Engineered lymphocytes

Abstract

The invention relates to lymphocytes which are genetically engineered to overexpress one or more maintenance factor(s), wherein, as compared to a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s), the lymphocytes exhibit enhanced stem-like or memory phenotype and a comparable or greater level of one or more effector functions in response to immune stimulation and a comparable or greater level of proliferation. The invention also relates to use of said lymphocytes in therapy, to methods for identifying said lymphocytes, and to methods for producing said lymphocytes.

Description

TECHNICAL FIELD OF THE INVENTION The invention relates to lymphocytes which are genetically engineered to overexpress one or more maintenance factor(s), wherein, as compared to a corresponding lymphocyte which is not engineered to overexpress said one or more a maintenance factor(s), the lymphocytes exhibit enhanced stem-like or memory phenotype and a comparable or greater level of one or more effector functions in response to immune stimulation and a comparable or greater level of proliferation. The invention also relates to use of said lymphocytes in therapy, to methods for identifying said lymphocytes, and to methods for producing said lymphocytes. BACKGROUND OF THE INVENTION The advent of immunotherapy has transformed the treatment of advanced stage cancers and dramatically improved patient outcomes over the past decade. Immune checkpoint inhibitors (ICI) targeting the surface molecules PD-1 and CTLA-4 are used in the therapy of several advanced cancer types and as neo-adjuvant therapy in earlier stage disease. However, a majority of patients fail to respond to checkpoint inhibition and require alternative treatment strategies. Cell therapy involves the in vitro or in vivo generation of lymphocytes, e.g. T cells, with either endogenous or genetically redirected specificity to disease antigens. For example, T cells expressing gene-engineered chimeric antigen receptor (CAR) targeting antigens expressed on the plasma membrane of cancer cells are routinely employed for treