of the HLA-B, HLA-C, and HLA-DR loci.

[0088] In one implementation, the subject may share at least one allele with cells from the selected cell bank at at least two of the HLA-A, HLA-B, and HLA-DR loci, preferably at least three of the HLA-A, HLA-B, HLA-C, and HLA-DR loci.

[0089] In one implementation, the cells in the cell bank are T-cell progenitor cells. After transplantation, the T-cell progenitor cells will undergo positive and negative selection in the thymus.

[0090] In one embodiment, the cells of the selected cell bank and the subject have one HLA mismatch. In one embodiment, the cells of the selected cell bank and the subject have two HLA mismatches. In one embodiment, the cells of the selected cell bank and the subject have three HLA mismatches. In one embodiment, the cells of the selected cell bank and the subject have four HLA mismatches. In one embodiment, the cells of the selected cell bank and the subject have five HLA mismatches. The mismatch may be at one haplotype or at two haplotypes.

[0091] In one embodiment, the selected cell bank is further selected because the cells exhibit a genetic polymorphism associated with better thymus implantation compared to another polymorphism. In one embodiment, at least one cell bank of interest is selected because the cells exhibit a genetic polymorphism associated with better lymphoid differentiation compared to another polymorphism. In one embodiment, at least one cell bank of interest is selected because the cells exhibit a genetic polymorphism associated with better thymus implantation and / or better lymphoid differentiation compared to another polymorphism.

[0092] The present invention also relates to a method for preparing a biobank comprising at least two different cell banks, each of the at least two cell banks being different from each other, wherein the cells of the cell banks have the same HLA homozygous haplotype.

[0093] In one implementation, the cells in the at least two cell banks are T cell progenitor cells.

[0094] In one implementation, HLA homozygous haplotypes of the cell bank to be included in the biobank are selected based on the coverage and frequency of each homozygous haplotype in the subject population.

[0095] In one implementation, two criteria are considered: coverage and frequency, selecting homozygous HLA haplotypes from among all haplotypes. The term "coverage" refers to the percentage of patients in the subject population who can receive cells from at least one cell bank with sufficient HLA compatibility. The term "sufficient HLA compatibility" refers to assessing the degree of compatibility between the patient and donor based on the number of mismatches (specifically determined using asymmetric counting) between the HLA haplotypes of the cells in the cell bank and the patient's HLA haplotype. The term "frequency" refers to the percentage of each haplotype found in the natural population and / or any cell bank. Not wishing to be bound by any theory, the applicant assumes that considering both HLA haplotype coverage and frequency makes it possible to treat a large number of patients and to find sufficient donors or cells for allogeneic T-cell transplantation, such as for allogeneic CAR-T cell therapy.

[0096] 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 cell 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), in The variable X = (HLA_1, HLA_2, ..., HLA_n) corresponds to the selection of n HLA haplotypes (e.g., umbilical cord blood haplotypes); argmax represents the independent variable corresponding to the maximum value, and it is familiar to skilled technicians; The coverage (X) corresponds to the coverage achieved by this selection and is obtained empirically based on a sample of the patient database; Frequency (X) corresponds to the product of the frequencies of HLA for each of the n donors, obtained empirically from a database sample based on the donors.

[0097] The present invention also relates to a biobank comprising or consisting of at least two cell banks (preferably at least two different cell banks), preferably wherein the at least two cell banks do not contain α-β T cells, wherein each cell bank contains cells from at least one donor, and wherein at least one of the at least two different cell banks, preferably each of the cell banks, has cells having one of the following homozygous HLA haplotypes: A*01-B*08-DRB1*03__A*01-B*08-DRB1*03、 A*01-B*13-DRB1*07__A*01-B*13-DRB1*07、 A*01-B*35-DRB1*11__A*01-B*35-DRB1*11、 A*02-B*07-DRB1*01__A*02-B*07-DRB1*01、 A*02-B*07-DRB1*04__A*02-B*07-DRB1*04、 A*02-B*07-DRB1*15__A*02-B*07-DRB1*15、 A*02-B*15-DRB1*04__A*02-B*15-DRB1*04、 A*02-B*18-DRB1*03__A*02-B*18-DRB1*03、 A*02-B*18- DRB1*11__A*02-B*18-DRB1*11、 A*02-B*35-DRB1*04__A*02-B*35-DRB1*04、 A*02-B*35-DRB1*11__A*02-B*35-DRB1*11、 A*02-B*44-DRB1*04__A*02-B*44-DRB1*04、 A*02-B*44-DRB1*07__A*02-B*44-DRB1*07、 A*02-B*44-DRB1*13__A*02-B*44-DRB1*13、 A*02-B*51-DRB1*04__A*02-B*51-DRB1*04、 A*02-B*51-DRB1*11__A*02-B*51-DRB1*11、 A*02-B*51-DRB1*13__A*02-B*51-DRB1*13、 A*03-B*07-DRB1*15__A*03-B*07-DRB1*15、 A*03-B*14-DRB1*01__A*03-B*14-DRB1*01、 A*03-B*35-DRB1*01__A*03-B*35-DRB1*01、 A*03-B*35-DRB1*04__A*03-B*35-DRB1*04、 A*11-B*35-DRB1*01__A*11-B*35-DRB1*01、 A*24-B*35-DRB1*11__A*24-B*35-DRB1*11、 A*24-B*44-DRB1*13__A*24-B*44-DRB1*13、 A*24-B*51-DRB1*11__A*24-B*51-DRB1*11、 A*29-B*44-DRB1*07__A*29-B*44-DRB1*07 or A*68-B*53-DRB1*13__A*68-B*53-DRB1*13 In one embodiment, at least one of at least two different cell banks, preferably each of which has cells with one of the following homozygous HLA haplotypes: A*01-B*08-DRB1*03__A*01-B*08-DRB1*03、 A*02-B*44-DRB1*04__A*02-B*44-DRB1*04、 A*02-B*44-DRB1*07__A*02-B*44-DRB1*07、 A*02-B*18-DRB1*11__A*02-B*18-DRB1*11、 A*02-B*51-DRB1*11__A*02-B*51-DRB1*11、 A*02-B*35-DRB1*04__A*02-B*35-DRB1*04、 A*24-B*35-DRB1*11__A*24-B*35-DRB1*11、 A*02-B*07-DRB1*15__A*02-B*07-DRB1*15、 A*02-B*35-DRB1*11__A*02-B*35-DRB1*11、 A*02-B*15-DRB1*04__A*02-B*15-DRB1*04、 A*29-B*44-DRB1*07__A*29-B*44-DRB1*07、 A*02-B*51-DRB1*13__A*02-B*51-DRB1*13、 A*02-B*07-DRB1*04__A*02-B*07-DRB1*04、 A*03-B*35-DRB1*01__A*03-B*35-DRB1*01、 A*24-B*51-DRB1*11__A*24-B*51-DRB1*11、 A*24-B*44-DRB1*13__A*24-B*44-DRB1*13、 A*11-B*35-DRB1*01__A*11-B*35-DRB1*01、 A*02-B*07-DRB1*01__A*02-B*07-DRB1*01、 A*03-B*35-DRB1*04__A*03-B*35-DRB1*04、 A*03-B*07-DRB1*15__A*03-B*07-DRB1*15、 A*24-B*51-DRB1*11__A*24-B*51-DRB1*11、 A*24-B*44-DRB1*13__ A*24-B*44-DRB1*13 or A*02-B*18-DRB1*03__A*02-B*18-DRB1*03.

[0098] In one embodiment, at least one of at least two different cell banks, preferably each of which has cells with one of the following homozygous HLA haplotypes: A*01-B*08-DRB1*03__A*01-B*08-DRB1*03、 A*02-B*44-DRB1*04__A*02-B*44-DRB1*04、 A*02-B*44-DRB1*07__A*02-B*44-DRB1*07、 A*02-B*18-DRB1*11__A*02-B*18-DRB1*11、 A*02-B*51-DRB1*11__A*02-B*51-DRB1*11、 A*02-B*35-DRB1*04__A*02-B*35-DRB1*04、 A*24-B*35-DRB1*11__A*24-B*35-DRB1*11、 A*02-B*07-DRB1*15__A*02-B*07-DRB1*15、 A*02-B*35-DRB1*11__A*02-B*35-DRB1*11、 A*02-B*15-DRB1*04__A*02-B*15-DRB1*04、 A*02-B*07-DRB1*01__A*02-B*07-DRB1*01、 A*03-B*35-DRB1*04__A*03-B*35-DRB1*04、 A*02-B*51-DRB1*13__A*02-B*51-DRB1*13 or A*03-B*07-DRB1*15__A*03-B*07-DRB1*15.

[0099] In one embodiment, at least one of at least two different cell banks, preferably each of which has cells with one of the following homozygous HLA haplotypes: A*01-B*08-DRB1*03__A*01-B*08-DRB1*03、 A*02-B*44-DRB1*04__A*02-B*44-DRB1*04、 A*02-B*44-DRB1*07__A*02-B*44-DRB1*07、 A*02-B*18-DRB1*11__A*02-B*18-DRB1*11、 A*02-B*51-DRB1*11__A*02-B*51-DRB1*11、 A*02-B*35-DRB1*11__A*02-B*35-DRB1*11 or A*02-B*07-DRB1*01__A*02-B*07-DRB1*01.

[0100] In one embodiment, at least one of the different cell banks, preferably each of the cells, has one of the following homozygous HLA haplotypes: A*01-B*13-DRB1*07__A*01-B*13-DRB1*07、 A*01-B*35-DRB1*11__A*01-B*35-DRB1*11、 A*02-B*07-DRB1*04__A*02-B*07-DRB1*04、 A*02-B*18-DRB1*03__A*02-B*18-DRB1*03、 A*02-B*18-DRB1*11__A*02-B*18-DRB1*11、 A*03-B*14-DRB1*01__A*03-B*14-DRB1*01、 A*03-B*35-DRB1*04__A*03-B*35-DRB1*04、 A*24-B*44-DRB1*13__A*24-B*44-DRB1*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.

[0101] In one embodiment, at least one of at least two different cell banks, preferably each of which has cells with one of the following homozygous HLA haplotypes: A*01-B*08-C*07-DRB1*03__A*01-B*08-C*07-DRB1*03, A*01-B*35-C*04-DRB1*04__A*01-B*35-C*04-DRB1*04、 A*01-B*35-C*04-DRB1*11__A*01-B*35-C*04-DRB1*11、 A*01-B*57-C*06-DRB1*07__A*01-B*57-C*06-DRB1*07、 A*02-B*07-C*07-DRB1*01__A*02-B*07-C*07-DRB1*01、 A*02-B*07-C*07-DRB1*04__A*02-B*07-C*07-DRB1*04、 A*02-B*07-C*07-DRB1-11__A*02-B*07-C*07-DRB1-11、 A*02-B*07-C*07-DRB1*13__A*02-B*07-C*07-DRB1*13、 A-02-B*07-C*07-DRB1*15__A-02-B*07-C*07-DRB1*15、 A*02-B*08-C*07-DRB1*03__A*02-B*08-C*07-DRB1*03, A*02-B*13-C*06-DRB1*07__A*02-B*13-C*06-DRB1*07、 A*02-B*14-C*08-DRB1*01__A*02-B*14-C*08-DRB1*01、 A*02-B*15-C*03-DRB1*04__A*02-B*15-C*03-DRB1*04、 A*02-B*15-C*03-DRB1*13__A*02-B*15-C*03-DRB1*13、 A*02-B*18-C*05-DRB1*03__A*02-B*18-C*05-DRB1*03、 A*02-B*18-C*07-DRB1*11__A*02-B*18-C*07-DRB1*11、 A*02-B*27-C*01-DRB1*01__A*02-B*27-C*01-DRB1*01、 A*02-B*27-C*02-DRB1*04__A*02-B*27-C*02-DRB1*04、 A*02-B*35-C*04-DRB1*04__A*02-B*35-C*04-DRB1*04、 A*02-B*35-C*04-DRB1*07__A*02-B*35-C*04-DRB1*07、 A*02-B*35-C*04-DRB1*11__A*02-B*35-C*04-DRB1*11、 A*02-B*35-C*04-DRB1*13__A*02-B*35-C*04-DRB1*13、 A*02-B*40-C*03-DRB1*04__A*02-B*40-C*03-DRB1*04、 A*02-B*44-C*05-DRB1*01__A*02-B*44-C*05-DRB1*01、 A*02-B*44-C*05-DRB1*04__A*02-B*44-C*05-DRB1*04、 A*02-B*44-C*05-DRB1*13__A*02-B*44-C*05-DRB1*13、 A*02-B*44-C*07-DRB1*07__A*02-B*44-C*07-DRB1*07、 A*02-B*49-C*07-DRB1*11__A*02-B*49-C*07-DRB1*11、 A*02-B*50-C*06-DRB1*07__A*02-B*50-C*06-DRB1*07、 A*02-B*51-C*15-DRB1*11__A*02-B*51-C*15-DRB1*11、 A*03-B*07-C*07-DRB1*04__A*03-B*07-C*07-DRB1*04、 A*03-B*07-C*07-DRB1*11__A*03-B*07-C*07-DRB1*11、 A*03-B*07-C*07-DRB1*15__A*03-B*07-C*07-DRB1*15、 A*03-B*35-C*04-DRB1*01__A*03-B*35-C*04-DRB1*01、 A*03-B*35-C*04-DRB1*04__A*03-B*35-C*04-DRB1*04、 A*03-B*35-C*04-DRB1*11__A*03-B*35-C*04-DRB1*11、 A*03-B*52-C*12-DRB1*15__A*03-B*52-C*12-DRB1*15、 A*11-B*35-C*04-DRB1*01__A*11-B*35-C*04-DRB1*01、 A*11-B*35-C*04-DRB1*04__A*11-B*35-C*04-DRB1*04、 A*23-B*44-C*04-DRB1*07__A*23-B*44-C*04-DRB1*07、 A*24-B*35-C*04-DRB1*04__A*24-B*35-C*04-DRB1*04、 A*24-B*35-C*04-DRB1*11__A*24-B*35-C*04-DRB1*11、 A*24-B*44-C*07-DRB1*15__A*24-B*44-C*07-DRB1*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-DRB1*15__A*25-B*18-C*12-DRB1*15、 A*29-B*44-C*16-DRB1*07__A*29-B*44-C*16-DRB1*07、 A*29-B*44-C*16-DRB1*11__A*29-B*44-C*16-DRB1*11、 A*30-B*13-C*06-DRB1*07__A*30-B*13-C*06-DRB1*07、 A*30-B*18-C*05-DRB1*03__A*30-B*18-C*05-DRB1*03 or A*68-B*53-C*04-DRB1*13__ A*68-B*53-C*04-DRB1*13.

[0102] In one embodiment, at least one of at least two different cell banks, preferably each of which has cells with one of the following homozygous HLA haplotypes: A*01-B*35-C*04-DRB1*04__A*01-B*35-C*04-DRB1*04、 A*01-B*35-C*04-DRB1*11__A*01-B*35-C*04-DRB1*11、 A*02-B*07-C*07-DRB1*01__A*02-B*07-C*07-DRB1*01、 A*02-B*07-C*07-DRB1*04__A*02-B*07-C*07-DRB1*04、 A*02-B*07-C*07-DRB1-11__A*02-B*07-C*07-DRB1-11、 A*02-B*07-C*07-DRB1*13__A*02-B*07-C*07-DRB1*13、 A*02-B*14-C*08-DRB1*01__A*02-B*14-C*08-DRB1*01、 A*02-B*15-C*03-DRB1*13__A*02-B*15-C*03-DRB1*13、 A*02-B*18-C*05-DRB1*03__A*02-B*18-C*05-DRB1*03、 A*02-B*18-C*07-DRB1*11__A*02-B*18-C*07-DRB1*11、 A*02-B*27-C*01-DRB1*01__A*02-B*27-C*01-DRB1*01、 A*02-B*27-C*02-DRB1*04__A*02-B*27-C*02-DRB1*04、 A*02-B*35-C*04-DRB1*04__A*02-B*35-C*04-DRB1*04、 A*02-B*35-C*04-DRB1*07__A*02-B*35-C*04-DRB1*07、 A*02-B*35-C*04-DRB1*11__A*02-B*35-C*04-DRB1*11、 A*02-B*35-C*04-DRB1*13__A*02-B*35-C*04-DRB1*13、 A*02-B*40-C*03-DRB1*04__A*02-B*40-C*03-DRB1*04、 A*02-B*44-C*05-DRB1*01__A*02-B*44-C*05-DRB1*01、 A*02-B*44-C*05-DRB1*13__A*02-B*44-C*05-DRB1*13、 A*02-B*44-C*07-DRB1*07__A*02-B*44-C*07-DRB1*07、 A*02-B*49-C*07-DRB1*11__A*02-B*49-C*07-DRB1*11、 A*02-B*50-C*06-DRB1*07__A*02-B*50-C*06-DRB1*07、 A*02-B*51-C*15-DRB1*11__A*02-B*51-C*15-DRB1*11、 A*03-B*07-C*07-DRB1*04__A*03-B*07-C*07-DRB1*04、 A*03-B*07-C*07-DRB1*11__A*03-B*07-C*07-DRB1*11、 A*03-B*35-C*04-DRB1*04__A*03-B*35-C*04-DRB1*04、 A*03-B*35-C*04-DRB1*11__A*03-B*35-C*04-DRB1*11、 A*03-B*52-C*12-DRB1*15__A*03-B*52-C*12-DRB1*15、 A*11-B*35-C*04-DRB1*01__A*11-B*35-C*04-DRB1*01、 A*11-B*35-C*04-DRB1*04__A*11-B*35-C*04-DRB1*04、 A*23-B*44-C*04-DRB1*07__A*23-B*44-C*04-DRB1*07、 A*24-B*35-C*04-DRB1*04__A*24-B*35-C*04-DRB1*04、 A*24-B*35-C*04-DRB1*11__A*24-B*35-C*04-DRB1*11、 A*24-B*44-C*07-DRB1*15__A*24-B*44-C*07-DRB1*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-DRB1*15__A*25-B*18-C*12-DRB1*15、 A*29-B*44-C*16-DRB1*11__A*29-B*44-C*16-DRB1*11、 A*30-B*13-C*06-DRB1*07__A*30-B*13-C*06-DRB1*07、 A*30-B*18-C*05-DRB1*03__A*30-B*18-C*05-DRB1*03 or A*68-B*53-C*04-DRB1*13__A*68-B*53-C*04-DRB1*13.

[0103] In one embodiment, cells in a biobank are genetically modified to reduce or eliminate (e.g., by knockout) the expression of HLA-A on the cell surface. Techniques for reducing or eliminating (e.g., by knockout) the expression of markers or receptors (such as HLA-A) on the cell surface are well known and described in the art, and are based on gene editing systems such as those described herein.

[0104] In one embodiment, at least one of at least two different cell banks, preferably each of which has cells with one of the following homozygous HLA haplotypes: B*08-DRB1*03__B*08-DRB1*03、 B*13-DRB1*07__B*13-DRB1*07、 B*35-DRB1*11__B*35-DRB1*11、 B*07-DRB1*01__B*07-DRB1*01、 B*07-DRB1*04__B*07-DRB1*04、 B*07-DRB1*15__B*07-DRB1*15、 B*15-DRB1*04__B*15-DRB1*04、 B*18-DRB1*03__B*18-DRB1*03、 B*18-DRB1*11_B*18-DRB1*11、 B*35-DRB1*04__B*35-DRB1*04、 B*35-DRB1*11__B*35-DRB1*11、 B*44-DRB1*04__B*44-DRB1*04、 B*44-DRB1*07__B*44-DRB1*07、 B*44-DRB1*13__B*44-DRB1*13、 B*51-DRB1*04__B*51-DRB1*04、 B*51-DRB1*11__B*51-DRB1*11、 B*51-DRB1*13__B*51-DRB1*13、 B*07-DRB1*15__B*07-DRB1*15、 B*14-DRB1*01__B*14-DRB1*01、 B*35-DRB1*01__B*35-DRB1*01、 B*35-DRB1*04__B*35-DRB1*04、 B*35-DRB1*01__B*35-DRB1*01、 B*35-DRB1*11__B*35-DRB1*11、 B*44-DRB1*13__B*44-DRB1*13、 B*51-DRB1*11__B*51-DRB1*11、 B*44-DRB1*07__B*44-DRB1*07 or B*53-DRB1*13__B*53-DRB1*13 In one embodiment, at least one of at least two different cell banks, preferably each of which has cells with one of the following homozygous HLA haplotypes: B*08-DRB1*03__B*08-DRB1*03、 B*44-DRB1*04__B*44-DRB1*04、 B*44-DRB1*07__B*44-DRB1*07、 B*18-DRB1*11__B*18-DRB1*11、 B*51-DRB1*11__B*51-DRB1*11、 B*35-DRB1*04__B*35-DRB1*04、 B*35-DRB1*11__B*35-DRB1*11、 B*07-DRB1*15__B*07-DRB1*15、 B*35-DRB1*11__B*35-DRB1*11、 B*15-DRB1*04__B*15-DRB1*04、 B*44-DRB1*07__B*44-DRB1*07、 B*51-DRB1*13__B*51-DRB1*13、 B*07-DRB1*04__B*07-DRB1*04、 B*35-DRB1*01__B*35-DRB1*01、 B*51-DRB1*11__B*51-DRB1*11、 B*44-DRB1*13__B*44-DRB1*13、 B*35-DRB1*01__B*35-DRB1*01、 B*07-DRB1*01__B*07-DRB1*01、 B*35-DRB1*04__B*35-DRB1*04、 B*07-DRB1*15__B*07-DRB1*15、 B*51-DRB1*11__B*51-DRB1*11、 B*44-DRB1*13__B*44-DRB1*13 or B*18-DRB1*03__B*18-DRB1*03.

[0105] In one embodiment, at least one of at least two different cell banks, preferably each of which has cells with one of the following homozygous HLA haplotypes: B*08-DRB1*03__B*08-DRB1*03、 B*44-DRB1*04__B*44-DRB1*04、 B*44-DRB1*07__B*44-DRB1*07、 B*18-DRB1*11__B*18-DRB1*11、 B*51-DRB1*11__B*51-DRB1*11、 B*35-DRB1*04__B*35-DRB1*04、 B*35-DRB1*11__B*35-DRB1*11、 B*07-DRB1*15__B*07-DRB1*15、 B*35-DRB1*11__B*35-DRB1*11、 B*15-DRB1*04__B*15-DRB1*04、 B*07-DRB1*01__B*07-DRB1*01、 B*35-DRB1*04__B*35-DRB1*04、 B*51-DRB1*13__B*51-DRB1*13 B*07-DRB1*15__B*07-DRB1*15.

[0106] In one embodiment, at least one of at least two different cell banks, preferably each of which has cells with one of the following homozygous HLA haplotypes: B*08-DRB1*03__B*08-DRB1*03、 B*44-DRB1*04__B*44-DRB1*04、 B*44-DRB1*07__B*44-DRB1*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 or B*07-DRB1*01__B*07-DRB1*01.

[0107] In one embodiment, at least one of the different cell banks, preferably each of the cells, has one of the following homozygous HLA haplotypes: B*13-DRB1*07__B*13-DRB1*07、 B*35-DRB1*11__B*35-DRB1*11、 B*07-DRB1*04__B*07-DRB1*04、 B*18-DRB1*03__B*18-DRB1*03、 B*18-DRB1*11__B*18-DRB1*11、 B*14-DRB1*01__B*14-DRB1*01、 B*35-DRB1*04__B*35-DRB1*04、 B*44-DRB1*13__B*44-DRB1*13、 B*51-DRB1*11__B*51-DRB1*11 or B*53-DRB1*13__B*53-DRB1*13.

[0108] In one embodiment, at least one of at least two different cell banks, preferably each of which has cells with one of the following homozygous HLA haplotypes: B*08-C*07-DRB1*03__B*08-C*07-DRB1*03、 B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*35-C*04-DRB1*11__B*35-C*04-DRB1*11、 B*57-C*06-DRB1*07__B*57-C*06-DRB1*07、 B*07-C*07-DRB1*01__B*07-C*07-DRB1*01、 B*07-C*07-DRB1*04__B*07-C*07-DRB1*04、 B*07-C*07-DRB1-11__B*07-C*07-DRB1-11、 B*07-C*07-DRB1*13__B*07-C*07-DRB1*13、 B*07-C*07-DRB1*15__B*07-C*07-DRB1*15、 B*08-C*07-DRB1*03__B*08-C*07-DRB1*03、 B*13-C*06-DRB1*07__B*13-C*06-DRB1*07、 B*14-C*08-DRB1*01__B*14-C*08-DRB1*01、 B*15-C*03-DRB1*04__B*15-C*03-DRB1*04、 B*15-C*03-DRB1*13__B*15-C*03-DRB1*13、 B*18-C*05-DRB1*03__B*18-C*05-DRB1*03、 B*18-C*07-DRB1*11__B*18-C*07-DRB1*11、 B*27-C*01-DRB1*01__B*27-C*01-DRB1*01、 B*27-C*02-DRB1*04__B*27-C*02-DRB1*04、 B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*35-C*04-DRB1*07__B*35-C*04-DRB1*07、 B*35-C*04-DRB1*11__B*35-C*04-DRB1*11、 B*35-C*04-DRB1*13__B*35-C*04-DRB1*13、 B*40-C*03-DRB1*04__B*40-C*03-DRB1*04、 B*44-C*05-DRB1*01__B*44-C*05-DRB1*01、 B*44-C*05-DRB1*04__B*44-C*05-DRB1*04、 B*44-C*05-DRB1*13__B*44-C*05-DRB1*13、 B*44-C*07-DRB1*07__B*44-C*07-DRB1*07、 B*49-C*07-DRB1*11__B*49-C*07-DRB1*11、 B*50-C*06-DRB1*07__B*50-C*06-DRB1*07、 B*51-C*15-DRB1*11__B*51-C*15-DRB1*11、 B*07-C*07-DRB1*04__B*07-C*07-DRB1*04、 B*07-C*07-DRB1*11__B*07-C*07-DRB1*11、 B*07-C*07-DRB1*15__B*07-C*07-DRB1*15、 B*35-C*04-DRB1*01__B*35-C*04-DRB1*01、 B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*35-C*04-DRB1*11__B*35-C*04-DRB1*11、 B*52-C*12-DRB1*15__B*52-C*12-DRB1*15、 B*35-C*04-DRB1*01__B*35-C*04-DRB1*01、 B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*44-C*04-DRB1*07__B*44-C*04-DRB1*07、 B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*35-C*04-DRB1*11__B*35-C*04-DRB1*11、 B*44-C*07-DRB1*15__B*44-C*07-DRB1*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-DRB1*15__B*18-C*12-DRB1*15, B*44-C*16-DRB1*07__B*44-C*16-DRB1*07、 B*44-C*16-DRB1*11__B*44-C*16-DRB1*11、 B*13-C*06-DRB1*07__B*13-C*06-DRB1*07、 B*18-C*05-DRB1*03__B*18-C*05-DRB1*03 or B*53-C*04-DRB1*13__*53-C*04-DRB1*13.

[0109] In one embodiment, at least one of at least two different cell banks, preferably each of which has cells with one of the following homozygous HLA haplotypes: B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*35-C*04-DRB1*11__B*35-C*04-DRB1*11、 B*07-C*07-DRB1*01__B*07-C*07-DRB1*01、 B*07-C*07-DRB1*04__B*07-C*07-DRB1*04、 B*07-C*07-DRB1-11__B*07-C*07-DRB1-11、 B*07-C*07-DRB1*13__B*07-C*07-DRB1*13、 B*14-C*08-DRB1*01__B*14-C*08-DRB1*01、 B*15-C*03-DRB1*13__B*15-C*03-DRB1*13、 B*18-C*05-DRB1*03__B*18-C*05-DRB1*03、 B*18-C*07-DRB1*11__B*18-C*07-DRB1*11、 B*27-C*01-DRB1*01__B*27-C*01-DRB1*01、 B*27-C*02-DRB1*04__B*27-C*02-DRB1*04、 B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*35-C*04-DRB1*07__B*35-C*04-DRB1*07、 B*35-C*04-DRB1*11__B*35-C*04-DRB1*11、 B*35-C*04-DRB1*13__B*35-C*04-DRB1*13、 B*40-C*03-DRB1*04__B*40-C*03-DRB1*04、 B*44-C*05-DRB1*01__B*44-C*05-DRB1*01、 B*44-C*05-DRB1*13__B*44-C*05-DRB1*13、 B*44-C*07-DRB1*07__B*44-C*07-DRB1*07、 B*49-C*07-DRB1*11__B*49-C*07-DRB1*11、 B*50-C*06-DRB1*07__B*50-C*06-DRB1*07、 B*51-C*15-DRB1*11__B*51-C*15-DRB1*11、 B*07-C*07-DRB1*04__B*07-C*07-DRB1*04、 B*07-C*07-DRB1*11__B*07-C*07-DRB1*11、 B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*35-C*04-DRB1*11__B*35-C*04-DRB1*11、 B*52-C*12-DRB1*15__B*52-C*12-DRB1*15, B*35-C*04-DRB1*01__B*35-C*04-DRB1*01、 B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*44-C*04-DRB1*07__B*44-C*04-DRB1*07, B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*35-C*04-DRB1*11__B*35-C*04-DRB1*11、 B*44-C*07-DRB1*15__B*44-C*07-DRB1*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-DRB1*15__B*18-C*12-DRB1*15, B*44-C*16-DRB1*11__B*44-C*16-DRB1*11、 B*13-C*06-DRB1*07__B*13-C*06-DRB1*07、 B*18-C*05-DRB1*03__B*18-C*05-DRB1*03 or B*53-C*04-DRB1*13__B*53-C*04-DRB1*13.

[0110] In one implementation, the at least two cell banks are at least two different cell banks, wherein each cell bank is physically separated from the other cell banks.

[0111] In one embodiment, the biobank of the present invention may comprise a first cell pool having a specific haplotype (i.e., a first cell bank) and a second different cell pool having another specific haplotype (i.e., a second cell bank); wherein the cell types (e.g., T cell progenitors, immune cells) and / or sources (e.g., umbilical cord blood, peripheral blood, bone marrow) of the cells in the two cell banks are the same.

[0112] In one embodiment, the biobank of the present invention may comprise a first cell pool having a specific haplotype (i.e., a first cell bank) and a second, different cell pool having the same specific haplotype (i.e., a second cell bank); wherein the cell type and / or origin of the cells are different between the two cell banks.

[0113] In one embodiment, the biobank of the present invention will enable treatment of at least about 20%, 25%, 30%, 35%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, and 95% of the subjects in need.

[0114] In one embodiment, the biobank comprises or consists of at least two cell banks (preferably based on cell banks differing in haplotype, origin, and / or cell type). In another embodiment, the biobank contains at least two cell banks. In yet another 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 cell banks (preferably based on cell banks differing in haplotype, origin, and / or cell type). In one embodiment, the biobank comprises or consists of fewer than 20 different cell banks, preferably fewer than 15 different cell banks, and more preferably 10 or fewer different cell banks (preferably based on cell banks differing in haplotype, origin, and / or cell type).

[0115] In one embodiment, the biobank contains more than 20 cell banks. In another embodiment, the biobank contains more than 20 cell banks. In yet another embodiment, the biobank contains 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 cell banks (preferably based on cell banks differing in haplotype, origin, and / or cell type). In one embodiment, the biobank contains fewer than 100 cell banks or comprises thereof.

[0116] In one implementation, the biobank is not a biobank containing tissue or blood samples containing cells.

[0117] In one embodiment, the cells in the cell bank do not contain α-β T cells. In one embodiment, the cells in the cell bank contain less than 1% α-β T cells. In one embodiment, the cells in the cell bank contain less than 0.1%; 0.2%; 0.3%; 0.4%; 0.5%; 0.6%; 0.7%; 0.8%; 0.9% or 1% α-β T cells. "α-β T cells" herein refers to a population of lymphocytes that express T cell receptors containing both α and β chains.

[0118] In one embodiment, the cell bank initially does not contain α-β T cells. In another embodiment, the cell bank has α-β T cells removed. Methods for removing α-β T cells from cell samples are well known to a skilled technician and include, but are not limited to, magnetic separation, fluorescence-activated cell sorting (FACS), or affinity chromatography.

[0119] In one embodiment, each cell bank contained in the biobank contains cells from one or more donors. In another embodiment, each cell bank contained in the biobank contains cells from at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 donors.

[0120] In one embodiment, each cell bank contains several batches of cells (which may, for example, be packaged in different containers), with each batch containing several doses of injectable cells. In the context of this invention, a new batch of cells is extracted or generated from the cell bank after the previous batch has been depleted.

[0121] In one embodiment, each dose of injectable cells is cryopreserved. In one embodiment, each batch of cells is cryopreserved. In one embodiment, each cell bank contains cryopreserved cells.

[0122] In one implementation, each cell bank comprises several batches of cells, each batch containing several doses of injectable cells, and each batch containing cells from one donor or more than one donor. Within a cell bank, the donors for different batches may differ, but all cells from all batches possess the same homologous HLA haplotype.

[0123] In one embodiment, each cell bank comprises several batches of cells, each batch containing several doses of injectable cells, and each batch containing cells from at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 donors.

[0124] In one embodiment, each batch of cells in the cell bank contains at least about 10 doses of injectable cells. In another embodiment, each batch of cells in the cell bank contains 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 yet another embodiment, each batch of cells in the cell bank contains more than 10 doses of injectable cells.

[0125] The term "dose of injectable cells" refers herein to the total nucleated cells (TNC) dose per kilogram (kg) of recipient body weight. In one embodiment, the optimal dose of TNC is 0.1 x 10⁻⁶ cells per kilogram of recipient body weight. 5 One to 1 x 10 7 One, preferably 0.5 x 10 per kilogram of recipient body weight. 5 Up to 5 x 10 6 More preferably, 1 x 10 per kilogram of recipient body weight. 6 3 x 10 6 Within a certain range. In one implementation, the optimal dose of TNC is 0.3 x 10⁻⁶. 5 One cell to 1.5 x 10 9 1 cell, preferably 1.5 x 10 5 7.5 x 10 cells 8 1 cell, and more preferably 3 x 10 6 Cells up to 4.5 x 10 8 The cell range is [number]. In one implementation, the optimal dose is 5 x 10 [units]. 5 1 cell to 5 x 10 8 1 cell, preferably 2.5 x 10 6 1 cell to 2.5 x 10 8 5 x 10 cells, and more preferably 5 x 10 7 1 to 1.5 x 10 cells 8 Within the cell range. In one implementation, the optimal dose of TNC for umbilical cord blood cells is 0.5 x 10⁻⁶ per kilogram of recipient body weight. 5 One to 1 x 10 6 One, preferably 0.5 x 10 per kilogram of recipient body weight. 5 Up to 5 x 10 5 More preferably 0.5 x 10 per kilogram of recipient body weight. 5 / kg per piece to 1.5 x 10 5 Within a certain range. In one implementation, the optimal dose of TNC for umbilical cord blood cells is 1.5 x 10⁻⁶. 5 7.5 x 10 cells 8 1 cell, preferably 1.5 x 10 5 7.5 x 10 cells 7 1.5 x 10 cells, and more preferably 1.5 x 10 5 Cells up to 2.25 x 10 7 Within the cell range. In one implementation, the optimal dose of TNC for umbilical cord blood cells is 2.5 x 10⁻⁶ cells / mL. 6 1 cell to 5 x 107 1 cell, preferably 2.5 x 10 6 1 cell to 2.5 x 10 7 1 cell, and more preferably 2.5 x 10 6 7.5 x 10 cells 6 Within a cell range. In one embodiment, a single dose of injectable cells may be administered to a subject. In another embodiment, several doses of cells may be administered to a subject over a period of time.

[0126] In one implementation, the optimal dose of CD7+ TNC is 0.1 x 10⁻⁶ per kilogram of recipient body weight. 5 One to 1 x 10 7 One, preferably 0.5 x 10 per kilogram of recipient body weight. 5 Up to 5 x 10 6 More preferably, 1 x 10 per kilogram of recipient body weight. 6 Up to 3 x 10 6 Within a certain range. In one implementation, the optimal dose of CD7+ TNC is 0.3 x 10⁻⁶. 5 One cell to 1.5 x 10 9 1 cell, preferably 1.5 x 10 5 7.5 x 10 cells 8 1 cell, and more preferably 3 x 10 6 Cells up to 4.5 x 10 8 Within the cell range. In one implementation, the optimal dose of CD7+ TNC is 5 x 10-1 cells. 5 5 x 10 cells 8 1 cell, preferably 2.5 x 10 6 1 cell to 2.5 x 10 8 5 x 10 cells, and more preferably 5 x 10 7 Cells up to 1.5 x 10 8 Within the cellular range. In one implementation, the optimal dose of CD7+ TCN from umbilical cord blood cells is 0.5 x 10⁻⁶ per kilogram of recipient body weight. 5 One to 1 x 10 6 One, preferably 0.5 x 10 per kilogram of recipient body weight. 5 Up to 5 x 10 5 More preferably 0.5 x 10 per kilogram of recipient body weight. 5 One to 1.5 x 10 5 Within a certain range. In one implementation, the optimal dose of CD7+ TNC from umbilical cord blood cells is 1.5 x 10⁻⁶. 5 One cell to 1.5 x 108 1 cell, preferably 1.5 x 10 5 Up to 7.5 x 10 7 1.5 x 10 cells, and more preferably 1.5 x 10 5 Up to 2.25 x 10 7 Within the cell range. In one implementation, the optimal dose of CD7+ TNC from umbilical cord blood cells is 2.5 x 10⁻⁶ cells / mL. 6 1 cell to 5 x 10 7 1 cell, preferably 2.5 x 10 6 Up to 2.5 x 10 7 Smaller and more preferably 2.5 x 10 6 Up to 7.5 x 10 7 Within a cell range. In one embodiment, a single dose of injectable cells may be administered to a subject. In another embodiment, several doses of cells may be administered to a subject over a period of time.

[0127] In one embodiment, each cell bank contained in the biobank may contain cells from at least about two donors, said donors having: (i) The same combination of two sets of HLA-A, HLA-B, and HLA-DRB1 haplotypes, and (ii) One of the following homozygous HLA haplotypes: A*01-B*08-DRB1*03__A*01-B*08-DRB1*03、 A*01-B*13-DRB1*07__A*01-B*13-DRB1*07、 A*01-B*35-DRB1*11__A*01-B*35-DRB1*11、 A*02-B*07-DRB1*01__A*02-B*07-DRB1*01、 A*02-B*07-DRB1*04__A*02-B*07-DRB1*04、 A*02-B*07-DRB1*15__A*02-B*07-DRB1*15、 A*02-B*15-DRB1*04__A*02-B*15-DRB1*04、 A*02-B*18-DRB1*03__A*02-B*18-DRB1*03、 A*02-B*18-DRB1*11__A*02-B*18-DRB1*11、 A*02-B*35-DRB1*04__A*02-B*35-DRB1*04、 A*02-B*35-DRB1*11__A*02-B*35-DRB1*11、 A*02-B*44-DRB1*04__A*02-B*44-DRB1*04、 A*02-B*44-DRB1*07__A*02-B*44-DRB1*07、 A*02-B*44-DRB1*13__A*02-B*44-DRB1*13、 A*02-B*51-DRB1*04__A*02-B*51-DRB1*04、 A*02-B*51-DRB1*11__A*02-B*51-DRB1*11、 A*02-B*51-DRB1*13__A*02-B*51-DRB1*13、 A*03-B*07-DRB1*15__A*03-B*07-DRB1*15、 A*03-B*14-DRB1*01__A*03-B*14-DRB1*01、 A*03-B*35-DRB1*01__A*03-B*35-DRB1*01、 A*03-B*35-DRB1*04__A*03-B*35-DRB1*04、 A*11-B*35-DRB1*01__A*11-B*35-DRB1*01、 A*24-B*35-DRB1*11__A*24-B*35-DRB1*11、 A*24-B*44-DRB1*13__A*24-B*44-DRB1*13、 A*24-B*51-DRB1*11__A*24-B*51-DRB1*11、 A*29-B*44-DRB1*07__A*29-B*44-DRB1*07 or A*68-B*53-DRB1*13__A*68-B*53-DRB1*13.

[0128] In one embodiment, each cell bank contained in the biobank may contain cells from at least about two donors, said donors having: (i) The same combination of two sets of HLA-A, HLA-B, HLA-C and HLA-DRB1 haplotypes, and (ii) One of the following homozygous HLA haplotypes: A*01-B*08-C*07-DRB1*03__A*01-B*08-C*07-DRB1*03, A*01-B*35-C*04-DRB1*04__A*01-B*35-C*04-DRB1*04、 A*01-B*35-C*04-DRB1*11__A*01-B*35-C*04-DRB1*11、 A*01-B*57-C*06-DRB1*07__A*01-B*57-C*06-DRB1*07、 A*02-B*07-C*07-DRB1*01__A*02-B*07-C*07-DRB1*01、 A*02-B*07-C*07-DRB1*04__A*02-B*07-C*07-DRB1*04、 A*02-B*07-C*07-DRB1-11__A*02-B*07-C*07-DRB1-11、 A*02-B*07-C*07-DRB1*13__A*02-B*07-C*07-DRB1*13、 A-02-B*07-C*07-DRB1*15__A-02-B*07-C*07-DRB1*15、 A*02-B*08-C*07-DRB1*03__A*02-B*08-C*07-DRB1*03, A*02-B*13-C*06-DRB1*07__A*02-B*13-C*06-DRB1*07、 A*02-B*14-C*08-DRB1*01__A*02-B*14-C*08-DRB1*01、 A*02-B*15-C*03-DRB1*04__A*02-B*15-C*03-DRB1*04、 A*02-B*15-C*03-DRB1*13__A*02-B*15-C*03-DRB1*13、 A*02-B*18-C*05-DRB1*03__A*02-B*18-C*05-DRB1*03、 A*02-B*18-C*07-DRB1*11__A*02-B*18-C*07-DRB1*11、 A*02-B*27-C*01-DRB1*01__A*02-B*27-C*01-DRB1*01、 A*02-B*27-C*02-DRB1*04__A*02-B*27-C*02-DRB1*04、 A*02-B*35-C*04-DRB1*04__A*02-B*35-C*04-DRB1*04、 A*02-B*35-C*04-DRB1*07__A*02-B*35-C*04-DRB1*07、 A*02-B*35-C*04-DRB1*11__A*02-B*35-C*04-DRB1*11、 A*02-B*35-C*04-DRB1*13__A*02-B*35-C*04-DRB1*13、 A*02-B*40-C*03-DRB1*04__A*02-B*40-C*03-DRB1*04、 A*02-B*44-C*05-DRB1*01__A*02-B*44-C*05-DRB1*01、 A*02-B*44-C*05-DRB1*04__A*02-B*44-C*05-DRB1*04、 A*02-B*44-C*05-DRB1*13__A*02-B*44-C*05-DRB1*13、 A*02-B*44-C*07-DRB1*07__A*02-B*44-C*07-DRB1*07、 A*02-B*49-C*07-DRB1*11__A*02-B*49-C*07-DRB1*11、 A*02-B*50-C*06-DRB1*07__A*02-B*50-C*06-DRB1*07、 A*02-B*51-C*15-DRB1*11__A*02-B*51-C*15-DRB1*11、 A*03-B*07-C*07-DRB1*04__A*03-B*07-C*07-DRB1*04、 A*03-B*07-C*07-DRB1*11__A*03-B*07-C*07-DRB1*11、 A*03-B*07-C*07-DRB1*15__A*03-B*07-C*07-DRB1*15、 A*03-B*35-C*04-DRB1*01__A*03-B*35-C*04-DRB1*01、 A*03-B*35-C*04-DRB1*04__A*03-B*35-C*04-DRB1*04、 A*03-B*35-C*04-DRB1*11__A*03-B*35-C*04-DRB1*11、 A*03-B*52-C*12-DRB1*15__A*03-B*52-C*12-DRB1*15、 A*11-B*35-C*04-DRB1*01__A*11-B*35-C*04-DRB1*01、 A*11-B*35-C*04-DRB1*04__A*11-B*35-C*04-DRB1*04、 A*23-B*44-C*04-DRB1*07__A*23-B*44-C*04-DRB1*07、 A*24-B*35-C*04-DRB1*04__A*24-B*35-C*04-DRB1*04、 A*24-B*35-C*04-DRB1*11__A*24-B*35-C*04-DRB1*11、 A*24-B*44-C*07-DRB1*15__A*24-B*44-C*07-DRB1*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-DRB1*15__A*25-B*18-C*12-DRB1*15、 A*29-B*44-C*16-DRB1*07__A*29-B*44-C*16-DRB1*07、 A*29-B*44-C*16-DRB1*11__A*29-B*44-C*16-DRB1*11、 A*30-B*13-C*06-DRB1*07__A*30-B*13-C*06-DRB1*07、 A*30-B*18-C*05-DRB1*03__A*30-B*18-C*05-DRB1*03 or A*68-B*53-C*04-DRB1*13__A*68-B*53-C*04-DRB1*13.

[0129] In one embodiment, each cell bank contained in the biobank may contain cells from at least about two donors, said donors having: (i) The same combination of two sets of HLA-B and DRB1 haplotypes, and (ii) One of the following homozygous HLA haplotypes: B*08-DRB1*03__B*08-DRB1*03、 B*13-DRB1*07__B*13-DRB1*07、 B*35-DRB1*11__B*35-DRB1*11、 B*07-DRB1*01__B*07-DRB1*01、 B*07-DRB1*04__B*07-DRB1*04、 B*07-DRB1*15__B*07-DRB1*15、 B*15-DRB1*04__B*15-DRB1*04、 B*18-DRB1*03__B*18-DRB1*03、 B*18- DRB1*11_ B*18-DRB1*11, B*35-DRB1*04__B*35-DRB1*04、 B*35-DRB1*11__B*35-DRB1*11、 B*44-DRB1*04__B*44-DRB1*04、 B*44-DRB1*07__B*44-DRB1*07、 B*44-DRB1*13__B*44-DRB1*13、 B*51-DRB1*04__B*51-DRB1*04、 B*51-DRB1*11__B*51-DRB1*11、 B*51-DRB1*13__B*51-DRB1*13、 B*07-DRB1*15__B*07-DRB1*15、 B*14-DRB1*01__B*14-DRB1*01、 B*35-DRB1*01__B*35-DRB1*01、 B*35-DRB1*04__B*35-DRB1*04、 B*35-DRB1*01__B*35-DRB1*01、 B*35-DRB1*11__B*35-DRB1*11、 B*44-DRB1*13__B*44-DRB1*13、 B*51-DRB1*11__B*51-DRB1*11、 B*44-DRB1*07__B*44-DRB1*07 or B*53-DRB1*13__B*53-DRB1*13.

[0130] In one embodiment, each cell bank contained in the biobank may contain cells from at least about two donors, said donors having: (i) The same combination of two sets of HLA-B, HLA-C and HLA-DRB1 haplotypes, and (ii) One of the following homozygous HLA haplotypes: AB*08-C*07-DRB1*03__B*08-C*07-DRB1*03、 B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*35-C*04-DRB1*11__B*35-C*04-DRB1*11、 B*57-C*06-DRB1*07__B*57-C*06-DRB1*07、 B*07-C*07-DRB1*01__B*07-C*07-DRB1*01、 B*07-C*07-DRB1*04__B*07-C*07-DRB1*04、 B*07-C*07-DRB1-11__B*07-C*07-DRB1-11、 B*07-C*07-DRB1*13__B*07-C*07-DRB1*13、 B*07-C*07-DRB1*15__B*07-C*07-DRB1*15、 B*08-C*07-DRB1*03__B*08-C*07-DRB1*03、 B*13-C*06-DRB1*07__B*13-C*06-DRB1*07、 B*14-C*08-DRB1*01__B*14-C*08-DRB1*01、 B*15-C*03-DRB1*04__B*15-C*03-DRB1*04、 B*15-C*03-DRB1*13__B*15-C*03-DRB1*13、 B*18-C*05-DRB1*03__B*18-C*05-DRB1*03、 B*18-C*07-DRB1*11__B*18-C*07-DRB1*11、 B*27-C*01-DRB1*01__B*27-C*01-DRB1*01、 B*27-C*02-DRB1*04__B*27-C*02-DRB1*04、 B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*35-C*04-DRB1*07__B*35-C*04-DRB1*07、 B*35-C*04-DRB1*11__B*35-C*04-DRB1*11、 B*35-C*04-DRB1*13__B*35-C*04-DRB1*13、 B*40-C*03-DRB1*04__B*40-C*03-DRB1*04、 B*44-C*05-DRB1*01__B*44-C*05-DRB1*01、 B*44-C*05-DRB1*04__B*44-C*05-DRB1*04、 B*44-C*05-DRB1*13__B*44-C*05-DRB1*13、 B*44-C*07-DRB1*07__B*44-C*07-DRB1*07、 B*49-C*07-DRB1*11__B*49-C*07-DRB1*11、 B*50-C*06-DRB1*07__B*50-C*06-DRB1*07、 B*51-C*15-DRB1*11__B*51-C*15-DRB1*11、 B*07-C*07-DRB1*04__B*07-C*07-DRB1*04、 B*07-C*07-DRB1*11__B*07-C*07-DRB1*11、 B*07-C*07-DRB1*15__B*07-C*07-DRB1*15、 B*35-C*04-DRB1*01__B*35-C*04-DRB1*01、 B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*35-C*04-DRB1*11__B*35-C*04-DRB1*11、 B*52-C*12-DRB1*15__B*52-C*12-DRB1*15、 B*35-C*04-DRB1*01__B*35-C*04-DRB1*01、 B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*44-C*04-DRB1*07__B*44-C*04-DRB1*07、 B*35-C*04-DRB1*04__B*35-C*04-DRB1*04、 B*35-C*04-DRB1*11__B*35-C*04-DRB1*11、 B*44-C*07-DRB1*15__B*44-C*07-DRB1*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-DRB1*15__B*18-C*12-DRB1*15、 B*44-C*16-DRB1*07__B*44-C*16-DRB1*07、 B*44-C*16-DRB1*11__B*44-C*16-DRB1*11、 B*13-C*06-DRB1*07__B*13-C*06-DRB1*07、 B*18-C*05-DRB1*03__B*18-C*05-DRB1*03 or B*53-C*04-DRB1*13__B*53-C*04-DRB1*13.

[0131] In one embodiment, the cells of each cell bank have a specific and defined combination of two HLA haplotypes, wherein the combination of the two HLA haplotypes is homozygous. In one embodiment, the cells of each cell bank have a specific and defined homozygous HLA haplotype, wherein the HLA haplotype is determined by the HLA-A, HLA-B, and HLA-DRB1 loci, or wherein the HLA haplotype is determined by the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci. In one embodiment, the cells of each cell bank have a specific and defined homozygous HLA haplotype, wherein the HLA haplotype is determined by the HLA-B and HLA-DRB1 loci, or wherein the HLA haplotype is determined by the HLA-B, HLA-C, and HLA-DRB1 loci.

[0132] In one embodiment, the cell bank contains or is composed of hematopoietic cells. In one embodiment, the cells contained in the cell bank are hematopoietic cells.

[0133] In one embodiment, the cell bank contains or is composed of immune cells. In one embodiment, the cell bank contains or is composed of cells rich in lymphoid progenitor cells. In one embodiment, the cell bank contains or is composed of T cell progenitor cells.

[0134] In one embodiment, the cells contained in the cell bank are immune cells. In another embodiment, the cells contained in the cell bank are cells rich in lymphoid progenitor cells.

[0135] In one embodiment, the cell bank contains or consists of at least one immune cell type selected from the group consisting of: T cell progenitors, γ-δ T cells, progenitors of innate lymphoid cells (ILCs), ILCs, progenitors of NK cells, NK cells, progenitors of dendritic cells (DCs), DCs, granulocyte-monocyte progenitors, monocytes, and macrophages.

[0136] In one embodiment, the cell bank contains at least about 50% and more than about 60%, 70%, 80%, 90%, and 95% of T progenitor cells and less than about 50%, 40%, 30%, 20%, 10%, and 5% of immune cells, said immune cells being selected from the group consisting of or including: γ-δ T cells, progenitor cells of innate lymphoid cells (ILCs), ILCs, progenitor cells of NK cells, NK cells, progenitor cells of dendritic cells (DCs), DCs, granulocyte-monocyte progenitor cells, monocytes, and macrophages.

[0137] In one embodiment, the immune cells are T cell progenitor cells. In one embodiment, the T cell progenitor cells comprise CD34-CD7+ T cell progenitor cells.

[0138] In one embodiment, the immune cell is a progenitor cell of NK cells. In another embodiment, the immune cell is an NK cell. In yet another embodiment, the immune cell is both a progenitor cell of NK cells and an NK cell.

[0139] In one embodiment, the immune cell is a progenitor cell of innate lymphoid cells (ILC). In one embodiment, the immune cell is an ILC comprising ILC-1, ILC-2, and / or ILC-3 populations. In one embodiment, the immune cell is a progenitor cell of an ILC.

[0140] In one embodiment, the immune cell is a progenitor cell of dendritic cells (DCs). In another embodiment, the immune cell is a DC. In yet another embodiment, the immune cell is both a progenitor cell of dendritic cells (DCs) and a DC.

[0141] In one implementation, the immune cells are granulocyte-monocyte progenitor cells and / or monocytes and / or macrophages.

[0142] In one embodiment, the immune cell is an immune progenitor cell. In another embodiment, the immune cell is an immune progenitor cell selected from the group consisting of or comprising: T cell progenitor cells, innate lymphoid cell (ILC) progenitor cells, NK cell progenitor cells, dendritic cell (DC) progenitor cells, and granulocyte-monocyte progenitor cells.

[0143] In one embodiment, at least one cell bank contains cells that are in vitro-generated T cell progenitor cells.

[0144] In one embodiment, the T cell progenitor cells contained in the cell bank are in vitro-generated cells obtained using 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 progenitor cells are obtained by culturing CD34+ cells in a medium containing fibronectin and immobilized Notch ligand. In one embodiment, the Notch ligand is immobilized on the inner surface of a culture vessel or on beads.

[0145] In one implementation, CD34+ cells are isolated from a human.

[0146] In one embodiment, CD34+ cells are isolated from an adult donor. In another embodiment, CD34+ cells are isolated from bone marrow aspiration or peripheral blood that has been mobilized, such as using G-CSF, from an adult donor.

[0147] In one implementation, CD34+ cells are isolated from umbilical cord blood.

[0148] Methods for isolating CD34+ cells are well known in the art, and include, but are not limited to, methods using beads coated with antibodies that recognize CD34.

[0149] In one embodiment, the CD34+ cell population used in the method of the present invention is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% pure.

[0150] In one implementation, approximately 10 per milliliter of culture medium 6 To about 10 7 CD34+ cells were inoculated at a concentration of 1 cell.

[0151] In one embodiment, the culture vessel is selected from conventional culture vessels, including (but not limited to) culture plates with 6 to 96 wells, Piper plates, flasks, stirring flasks, microtiter plates, test tubes, hollow fiber devices, cell foams, and bags. Those skilled in the art can adjust the amount of cells inoculated according to the culture vessel used.

[0152] In one embodiment, the culture medium is suitable for culturing CD34+ cells. Examples of culture media suitable for culturing CD34+ cells include, but are not limited to, α-MEM, DMEM, RPMI 1640, IMDM, BME, McCoy's 5A medium, SFII (StemCell Technologies) medium, and Fischer's medium.

[0153] In one implementation, the culture conditions are those without feeder cells.

[0154] In one embodiment, the culture medium is serum-free. In another embodiment, the culture medium is supplemented with fetal bovine serum (FBS) or fetal calf serum (FCS), preferably supplemented with at least 15% or 20% v / v of FBS or FCS.

[0155] Notch proteins are transmembrane receptors that regulate cellular responses to a wide range of environmental signals. In mammals, four Notch receptors (Notch 1–4) and five ligands (δ-like-1, δ-like-3, δ-like-4, Jagged-1, and Jagged-2) have been described (Weinmaster Curr Opin Genet Dev 2000: 10: 363–369).

[0156] In one embodiment, the Notch ligand is δ-sample-4, preferably human δ-sample-4 (also known as DL-4, UniProt accession number: Q9NR61, SEQ ID NO: 1) or a fragment thereof.

[0157] SEQ ID NO: 1 MAAASRSASGWALLLLVALWQQRAAGSGVFQLQLQEFINERGVLASGRPCEPGCRTFFRVCLKHFQAVVSPGPCTFGTVSTPVLGTNSFAVRDDSSGGGRNPLQLPFNFTWPGTFSLIIEAWHAPGDDLRPEALPPDALISKIAIQGSLAVGQNWLLDEQTSTLTRLRYSY RVICSDNYYGDNCSRLCKKRNDHFGHYVCQPDGNLSCLPGWTGEYCQQPICLSGCHEQNGYCSKPAECLCRPGWQGRLCNECIPHNGCRHGTCSTPWQCTCDEGWGGLFCDQDLNYCTHHSPCKNGATCSNSGQRSYTCTCRPGYTGVDCELELSECDSNPCRNGGSCKDQ EDGYHCLCPPGYYGLHCEHSTLSCADSPCFNGGSCRERNQGANYACECPPNFTGSNCEKKVDRCTSNPCANGGQCLNRGPSRMCRCRPGFTGTYCELHVSDCARNPCAHGGTCHDLENGLMCTCPAGFSGRRCEVRTSIDACASSPCFNRATCYTDLSTDTFVCNCPYGFV GSRCEFPVGLPPSFPWVAVSLGVGLAVLLVLLGMVAVAVRQLRLRRPDDGSREAMNNLSDFQKDNLIPAAQLKNTNQKKELEVDCGLDKSNCGKQQNHTLDYNLAPGPLGRGTMPGKFPHSDKSLGEKAPLRLHSEKPECRISAICSPRDSMYQSVCLISEERNECVIATEV In one embodiment, the Notch ligand is a soluble domain of at least one Notch ligand. In another embodiment, the soluble domain of the Notch ligand represents the extracellular portion of the ligand.

[0158] In one embodiment, the Notch ligand or a fragment thereof (preferably a soluble domain of the Notch ligand) is fused to a protein, thereby allowing the Notch ligand to be immobilized on a vector.

[0159] In one embodiment, a Notch ligand or a fragment thereof (preferably a soluble domain of the Notch ligand) is fused to the Fc region of an IgG protein (such as human IgG protein). In another embodiment, a Notch ligand or a fragment thereof (preferably a soluble domain of the Notch ligand) is fused to the Fc region of an IgG2 protein (such as human IgG2 protein) (NCBI accession number: 4HAF_A, SEQ ID NO: 2).

[0160] SEQ ID NO: 2 VECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKT ISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK In one embodiment, the culture medium contains DL-4 or a fragment thereof, preferably containing soluble domains of DL-4 or fragments thereof.

[0161] 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 yet another embodiment, the soluble domain of DL-4 comprises or consists of amino acids 1-524 of SEQ ID NO: 1.

[0162] In one embodiment, DL-4 or a soluble domain thereof is fused to an IgG protein (such as human IgG protein), particularly IgG2 protein, and preferably the Fc receptor region of human IgG2. An example of a protein comprising a soluble domain of DL-4 fused to the Fc receptor region of human IgG2 protein is SEQ ID NO: 3.

[0163] SEQ ID NO: 3 MAAASRSASGWALLLLVALWQQRAAGSGVFQLQLQEFINERGVLASGRPCEPGCRTFFRVCLKHFQAVVSPGPCTFGTVSTPVLGTNSFAVRDDSSGGGRNPLQLPFNFTWPGTFSLIIEAWHAPGDDLRPEALPPDALISKIAIQGSLAVGQNWLLDEQTSTLTRLRYSYRVICSDNYYGDNCSRLCKKRNDHFGHYVCQPDGNLSCLPGWTGEYCQQPICLSGCHEQNGYCSKPAECLCRPGWQGRLCNECIPHNGCRHGTCSTPWQCTCDEGWGGLFCDQDLNYCTHHSPCKNGATCSNSGQRSYTCTCRPGYTGVDCELELSECDSNPCRNGGSCKDQEDGYHCLCPPGYYGLHCEHSTLSCADSPCFNGGSCRERNQGANYACECPPNFTGSNCEKKVDRCTSNPCANGGQCLNRGPSRMCRCRPGFTGTYCELHVSDCARNPCAHGGTCHDLENGLMCTCPAGFSGRRCEVRTSIDACASSPCFNRATCYTDLSTDTFVCNCPYGFVGSRCEFPVGLPPSTMVRSVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGMEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK In one embodiment, Notch ligands or fragments thereof are immobilized on a culture vessel used for culturing (i.e., bound to a solid carrier), although it is possible that certain elements may be found in solution. In one embodiment, Notch ligands or fragments thereof are immobilized on the surface of the culture vessel, preferably the inner surface. Not wishing to be bound by any theory, the applicant proposes that immobilization of Notch ligands or fragments thereof stabilizes them, thereby promoting interaction with CD34+ cells and thus allowing Notch receptor activation on CD34+ cells. In another embodiment, Notch ligands or fragments thereof are immobilized on beads present in the culture medium, preferably microbeads or surfaces such as polymer or magnetic beads (typically with diameters between 1 and 5 μm).

[0164] The binding of Notch ligands or fragments thereof (e.g., to beads or to the surface of a culture vessel) may or may not be covalent. Binding of Notch ligands can be non-covalently accomplished by adsorbing Notch ligands or fragments thereof onto the surface of a culture vessel or bead. Methods for attaching proteins or peptides to beads or culture vessels are known in the art and include, but are not limited to, crystallizable (Fc) regions of fragments of immunoglobulin molecules such as human IgG.

[0165] In one embodiment, according to WO2016 / 055396, when using 5 μg / ml, approximately 75% of the Notch ligand, particularly DL-4, will adhere to the surface of the culture vessel or beads. In one embodiment, the composition used to coat the culture vessel or beads with the Notch ligand contains a Notch ligand at a concentration greater than or equal to 1.25 μg / ml, and preferably in the range of about 2.5 to 5 μg / ml.

[0166] In one embodiment, the culture medium comprises fibronectin or a fibronectin fragment (fibronectin may have a sequence corresponding to uniprot accession number P02751: SEQ ID NO: 4). In one embodiment, the fibronectin fragment comprises or consists of an RGDS motif, a linker fragment 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.

[0167] Fibronectin is a protein that, in its native form, is a large V-shaped dimer, 100 nm long and 460 kDa. Two monomers are linked at their C-termini by two disulfide bridges. The terms “fibronectin” or “fibronectin fragment” should be understood to refer to native fibronectin (i.e., any isoform produced by alternative splicing), and either a monomer of the protein or a fragment of the protein (when specified, containing the RGDS motif, CS-1 motif, and heparin binding site).

[0168] An example of a fibronectin fragment particularly well-suited for the methods disclosed herein is Retronectin®. This protein corresponds to a fragment of human fibronectin (CH-296 fragment, Kimizuka et al., J Biochem., Aug 1991 110(2):284-91; Chono et al. J Biochem Sep 2001 130(3):331-4) and contains a cell-binding C domain (containing the RGDS motif, heparin-binding domain, and CS-1 motif). This protein is specifically marketed by Takara Bio Inc. (Shiga, Japan), Clinisciences (Nanterre, France, also called NovoNectin®), and Fisher Scientific (Hampton, United States).

[0169] In one embodiment, fibronectin fragments are immobilized on the inner surface of the culture container or on beads.

[0170] The term "RGDS motif" is intended to refer to any peptide or protein containing the RGDS (SEQ ID NO: 5) pattern, such that it can bind integrin VLA-5. The ability of such peptides or proteins to bind VLA-5 integrin can be tested using methods known and reported in the art. The RGDS motif binds to integrin VLA-5 (Very Late Antigen-5), a dimer composed of CD49e (α5) and CD29 (β1).

[0171] Heparin-binding domains are known in the art and are present in many heparin-binding proteins. Their sequences are typically XBBXBX or XBBBXXBX (B = basic amino acid; X = hydrophilic amino acid; Cardin and Weintraub, Arterioscler Thromb Vasc Biol. 1989;9:21-32). The presence of such heparin-binding domains is particularly advantageous when CD34+ cells are exposed to viral (especially retroviral) vectors to transduce them and obtain transgenic T-cell progenitor cells.

[0172] The CS-1 motif is a 25-amino acid 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 (α4) and CD29 (β1).

[0173] In one embodiment, fibronectin or fibronectin fragments are immobilized (i.e., bound to a solid carrier). The binding of fibronectin or fibronectin fragments (e.g., to beads or to the surface of a culture vessel) may or may not be covalent. In one embodiment, fibronectin or fibronectin fragments are immobilized to the inner surface of the culture vessel (although some elements may be present in solution). In another embodiment, fibronectin or fibronectin fragments are immobilized on beads, preferably microbeads or surfaces such as polymer or magnetic beads (typically between 1 and 5 μm in diameter). In one embodiment, Notch ligand or fragments thereof and fibronectin or fragments thereof are immobilized on the same beads. In another embodiment, Notch ligand or fragments thereof and fibronectin or fragments thereof are immobilized on different beads.

[0174] In one embodiment, immobilization of fibronectin or fibronectin fragments is performed non-covalently by adsorbing fibronectin or fragments thereof onto the inner surface of a culture vessel or the surface of a bead. Methods for attaching proteins or peptides to the surface of beads or culture vessels are known in the art and are set forth above.

[0175] WO2016 / 055396 discloses a method for coating culture containers or beads with fibronectin or fragments thereof. In one embodiment, the composition used to coat culture containers or beads with fibronectin or fragments thereof comprises fibronectin or fragments thereof at a concentration in the range of 10 to 100 μg / ml, preferably about 25 μg / ml.

[0176] In one embodiment, the culture medium may contain cytokines and growth factors. These cytokines and growth factors are selected from the group consisting of or composed of the following: SCF (stem cell factor), thrombopoietin (TPO, also known as megakaryocyte growth and development factor, 20 MGDF), Flt3-ligand (which is a hematopoietic growth factor), interleukin-3 (IL-3), interleukin-7 (IL-7), and SCF (stem cell factor).

[0177] In one embodiment, the culture medium contains at least 1, 2, 3 or 4 cytokines (such as 1, 2, 3 or 4) selected from the group consisting of or including: human SCF, human Flt3-L, human TPO and human IL-7.

[0178] In one embodiment, the concentration of SCF, preferably hSCF, is in the range of about 2 to about 300 ng / mL, preferably about 40 to about 300 ng / mL or about 40 ng / mL to about 200 ng / mL, and more preferably about 100 ng / mL.

[0179] In one embodiment, the concentration of Flt3-L, preferably hFlt3-L, is in the range of about 2 to about 300 ng / mL, preferably about 40 to about 300 ng / mL or about 40 ng / mL to about 200 ng / mL, and more preferably about 100 ng / mL.

[0180] In one embodiment, the concentration of TPO, preferably hTPO, is in the range of about 2 to about 300 ng / mL, preferably about 40 to about 300 ng / mL or about 40 ng / mL to about 200 ng / mL, and more preferably about 100 ng / mL.

[0181] In one embodiment, the concentration of IL-7, preferably hIL-7, is in the range of about 2 to about 300 ng / mL, preferably about 40 to about 300 ng / mL or about 40 ng / mL to about 200 ng / mL, and more preferably about 100 ng / mL.

[0182] In one embodiment, the culture medium contains IL-3, preferably human IL-3. In another embodiment, the culture medium does not contain IL-3.

[0183] In one embodiment, in addition to TNF-α, the culture medium contains at least three, preferably at least four, of these cytokines or growth factors.

[0184] In one embodiment, CD34+ cells are cultured in a medium containing TNF-α and / or an aryl hydrocarbon / dioxin receptor antagonist. In one embodiment, TNF-α is human TNF-α having, for example, the sequence SEQ ID NO: 7 (UniProt accession number: P01375).

[0185] SEQ ID NO: 7 MSTESMIRDVELAEEALPKKTGGPQGSRRCLFLSLFSFLIVAGATTLFCLLHFGVIGPQREEFPRDLSLISPLAQAVRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANG VELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL TNF-α is primarily produced as a type II transmembrane protein arranged in stable homodimers, with each monomer containing 233 amino acids in humans. In humans, the soluble portion of human TNF-α consists of amino acids 77 to 233 of SEQ ID NO: 7.

[0186] In one embodiment, the culture medium contains full-length TNF-α or a soluble fragment thereof.

[0187] In one embodiment, TNF-α or a fragment thereof is added from day 0 of the culture. In one embodiment, TNF-α or a fragment thereof is present in the culture medium from day 0 and for at least about 1, 2, 3, 4, 5, 6, or 7 days. In one embodiment, TNF-α or a fragment thereof is present in the culture medium from day 0 until the end of the culture.

[0188] In one embodiment, TNF-α or a fragment thereof is used at a concentration in the range of about 10 to about 300 ng / mL, such as at least about 10, 20, 30, 40, 50, 100, 200, or 300 ng / mL. In one embodiment, TNF-α or a 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.

[0189] In one embodiment, the antagonist of the aryl hydrocarbon / dioxin receptor is StemRegenin 1 (SR1, 4-(2-(2-(benzo[b]thiophene-3-yl)-9-isopropyl-9H-purine-6-ylamino)ethyl)phenol, CAS 1227633-49-10).

[0190] In one implementation, the aryl hydrocarbon / dioxin receptor antagonist is present in the culture medium from day 0 of culture.

[0191] In one embodiment, an antagonist of the aryl hydrocarbon / dioxin receptor is added to the culture medium at a concentration ranging from about 1 ng / ml to about 300 ng / ml, and preferably greater than or equal to 1 ng / ml, or greater than or equal to 3 ng / ml, or greater than or equal to 10 ng / ml, and preferably less than 200 ng / ml, or 150 ng / ml, and typically between 3 ng / ml and 100 ng / ml.

[0192] In one implementation, CD34+ cells are cultured for up to 10 days, preferably 3 to 7 days.

[0193] In one implementation, CD34+ cells from human CB or mobilized peripheral blood, bone marrow, ESC (embryonic stem cells) or iPSC samples are cultured together with recombinant human fibronectin and DL-4, as well as recombinant human cytokines interleukin-7 (IL-7), Flt3-ligand (Flt-3L), stem cell factor (SCF), and thrombopoietin (TPO) in the presence or absence of TNF-α.

[0194] The term "embryonic stem cell (ESC)" refers herein to a class of pluripotent stem cells derived from the germ cell stage of an early mammalian embryo and capable of differentiating into an unlimited number of different cell types (i.e., all somatic cell types in the embryo). In one implementation, ESCs are not obtained by performing steps that destroy a human embryo.

[0195] In one embodiment, the cells contained in the cell bank are stem cells. The stem cells may be HSPCs. In one embodiment, the HSPC is CD34. + (That is, they express CD34 markers). In one implementation, HSPC is CD133. + (That is, they express the CD133 marker). HSPCs may be selected, for example, from the group consisting of or composed of: UCB (umbilical cord blood) HSPCs (stem / progenitor cells), mPB (mobilized peripheral blood from adult donors) HSCPs, bone marrow HSPCs, ESC-derived HSPCs (embryonic stem cell-derived HSPCs), and iPSC-derived HSPCs (induced pluripotent stem cell-derived HSPCs).

[0196] In one embodiment, the cells contained in the cell bank are a mixture of at least two UCB HSPC samples obtained from different donors. The selection of different donors is based on HLA haplotype as described in this invention. In one embodiment, the cells contained in the cell bank are a mixture of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 UCB HSPC samples from different donors.

[0197] In one embodiment, the cells contained in the cell bank are a mixture of at least two mPB HSPC samples from different donors. The selection of different donors is based on HLA haplotype as described in this invention. In one embodiment, the cells contained in the cell bank are a mixture of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 mPB HSPC samples from different donors.

[0198] In one embodiment, the cells contained in the cell bank are a mixture of at least two iPSC-derived HSPC samples from different donors. The selection of different donors is based on HLA haplotypes as described in this invention. In one embodiment, the cells contained in the cell bank are a mixture of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 iPSC-derived HSPC samples from different donors.

[0199] In one embodiment, the cells contained in the cell bank are a mixture of at least two ESC-derived HSPC samples from different donors. The selection of different donors is based on HLA haplotypes as described in this invention. In one embodiment, the cells contained in the cell bank are a mixture of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 ESC-derived HSPC samples from different donors.

[0200] In one embodiment, the cells contained in the cell bank are a mixture of at least two bone marrow HSPCs from different donors. The selection of different donors is based on HLA haplotype as described in this invention. In one embodiment, at least one cell bank contains a mixture of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 bone marrow HSPC samples from different donors.

[0201] In one embodiment, the cells contained in the cell bank contain a sequence encoding a chimeric antigen receptor (CAR). In one embodiment, at least one cell contained in the cell bank expresses a CAR on its cell surface. CARs are widely known and described in the art and typically consist of an extracellular binding domain, a hinge region, a transmembrane domain, and an intracellular signal transduction domain. CARs provide cells with specificity for a particular target / antigen.

[0202] In one embodiment, the cells contained in the cell bank are genetically modified T cells and contain a sequence encoding a foreign T cell receptor (TCR). In one embodiment, the cells contained in the cell bank express a TCR, preferably a foreign TCR. The TCR recognizes antigens presented by major histocompatibility complex (MHC) molecules and confers antigen specificity to T cells. Genetically modified T cells that express foreign TCRs are widely known and described in the art, and are based on altering / modifying T cell specificity by expressing foreign antigen-specific TCRs (e.g., tumor-specific antigens).

[0203] In one embodiment, the cells contained in the cell bank contain sequences encoding CAR and / or exogenous TCR. In another embodiment, the cells contained in the cell bank express CAR and / or exogenous TCR on their cell surface.

[0204] In one implementation, the cells contained in the cell bank are genetically modified using viral vectors, nucleic acid fragments, plasmids, or plasmid RNA or DNA sequences, such as to introduce or silence genes of interest in these cells.

[0205] In one implementation, cells contained in a cell bank are transfected or transduced with exogenous nucleic acids, wherein the exogenous nucleic acids may, for example, encode exogenous proteins.

[0206] In one implementation, cells contained in a cell bank are transfected or transduced with exogenous nucleic acids encoding chimeric antigen receptors (CARs) or exogenous TCRs.

[0207] In one embodiment, gene editing, base editing, or lead editing systems are used to genetically modify cells contained in a cell bank. In another embodiment, cells are exposed to systems that enable gene editing, base editing, or lead editing. Such systems are widely known and described in the art and are substantially based on nucleic acid double break repair. Such systems may use nucleases selected from the group consisting of: broad-spectrum nucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR-Cas nucleases. Such systems may use natural or synthetic transposon systems based on transposase activity, such as the Sleeping Beauty (SB) transposon system.

[0208] In one embodiment, the cells contained in the cell bank are epigenetically modified at specific sites. Such modifications are widely known and described in the art and are essentially based on DNA-related modifications (e.g., nucleotide methylation or hydroxymethylation), histone-related modifications (e.g., acetylation, methylation, phosphorylation), and non-coding RNA (ncRNA)-related modifications, without modification of the amino acid sequence. In one embodiment, the cells are exposed to a system that enables epigenetic modification at specific sites. Such systems are widely known and described in the art. Such systems may use nucleases selected from the group consisting of: broad-spectrum nucleases, zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALENs), and CRISPR-Cas nucleases. Such systems may use natural or synthetic transposon systems based on transposase activity, such as the Sleeping Beauty (SB) transposon system. In one embodiment, the cells contained in the cell bank are genetically and epigenetically modified as indicated above.

[0209] In one implementation, the genetic modification and / or epigenetic modification as described herein is performed on immune cells or HSPCs or on cells generated in vitro as described herein.

[0210] In one embodiment, the cells contained in the cell bank are genetically modified to promote their resistance to drugs, preferably anti-inflammatory drugs and more preferably resistance to glucocorticoids. In one embodiment, the cells contained in the cell bank are genetically modified to promote resistance to chemicals that can be used for cell selection, such as neomycin or ganciclovir. In one embodiment, the cells contained in the cell bank are genetically modified to promote resistance to antibodies that can be used for regulation, such as anti-CD45 antibodies or anti-CD3 antibodies. In one embodiment, reducing or eliminating (e.g., by knockout) the expression of drug-specifically targeted receptors promotes resistance. Not wishing to be bound by any theory, the applicant proposes that promoting resistance to at least one cell bank increases the viability and / or efficiency of cells in a cell bank after transplantation.

[0211] In one embodiment, the cells contained in the cell bank are genetically modified to reduce or eliminate (e.g., by knockout) the expression of receptors specifically targeted by drugs (such as anti-inflammatory or immunomodulatory drugs). In another embodiment, the cells contained in the cell bank are genetically modified to reduce or eliminate (e.g., by knockout) the expression of glucocorticoid receptors. Such modifications are widely known and described in the art and can be performed, for example, using gene editing systems, base editing or lead editing systems, targeted epigenetic modifications, or all the systems described herein.

[0212] In one embodiment, the cells contained in at least one cell bank are genetically or epigenetically modified to reduce their sensitivity to therapeutic agents, including but not limited to antibodies (such as antibodies targeting differentiation clusters (CDs) expressed in mature immune cells or antibodies targeting T cells, such as anti-CD3, CD4, CD8, CD2, or CD45 antibodies), or T-cell connectors. In one embodiment, the cells contained in at least one cell bank are genetically modified to reduce or eliminate (e.g., by knockout) the expression of differentiation clusters (CDs) (such as CD3, CD4, CD8, CD2, or CD45) expressed in mature immune cells. Such modifications are widely known and described in the art and can be performed, for example, using gene editing systems, base editing or lead editing systems, or all of the systems described above. Not wishing to be bound by any theory, the applicant proposes that reducing or eliminating (e.g., by knocking out) the expression of differentiation clusters (CDs) in cells contained in the cell bank would allow for a reduction in the sensitivity of said cells to certain antibodies, such as those targeting differentiation clusters (CDs) expressed in mature immune cells or those targeting T cells, such as anti-CD3, CD4, CD8, CD2, or CD45 antibodies.

[0213] In one embodiment, the cells contained in the cell bank are genetically or epigenetically modified to evade allogeneic reactivity from at least one mature cell population from the recipient. Examples of mature cell populations from the recipient include, but are not limited to, T cell populations, B cell populations, NK cell populations, dendritic cell populations, macrophage populations, or ILC populations. Evading allogeneic reactivity from at least one mature cell population from the recipient can allow for reduced transplant rejection, particularly if a mismatch exists between the donor and recipient. Additionally, evading allogeneic reactivity from at least one mature cell population from the recipient can increase the viability and / or efficiency of the cells in the cell bank after transplantation. To facilitate allogeneic reactivity evasion by the cells in the cell bank, cells expressing mature cell receptors (such as CD2, CD3, or CD45) from the recipient can be knocked out or removed, for example, using specific antibodies targeting the receptor. Therefore, transplanted cells from the cell bank, which are genetically or epigenetically modified as described herein to exhibit reduced sensitivity to specific antibodies, will not be knocked out. The term "sensitivity" herein refers to a weaker ability of the antibody to recognize a binding site (e.g., antigen, receptor, differentiation cluster).

[0214] In one embodiment, the cells contained in the cell bank are derived from or obtained from UCB (umbilical cord blood) HSPCs (hematopoietic stem / progenitor cells). As described in this invention, the cells may be derived from or obtained from UCB HSPCs from a single donor or a mixture of UCB HSPCs from different donors. In one embodiment, as described in this invention, the cells contained in the cell bank are derived from or obtained from UCB HSPCs from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different donors.

[0215] In one embodiment, the cells contained in the cell bank are derived from or obtained from mPB (mobilized peripheral blood HSPCs) from adult donors. As described in this invention, the cells may be derived from or obtained from mPB HSPCs from a single donor or a mixture of mPB HSPCs from different donors. In one embodiment, as described in this invention, the cells contained in the cell bank are derived from or obtained from mPB HSPCs from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different donors.

[0216] In one embodiment, the cells contained in the cell bank are derived from or obtained from iPSC-derived HSPCs (induced pluripotent stem cell-derived HSPCs). As described in this invention, the cells may be derived from or obtained from iPSC-derived HSPCs from a single donor or a mixture of iPSC-derived HSPCs from different donors. In one embodiment, as described in this invention, the cells contained in the cell bank are derived from or obtained from iPSC-derived HSPCs from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different donors.

[0217] In one embodiment, the cells contained in the cell bank are derived from or obtained from ESC-derived HSPCs (embryonic stem cell-derived HSPCs). As described in this invention, the cells may be derived from or obtained from ESC-derived HSPCs from a single donor or a mixture of ESC-derived HSPCs from different donors. In one embodiment, as described in this invention, the cells contained in the cell bank are derived from or obtained from ESC-derived HSPCs from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different donors.

[0218] In one embodiment, the cells contained in the cell bank are derived from or obtained from bone marrow HSPCs. As described in this invention, the cells may be derived from or obtained from bone marrow HSPCs from a single donor or a mixture of bone marrow HSPCs from different donors. In one embodiment, as described in this invention, the cells contained in the cell bank are derived from or obtained from bone marrow HSPCs from at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different donors.

[0219] In one embodiment, the cells contained in the cell bank may be derived from or obtained from UCB HSPC, mPB HSPC, ESC-derived HSPC, iPSC-derived HSPC, or bone marrow HSPC using various methods known in the art, including but not limited to cell differentiation, cell culture, cell isolation, cell enrichment, or cell knockout.

[0220] In one implementation, HSPCs are isolated and / or enriched from human cord blood, bone marrow, mPB, ESC, or iPSC samples. Isolation or enrichment herein refers to an increase in the percentage of HSPCs, particularly CD34+ or CD133+ HSPCs. Isolation or enrichment can be performed using magnetic separation, fluorescence-activated cell sorting (FACS), or affinity chromatography. Isolation or enrichment of HSPCs may also induce α / β T cell knockout.

[0221] In one implementation scheme, UCB, bone marrow, mPB, ESC, and iPSC samples are obtained from donors of different ethnicities, such as African Americans, Caucasians, Asians, Hispanics, Native Americans, Australian Aborigines, Inuit, Pacific Islanders, Irish, Italians, Indians, Japanese, Chinese, Russians, etc.

[0222] In one implementation, UCB, bone marrow, mPB, ESC, and iPSC samples are obtained from Caucasian donors. In one implementation, UCB, bone marrow, mPB, ESC, and iPSC samples are obtained from African American donors. In one implementation, UCB, bone marrow, mPB, ESC, and iPSC samples are obtained from Native American donors. In one implementation, UCB, bone marrow, mPB, ESC, and iPSC samples are obtained from Asian donors. In one implementation, UCB, bone marrow, mPB, ESC, and iPSC samples are obtained from African donors. In one implementation, UCB, bone marrow, mPB, ESC, and iPSC samples are obtained from Australian donors. In one implementation, UCB, bone marrow, mPB, ESC, and iPSC samples are obtained from Inuit donors. In one implementation, UCB, bone marrow, mPB, ESC, and iPSC samples are obtained from Pacific Islander donors.

[0223] In one embodiment, at least one cell bank is used for Caucasian recipients. In one embodiment, at least one cell bank is used for African American recipients. In one embodiment, at least one cell bank is used for Native American recipients. In one embodiment, at least one cell bank is used for Asian recipients. In one embodiment, at least one cell bank is used for African recipients. In one embodiment, at least one cell bank is used for Australian Aboriginal recipients. In one embodiment, at least one cell bank is used for Pacific Islander recipients. In one embodiment, at least one cell bank is used for Hispanic recipients. In one embodiment, at least one cell bank is used for Inuit recipients.

[0224] In one implementation, the in vitro method for selecting at least one cell bank from a biobank to be administered to a subject is a computer-implemented method.

[0225] Some of the methods described above can be implemented using an apparatus including a computer, which includes a memory for storing program instructions that can be loaded into a circuit and adapted to cause the circuit to perform the steps of those methods when the program instructions are run by the circuit. The memory may also store data and useful information for performing the steps of those methods as described above.

[0226] The circuit can be, for example: - A processor or processing unit adapted to interpret instructions in a computer language, the processor or processing unit may include memory, may be associated with or connected to memory, the memory containing instructions, or - A combination of a processor / processing unit and memory, wherein the processor or processing unit is adapted to interpret instructions in a computer language, and the memory contains the instructions, or - An electronic card, wherein the steps of the invention are described within a silicon chip, or - Programmable electronic chips, such as FPGA chips (Field-Programmable Gate Array).

[0227] The computer may also include input interfaces and output interfaces for receiving data.

[0228] To facilitate interaction with a computer, a screen and keyboard can be provided and connected to the computer circuitry.

[0229] The present invention also relates to at least one cell bank selected according to the methods defined herein, said at least one cell bank being used as a pharmaceutical agent, particularly for treating immunodeficiency, immune disorders and / or diseases (such as inflammatory diseases or autoimmune diseases), lymphopenia or cancer in subjects of need.

[0230] In one embodiment, at least one selected cell bank is a pharmaceutical agent used in the treatment of immunodeficiency, which may be caused by exposure to radiation or compounds (such as chemotherapy).

[0231] In one implementation, at least one selected cell bank is a pharmaceutical agent used in the treatment of inflammatory diseases such as inflammatory bowel disease, psoriasis, and arthritis.

[0232] In one implementation, at least one selected cell bank is a drug used in the treatment of autoimmune diseases such as rheumatoid arthritis, type I diabetes, chronic hepatitis, multiple sclerosis, and systemic lupus erythematosus.

[0233] The present invention also relates to a method for treating immunodeficiency, immune disorders and / or diseases (such as inflammatory diseases or autoimmune diseases), lymphopenia, or cancer in a subject of need, said method comprising administering a selected cell bank to the subject. In one embodiment, the treatment method includes the step of selecting a cell bank to be administered to the subject according to the method described herein.

[0234] In one implementation, a therapeutically effective amount of cells is administered to the subject.

[0235] In one implementation, the selected cell bank is administered alone.

[0236] In one implementation, the selected cell bank is combined with another therapeutic substance to treat immunodeficiency, immune disorders and / or diseases (such as inflammatory diseases or autoimmune diseases), lymphopenia, or cancer. Therefore, according to this implementation, the selected cell bank is administered to the subject, along with another therapeutic substance, such as an immunosuppressant or a therapeutic agent to prevent GVHD and / or rejection. Administration may be simultaneous or sequential.

[0237] In one implementation, the selected cell bank is combined with another cell bank from a biosample bank. Therefore, according to this implementation, two cell banks are administered to the subject. Administration can be simultaneous or sequential.

[0238] In one implementation, the selected cell bank is combined with at least one umbilical cord blood transplant or at least one mPB transplant. Therefore, according to this implementation, the selected cell bank is administered to the subject along with at least one umbilical cord blood transplant or at least one mPB transplant. Administration may be simultaneous or sequential.

[0239] The present invention also relates to the use of at least one cell bank selected as described herein, said at least one cell bank for manufacturing an agent for treating immunodeficiency, immune disorders and / or diseases (such as inflammatory diseases or autoimmune diseases), lymphopenia, or cancer in a subject in need. In one embodiment, at least one selected cell bank is used to manufacture an agent for use in combination with at least one other cell bank to treat immunodeficiency, immune disorders and / or diseases (such as inflammatory diseases or autoimmune diseases), lymphopenia, or cancer in a subject in need. In one embodiment, at least one selected cell bank is used to manufacture an agent for use in combination with another therapeutic substance to treat immunodeficiency, immune disorders and / or diseases (such as inflammatory diseases or autoimmune diseases), lymphopenia, or cancer in a subject in need. In one embodiment, at least one selected cell bank is used to manufacture an agent for use in combination with at least one umbilical cord blood transplant or at least one mPB transplant to treat immunodeficiency, immune disorders and / or diseases (such as inflammatory diseases or autoimmune diseases), lymphopenia, or cancer in a subject in need.

[0240] In one embodiment, the at least one selected cell bank is used as a pharmaceutical agent in the treatment of hereditary conditions such as: anemia, familial aplasia, Fanconi syndrome, Bloom syndrome, pure red cell aplasia (PRCA), congenital dyskeratosis, Blackfan-Diamond syndrome, congenital erythropoiesis syndromes I-IV, Chwachmann-Diamond syndrome, dihydrofolate reductase deficiency, methylaminotransferase deficiency, Lesch-Nyhan syndrome, congenital spherocytosis, congenital elliptic polycythemia, congenital stomatocytosis, congenital Rh-negative disease, paroxysmal nocturnal hemoglobinuria, and G6PD. (Glucose-6-phosphate dehydrogenase) variants 1, 2, 3, pyruvate kinase deficiency, congenital erythropoietin sensitivity deficiency, sickle cell disease and traits, α-thalassemia, β-thalassemia, γ-thalassemia, methemoglobinemia, congenital immune disorders, severe combined immunodeficiency disease (SCID), naked lymphocyte syndrome, ionocarrier reactive combined immunodeficiency, combined immunodeficiency with capping abnormalities, nucleoside phosphorylase deficiency.

[0241] In one embodiment, the at least one selected cell bank is used as a pharmaceutical agent in the treatment of the following diseases: osteosclerosis, myeloschisis, acquired hemolytic anemia, acquired immunodeficiency, infectious diseases causing primary or secondary infections; bacterial infections (e.g., brucellosis, listerosis, tuberculosis, leprosy), parasitic infections (e.g., malaria, leishmaniasis), fungal infections, diseases involving lymphoid cell aggregation imbalance and age-related immunodeficiency, phagocytic disorders, Kostmann's agranulocytosis. agranulocytosis, chronic granulomatous disease, Chediak-Higachi syndrome, neutrophil actin deficiency, neutrophil membrane GP-180 deficiency, metabolic storage diseases, mucopolysaccharide storage diseases, mucolipide storage diseases, various diseases involving immune mechanisms, Wiskott-Aldrich syndrome, granulocyte actin deficiency, infantile agranulocytosis, Gaucher's disease, adenosine deaminase deficiency, Kostmann's syndrome, reticular cell dysplasia, and congenital leukocyte dysfunction syndrome.

[0242] In one implementation, the cause of lymphopenia can be a specific medical condition, such as cancer, human immunodeficiency virus (HIV) infection, partial thymectomy, autoimmune disease, and / or organ transplantation.

[0243] In one implementation, the causes of immunodeficiency can be varied: hereditary immunodeficiency, chemotherapy (such as for leukemia), conditioning, grafts containing only stem cells, ionizing radiation, post-transplant treatment for the prevention of GVHD (graft-versus-host disease), patient age, and complications (such as infections). In particular, immunodeficiency may be due to the elimination of immune cells following pre-transplant treatment of hematopoietic stem cells.

[0244] In one implementation, the cancer is selected from, but is not limited to, the group including: 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 lymphoma, 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., hepatocellular carcinoma), sarcoma, carcinoma (e.g., renal cell carcinoma, breast cancer). Carcinoma), small cell lung cancer, non-small cell lung cancer, pediatric solid tumors, CD133+ cancer stem cells, NKGDL+ cancer cells, PD-L1+ cancer cells, oral and oropharyngeal cancers (e.g., tongue cancer, esophageal cancer, laryngeal cancer, pharyngeal cancer), methylcholanthrene-induced sarcomas, and colorectal cancer.

[0245] The present invention also relates to a method for treating a subject in need, the method comprising administering to the subject at least one selected cell bank. In one embodiment, the subject will be treated for the disease described above.

[0246] In one embodiment, subjects receiving at least one selected cell bank do not receive immunosuppressive therapy or therapeutic agents for the prevention of GVHD and / or rejection. In another embodiment, subjects receiving at least one selected cell bank receive immunosuppressive therapy or therapeutic agents for the prevention of GVHD and / or rejection.

[0247] In one implementation, the method for treating a subject in need includes or comprises the following steps: a) Select at least one cell bank from a biobank comprising at least two different cell banks or biobanks thereof, as described herein, and b) Administer the at least one cell bank selected in step (a) to the subject.

[0248] In one embodiment, a method for treating a subject in need includes administering at least one selected cell bank and another selected cell bank to the subject. In one embodiment, a method for treating a subject in need includes administering at least one selected cell bank and umbilical cord blood transplantation or mPB transplantation to the subject. In one embodiment, a method for treating a subject in need includes administering at least one selected cell bank and another therapeutic substance to the subject.

[0249] In one implementation, the cell bank is cryopreserved and thawed before being administered to a subject.

[0250] In one implementation, a therapeutically effective amount of cells from at least one selected cell bank is administered (or used for administration) to a subject in need.

[0251] In one implementation, a therapeutically effective amount of cells from at least one selected cell bank is administered (or used for administration) to a subject in need, or, as described herein, for the treatment of an immunodeficiency, immune condition and / or disease (such as an inflammatory disease or an autoimmune disease), lymphopenia, or cancer in a subject in need.

[0252] The therapeutically effective dose of cells from at least one selected cell bank can be approximately 0.1 x 10⁻⁶ per kilogram of body weight. 5 To approximately 1x10 7 Cells, preferably approximately 0.5 x 10⁻⁶ per kilogram of body weight. 5 Approximately 5x10 6 1 cell per kilogram of body weight, and more preferably about 1 x 10 cells per kilogram of body weight. 6 Approximately 3x10 6 Within the range of individual cells. The therapeutically effective dose of cells from at least one selected cell bank can be approximately 0.3 x 10⁻⁶. 5 One cell to 1.5 x 10 9 1 cell, approximately 1.5 x 10 5 Up to 7.5 x 10 8 1 cell, and more preferably about 3 x 10 6 Up to 4.5 x 10 8 Within the range of individual cells. The therapeutically effective dose of cells from at least one selected cell bank can be approximately 5 x 10⁻⁶ cells. 5 1 cell to 5 x 10 8 1 cell, approximately 2.5 x 10 6 Up to 2.5 x 10 81 cell, and more preferably about 5 x 10 7 Up to 1.5 x 10 8 Within a single cell range.

[0253] In one embodiment, the selected cell bank may be co-administered with at least one other cell bank as described herein, wherein the other cell bank has the same homozygous HLA haplotype as the selected cell bank. The cell bank is selected based on homozygous HLA haplotypes as disclosed herein, and the cells in the cell bank may be of different cell types, such as a first cell bank to be administered containing immune cells and a second cell bank to be administered containing HSPCs; or a first cell bank to be administered containing T cell progenitor cells and a second cell bank to be administered containing dendritic cells (DCs). In one embodiment, the first and second cell banks to be administered have the same homozygous HLA haplotype. In one embodiment, the agent administered to the subject further comprises at least one other cell bank, wherein the at least one other cell bank has the same homozygous HLA haplotype as the selected cell bank. In one embodiment, the administration of cells from at least one of the selected cell banks is performed exactly before, exactly after, or simultaneously with the at least one other cell bank.

[0254] In one embodiment, cells from at least one selected cell bank as described herein are administered to a subject in combination with HSPCs, wherein the HSPCs comprise CD34+ or CD133+ cells. Cells such as in vitro-generated cells, T cell progenitors, γ-δ T cells, innate lymphoid cell (ILC) progenitors, ILCs, NK cell progenitors, NK cells, dendritic cell (DC) progenitors, DCs, granulocyte-monocyte progenitors, monocytes, or macrophages may be administered together with HSPCs, wherein the HSPCs comprise CD34+ or CD133+ cells. In one embodiment, the administration of cells from at least one of the selected cell banks occurs precisely before, precisely after, or simultaneously with HSPC transplantation in the subject.

[0255] In one implementation, cells from at least one of the selected cell banks are used as the drug. The drug is to be administered to the subject in combination with at least one umbilical cord blood transplant or at least one mPB transplant.

[0256] In one embodiment, cells from at least one selected cell bank are co-administered with at least one cord blood transplant. In another embodiment, cells from at least one of the selected cell banks are administered precisely before, precisely after, or simultaneously with the cord blood transplant performed on the subject.

[0257] In one implementation, cells from at least one selected cell bank are co-administered with at least mPB transplantation. In another implementation, cells from at least one of the selected cell banks are administered precisely before, precisely after, or simultaneously with mPB transplantation in the subject.

[0258] In one embodiment, cells from at least one of the selected cell banks are used as a pharmaceutical agent. The pharmaceutical agent is to be administered to a subject in combination with at least one other therapeutic substance. In one embodiment, cells from at least one of the selected cell banks are administered precisely before, precisely after, or simultaneously with the at least one other therapeutic substance.

[0259] In one embodiment, the method includes administering a combination of at least one selected cell bank and another therapeutic substance to a subject. In one embodiment, the agent to be administered to the subject further comprises at least one other therapeutic substance. In one embodiment, the other therapeutic substance comprises cytokines, chemokines, growth factors, antibodies (such as anti-PD1 (programmed cell death protein 1) or PD-L1 (programmed cell death-ligand 1)), chemotherapy molecules, hormones, immunosuppressive drugs, cell populations, cell connectors, or recombinant proteins. In one embodiment, cells of at least one of the selected cell banks are administered to the subject precisely before, precisely after, or simultaneously with the other therapeutic substance.

[0260] The present invention also relates to a composition comprising or substantially composed of cells from at least one selected cell bank of the present invention.

[0261] In one embodiment, the composition is a pharmaceutical composition and further comprises a pharmaceutically acceptable excipient.

[0262] Examples of pharmaceutically acceptable excipients that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates, glycine, sorbic acid, potassium sorbate), mixtures of metaglycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances (e.g., sodium carboxymethyl cellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0263] In one embodiment, the composition is a pharmaceutical agent.

[0264] The present invention also relates to a composition comprising at least one selected cell bank of the present invention or substantially composed thereof, said composition being used, as described herein, for or for treating immunodeficiency, immune disorders and / or diseases (such as inflammatory diseases or autoimmune diseases), lymphopenia, or cancer in a subject in need.

[0265] As used herein, the term “generally composed of” in relation to a composition, pharmaceutical composition, or pharmaceutical agent means that at least one cell from a selected cell bank is the only therapeutic or biologically active agent in the composition, pharmaceutical composition, or pharmaceutical agent. Attached Figure Description

[0266] Figure 1 This is a representative illustration of mismatch counting using asymmetric counting methods.

[0267] Figure 2A is a graph showing the population coverage obtained using k optimal choices of donor HLA haplotypes (HLA-A, B, C, and DRB1) as k (i.e., the size of the cell bank) increases from 1 to 40. Different lines correspond to different compatibility definitions based on the number of mismatches determined by using only asymmetric counting as 0 or 1, i.e., considering only HLA alleles from donor cells not found in the patient or subject. Figure 2B This is a graph showing the frequency of HLA haplotypes (HLA-A, B, and DRB1) as the number of optimal haplotypes (i.e., the size of the cell pool) increases from 1 to 40.

[0268] Figure 3A is a graph showing the population coverage obtained using k optimal choices of donor HLA haplotypes (HLA-A, B, C, and DRB1) as k (i.e., the size of the cell bank) increases from 1 to 40. Different lines correspond to different compatibility definitions based on the number of mismatches determined by using only asymmetric counting as 0 or 1, i.e., considering only HLA alleles from donor cells not found in the patient or subject. Figure 3B This is a graph showing the frequency of HLA haplotypes (HLA-A, B, C, and DRB1) as the number of optimal haplotypes (i.e., the size of the cell pool) increases from 1 to 40.

[0269] Figure 4A is a representative illustration of a preclinical mouse model (NSG mouse) used to evaluate the occurrence of GvHD after injection of human CAR-ProT cells or human mature CAR T cells. Figure 4B This is a graph showing the percentage weight loss over time in mice that received human CAR-ProT cells or mature human CAR T cells. Figure 4CThis is a graph showing the assessment of the occurrence of GvHD in mice that received human CAR-ProT cells or mice that received mature human CAR T cells. The assessment was performed according to a GvHD score, which was obtained by a binary assessment (presence / absence) of five clinical criteria for GvHD manifestation (weight loss >10%, hunched posture, skin lesions, dull skin color, and diarrhea).

[0270] Example The present invention is further illustrated by the following embodiments.

[0271] Example 1 : The most likely to cover a large number of patients and with a frequency sufficient to support efficient acquisition of homozygous HLA haplotypes Conquest: Target The goal is to characterize the optimal HLA haplotype for preparing a cell bank most likely to cover a large number of patients, considering the following two criteria: - Assess the percentage of patients in the Caucasian population who are able to receive the cell bank at an adequate level of HLA compatibility; and - Frequency of HLA haplotype occurrence in the donor library.

[0272] Materials and methods database HLA haplotypes of 8298 patients who underwent UCBT at European EBMT centers (including Russia and Turkey) between 1994 and 2022 were retrospectively collected and analyzed from the Eurocord / EBMT database. The Eurocord database contains the HLA types of transplant recipients and the umbilical cord blood used for transplantation. HLA-A, HLA-B, and HLA-DRB1 were analyzed using low-resolution HLA typing results, considering 8092 patients and corresponding to a total of 16184 alleles. A second analysis was performed separately, considering HLA-C information from 6903 patients, corresponding to a total of 13806 alleles. Table 1 lists the ten most frequent haplotypes.

[0273] Mismatch Count The compatibility between patient and donor is assessed by counting mismatches between the donor's and patient's HLA. In practice, 1 to 2 mismatches are permissible for most cord blood HSCTs (74-83%) – in fact, 6 / 6 or 5 / 6 HLA-matched UCB / recipient pairings give similar results in terms of survival, engraftment, GvHD, and relapse.

[0274] In this invention, the method for counting mismatches is asymmetric counting. Figure 1The number of mismatches is determined by the number of donor HLA alleles not found in the patient. Asymmetric counting naturally favors homozygous donors (homozygous HLA haplotypes). In Figure 2, 0 mismatches mean that the patient shares at least one allele with the donor cell at each of the HLA-A, HLA-B, and HLA-DRB1 loci, while 1 mismatch means that the patient shares at least one allele with the selected cell bank at only two of the HLA-A, HLA-B, and HLA-DR loci. Therefore, in Figure 3, 0 mismatches mean that the patient shares at least one allele with the donor cell at each of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci, while 1 mismatch means that the patient shares at least one allele with the selected cell bank at only three of the HLA-A, HLA-B, HLA-C, and HLA-DR loci.

[0275] If the donor cells are homozygous for the HLA antigen, the likelihood of antigen rejection is low.

[0276] Guidelines Coverage criteria alone are insufficient to quantitatively assess the value of selecting from n cord blood HLA haplotypes. In practice, it's easy to imagine selecting from n cord blood HLA haplotypes to maximize coverage, but this is practically worthless because these HLA types are not actually found in the natural population and / or in any donor bank. Therefore, a second selection criterion is used: the frequency of occurrence in the donor bank.

[0277] The frequencies of the donor's complete haplotypes (HLA_1, HLA_2) were evaluated using the following approximation method: Frequency (HLA_1, HLA_2) = Frequency (HLA_1) x Frequency (HLA_2) The value of selection from n umbilical cord blood HLA haplotypes is quantitatively assessed using the following criteria: Criterion = Coverage x Frequency Mathematical strategies Given the criteria established above, the goal is to determine the optimal selection of n umbilical cord blood HLA haplotypes relative to the latter criterion. This latter problem can be mathematically formulated as: X* = argmax_(X in {all possible choices}) = coverage(X) x frequency(X) Where the variable X = (HLA_1, HLA_2, ..., HLA_n) corresponds to the selection of n umbilical cord blood HLA haplotypes; coverage (X) corresponds to the coverage achieved by the selection and is obtained empirically based on the patient's Eurocord sample; frequency (X) corresponds to the product of the frequencies of HLA for each of the n donors, obtained empirically based on the donor's Eurocord sample.

[0278] The optimization problem described above is not trivial and can be solved numerically using, for example, integer linear programming (ILP). However, given the enormous set of all possible choices of X, such ILP methods may be computationally prohibitive if applied directly. We argue that using the recursive optimization algorithm described below as an alternative yields a very close solution with significantly lower computational cost.

[0279] initialization: The HLA of the first donor (denoted as HLA_1) was obtained as follows: HLA_1 = argmax_(HLA coverage (HLA) x frequency (HLA) of all possible donors) k is recursively extended to k+1: HLA_{k+1} = argmax_(HLA in all possible donors) incremental coverage_{k}(HLA) x frequency(HLA) The incremental coverage rate _{k} (HLA) corresponds to the coverage achieved by HLA, but is calculated based on a subgroup consisting of patients not yet covered by the first k selected donors (HLA_1, HLA_2, ..., HLA_k).

[0280] From an implementation perspective, this recursive scheme can be easily applied after calculating the compatibility matrix C as defined below: Cij = 1 if patient i is compatible with donor j, and 0 if they are incompatible. This requires first calculating the mismatch matrix M as defined below: Mij ​​= the number of mismatches between patient i and donor j Matrix C and M are both rectangles of size N x M, where N is the number of patients in the Eurocord sample and M is the number of different donors.

[0281] result Using the method described above, the optimal homozygous HLA haplotypes containing HLA A, B, and DRB1 were first characterized. As shown in Figure 2A, if zero asymmetric mismatches are required for compatibility, the coverage of the 20 HLA haplotypes reaches approximately 35% of the population; however, if a maximum of one asymmetric mismatch is required for compatibility, this increases to approximately 92%. These coverages are achieved when all haplotypes belong to the most frequent HLA haplotypes. Figure 2B This is achieved in those HLA haplotype cases. The HLA haplotypes are listed in Table 2.

[0282] In the second assessment, HLA-C was taken into account. As shown in Figure 3A, if compatibility requires zero asymmetric mismatches, the coverage of the 20 HLA haplotypes reaches approximately 25% of the population, but if compatibility requires at most one asymmetric mismatch, this increases to approximately 70%. These coverages are based on the most frequent HLA haplotypes (see Figure 3A). Figure 3B This is achieved in those HLA haplotype cases. The HLA haplotypes are listed in Table 3.

[0283] Based on the Eurocord dataset, if homozygous cord blood units (UCBs) are available from very large cell banks, and if a mismatch with the recipient is tolerated, fewer than 20 different haplotypes HLA-A, HLA-B, HLA-DRB1 and approximately 20 different haplotypes HLA-A, HLA-B, HLA-C, HLA-DRB1 are sufficient to cover 70% of the Caucasian population. If only perfectly matched haplotypes HLA-A, HLA-B, HLA-DRB1 or HLA-A, HLA-B, HLA-C, HLA-DRB1 are accepted, the population coverage of the 20 cell banks would be approximately 35% and 25%, respectively.

[0284] Example 2: Characterization of GvHD occurrence after CAR-ProT cell injection in a preclinical model Target The goal is to characterize the safety of administration of the resulting human ProT cells using the NSG mouse model.

[0285] Materials and methods Human ProT cells Human CD7+ CD34- ProT cells were obtained using the culture protocol described in WO2016 / 055396. In short, CD34+ cells were transduced using a lentiviral vector encoding CAR anti-human CD19. The modified CD34+ cells were then cultured for 7 days in a medium containing interleukin-7 (IL-7), Flt3-ligand (Flt-3L), stem cell factor (SCF), thrombopoietin (TPO), TNF-α, fibronectin, and immobilized Notch ligand.

[0286] mouse model A group of newborn NSG mice received 2x10 [units of something] via intrahepatic injection. 6 One group of mice received HLA-mismatched CAR-ProT cells derived from umbilical cord blood-derived CD34+ cells. A second group of mice received 2 x 10 HLA-mismatched CAR-ProT cells from healthy donor PBMCs at 6 weeks of age. 6 HLA-mismatched mature CD3+ T cells. Both groups received subcutaneous injections of human IL2 (2500 U three times) and IL7 (5 μg twice) between 6 and 8 weeks of age, and GvHD was scored during these two weeks (see Figure 4A). GvHD was assessed according to the scoring system proposed by Naserian et al. (2018), which is a binary assessment (presence / absence) of five clinical criteria for GvHD manifestations (weight loss >10%, hunched posture, skin lesions, dull skin color, and diarrhea).

[0287] result like Figure 4B and Figure 4C As shown, mice receiving HLA-mismatched CAR-ProT cells did not lose weight or develop GvHD compared to mice receiving mature CAR T cells with HLA mismatch.

[0288] Therefore, the results confirm that ProT cells did not induce GvHD despite the absence of HLA matching.

Claims

1. An in vitro method for selecting at least one cell bank from a biobank to be administered to a subject, said biobank comprising at least two different cell banks, each of said at least two cell banks being distinct from each other and containing T cell progenitor cells, wherein said T cell progenitor cells of the cell banks have the same HLA homozygous haplotype, wherein said method comprises the steps described above: a. Determine the HLA haplotypes of the subject's HLA-B and HLA-DR loci. b. Compare the HLA haplotype determined in step a) with the HLA haplotype of the cells in the cell bank, and c. Based on the comparison, select at least one cell bank, wherein the subject (i) shares at least one allele with the cells of the selected cell bank at at least one of the HLA-B locus or the HLA-DR locus, or (ii) shares an HLA-B leader sequence with the cells of the selected biosample bank.

2. The in vitro method according to claim 1, wherein the method comprises the following steps: a. Determine the HLA haplotypes of the subject at the HLA-A, HLA-B, and HLA-DR loci. b. Compare the HLA haplotype determined in step a) with the HLA haplotype of the cells in the cell bank, and c. Based on the comparison, select at least one cell bank, wherein the subject (i) shares at least one allele with the cells of the selected cell bank at at least two of the HLA-A locus, the HLA-B locus, and the HLA-DR locus, or (ii) shares an HLA-B leader sequence with the cells of the selected biosample bank and shares at least one allele with the cells of the selected cell bank at at least one of the HLA-A locus and the HLA-DR locus.

3. The in vitro method of claim 1, wherein step a) further comprises determining the subject's HLA haplotype at the HLA-C locus, and wherein in step c) at least one cell bank is selected, wherein the subject (i) shares at least one allele with the cells of the selected cell bank at at least two of the HLA-B locus, the HLA-C locus, and the HLA-DR locus, or (ii) shares an HLA-B leader sequence with the cells of the selected biosample bank and shares at least one allele with the cells of the selected cell bank at at least one of the HLA-C locus and the HLA-DR locus.

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

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 eliminate the expression of HLA-A on the cell surface.

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

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

8. The in vitro method according to any one of claims 1 to 7, wherein the cells of the selected cell 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. The selected cell bank containing T cell progenitor cells according to any one of claims 1 to 9, wherein the selected cell bank is used as a pharmaceutical agent, preferably for treating immunodeficiency, immune disorders and / or diseases, lymphopenia or cancer in subjects in need.

11. A selected cell bank comprising T-cell progenitor cells for use according to claim 10, wherein the agent is to be administered to the subject in combination with: a. At least another cell bank, wherein the other cell bank has the same homozygous HLA haplotype as the selected cell bank. b. At least another 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 cell banks, wherein the selection of homozygous HLA haplotypes is evaluated using the following formula: The variable X = (HLA_1, HLA_2, ..., HLA_n) corresponds to the selection of n HLA haplotypes; argmax represents the independent variable corresponding to the maximum value, and it is familiar to skilled technicians; The coverage (X) corresponds to the coverage achieved by this selection and is obtained empirically based on a sample of the patient database; Frequency (X) corresponds to the product of the frequencies of HLA for each of the n donors, obtained empirically from a database sample based on the donors.

13. A biobank comprising at least two different cell banks, wherein said at least two cell banks do not contain α-β T cells, wherein each cell bank contains cells from at least one donor and wherein, preferably, the cells of at least one of said at least two different cell banks have one of the following homozygous HLA haplotypes: A*01-B*08-DRB1*03__A*01-B*08-DRB1*03、 A*01-B*13-DRB1*07__A*01-B*13-DRB1*07、 A*01-B*35-DRB1*11__A*01-B*35-DRB1*11、 A*02-B*07-DRB1*01__A*02-B*07-DRB1*01、 A*02-B*07-DRB1*04__A*02-B*07-DRB1*04、 A*02-B*07-DRB1*15__A*02-B*07-DRB1*15、 A*02-B*15-DRB1*04__A*02-B*15-DRB1*04、 A*02-B*18-DRB1*03__A*02-B*18-DRB1*03、 A*02-B*18-DRB1*11__A*02-B*18-DRB1*11、 A*02-B*35-DRB1*04__A*02-B*35-DRB1*04、 A*02-B*35-DRB1*11__A*02-B*35-DRB1*11、 A*02-B*44-DRB1*04__A*02-B*44-DRB1*04、 A*02-B*44-DRB1*07__A*02-B*44-DRB1*07、 A*02-B*44-DRB1*13__A*02-B*44-DRB1*13、 A*02-B*51-DRB1*04__A*02-B*51-DRB1*04、 A*02-B*51-DRB1*11__A*02-B*51-DRB1*11、 A*02-B*51-DRB1*13__A*02-B*51-DRB1*13、 A*03-B*07-DRB1*15__A*03-B*07-DRB1*15、 A*03-B*14-DRB1*01__A*03-B*14-DRB1*01、 A*03-B*35-DRB1*01__A*03-B*35-DRB1*01、 A*03-B*35-DRB1*04__A*03-B*35-DRB1*04、 A*11-B*35-DRB1*01__A*11-B*35-DRB1*01、 A*24-B*35-DRB1*11__A*24-B*35-DRB1*11、 A*24-B*44-DRB1*13__A*24-B*44-DRB1*13、 A*24-B*51-DRB1*11__A*24-B*51-DRB1*11、 A*29-B*44-DRB1*07__A*29-B*44-DRB1*07 or A*68-B*53-DRB1*13__A*68-B*53-DRB1*13.

14. The biobank of claim 13, wherein the cells of at least one cell bank have one of the following homozygous HLA haplotypes: A*01-B*13-DRB1*07__A*01-B*13-DRB1*07、 A*01-B*35-DRB1*11__A*01-B*35-DRB1*11、 A*02-B*07-DRB1*04__A*02-B*07-DRB1*04、 A*02-B*18-DRB1*03__A*02-B*18-DRB1*03、 A*02-B*18-DRB1*11__A*02-B*18-DRB1*11、 A*03-B*14-DRB1*01__A*03-B*14-DRB1*01、 A*03-B*35-DRB1*04__A*03-B*35-DRB1*04、 A*24-B*44-DRB1*13__A*24-B*44-DRB1*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 of claim 13 or 14, wherein at least one of the at least two different cell banks, preferably each of the cells, has one of the following homozygous HLA haplotypes: A*01-B*08-C*07-DRB1*03__A*01-B*08-C*07-DRB1*03, A*01-B*35-C*04-DRB1*04__A*01-B*35-C*04-DRB1*04、 A*01-B*35-C*04-DRB1*11__A*01-B*35-C*04-DRB1*11、 A*01-B*57-C*06-DRB1*07__A*01-B*57-C*06-DRB1*07、 A*02-B*07-C*07-DRB1*01__A*02-B*07-C*07-DRB1*01、 A*02-B*07-C*07-DRB1*04__A*02-B*07-C*07-DRB1*04、 A*02-B*07-C*07-DRB1-11__A*02-B*07-C*07-DRB1-11、 A*02-B*07-C*07-DRB1*13__A*02-B*07-C*07-DRB1*13、 A-02-B*07-C*07-DRB1*15__A-02-B*07-C*07-DRB1*15、 A*02-B*08-C*07-DRB1*03__A*02-B*08-C*07-DRB1*03、 A*02-B*13-C*06-DRB1*07__A*02-B*13-C*06-DRB1*07、 A*02-B*14-C*08-DRB1*01__A*02-B*14-C*08-DRB1*01、 A*02-B*15-C*03-DRB1*04__A*02-B*15-C*03-DRB1*04、 A*02-B*15-C*03-DRB1*13__A*02-B*15-C*03-DRB1*13、 A*02-B*18-C*05-DRB1*03__A*02-B*18-C*05-DRB1*03、 A*02-B*18-C*07-DRB1*11__A*02-B*18-C*07-DRB1*11、 A*02-B*27-C*01-DRB1*01__A*02-B*27-C*01-DRB1*01、 A*02-B*27-C*02-DRB1*04__A*02-B*27-C*02-DRB1*04、 A*02-B*35-C*04-DRB1*04__A*02-B*35-C*04-DRB1*04、 A*02-B*35-C*04-DRB1*07__A*02-B*35-C*04-DRB1*07、 A*02-B*35-C*04-DRB1*11__A*02-B*35-C*04-DRB1*11、 A*02-B*35-C*04-DRB1*13__A*02-B*35-C*04-DRB1*13、 A*02-B*40-C*03-DRB1*04__A*02-B*40-C*03-DRB1*04、 A*02-B*44-C*05-DRB1*01__A*02-B*44-C*05-DRB1*01、 A*02-B*44-C*05-DRB1*04__A*02-B*44-C*05-DRB1*04、 A*02-B*44-C*05-DRB1*13__A*02-B*44-C*05-DRB1*13、 A*02-B*44-C*07-DRB1*07__A*02-B*44-C*07-DRB1*07、 A*02-B*49-C*07-DRB1*11__A*02-B*49-C*07-DRB1*11、 A*02-B*50-C*06-DRB1*07__A*02-B*50-C*06-DRB1*07、 A*02-B*51-C*15-DRB1*11__A*02-B*51-C*15-DRB1*11、 A*03-B*07-C*07-DRB1*04__A*03-B*07-C*07-DRB1*04、 A*03-B*07-C*07-DRB1*11__A*03-B*07-C*07-DRB1*11、 A*03-B*07-C*07-DRB1*15__A*03-B*07-C*07-DRB1*15、 A*03-B*35-C*04-DRB1*01__A*03-B*35-C*04-DRB1*01、 A*03-B*35-C*04-DRB1*04__A*03-B*35-C*04-DRB1*04、 A*03-B*35-C*04-DRB1*11__A*03-B*35-C*04-DRB1*11、 A*03-B*52-C*12-DRB1*15__A*03-B*52-C*12-DRB1*15、 A*11-B*35-C*04-DRB1*01__A*11-B*35-C*04-DRB1*01、 A*11-B*35-C*04-DRB1*04__A*11-B*35-C*04-DRB1*04、 A*23-B*44-C*04-DRB1*07__A*23-B*44-C*04-DRB1*07、 A*24-B*35-C*04-DRB1*04__A*24-B*35-C*04-DRB1*04、 A*24-B*35-C*04-DRB1*11__A*24-B*35-C*04-DRB1*11、 A*24-B*44-C*07-DRB1*15__A*24-B*44-C*07-DRB1*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-DRB1*15__A*25-B*18-C*12-DRB1*15、 A*29-B*44-C*16-DRB1*07__A*29-B*44-C*16-DRB1*07、 A*29-B*44-C*16-DRB1*11__A*29-B*44-C*16-DRB1*11、 A*30-B*13-C*06-DRB1*07__A*30-B*13-C*06-DRB1*07、 A*30-B*18-C*05-DRB1*03__A*30-B*18-C*05-DRB1*03 or A*68-B*53-C*04-DRB1*13__A*68-B*53-C*04-DRB1*13.

16. The biobank according to any one of claims 13 to 15, wherein the cells contained in the cell bank comprise or are composed of immune cells, preferably comprise or are composed of cells rich in lymphoid progenitor cells, and more preferably comprise or are composed of T cell progenitor cells.

17. The biobank according to any one of claims 13 to 16, wherein the cells contained in the cell bank are in vitro-generated T cell progenitors obtained by culturing CD34+ cells in a culture medium containing fibronectin, immobilized Notch ligand, TNF-α and / or aryl hydrocarbon / dioxin receptor antagonists, particularly StemRegenin 1 (SR1), and at least three, preferably four, 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 contained in the cell bank contain sequences encoding chimeric antigen receptor (CAR) and / or exogenous T cell receptor (TCR).

19. A biobank according to any one of claims 13 to 18; wherein the cells contained in the cell bank are genetically modified by viral vectors, nucleic acid fragments, plasmids or plasmid RNA or DNA sequences, gene editing systems, base editing systems, guided editing systems and / or wherein the cells contained in the cell bank are epigenetically modified.

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

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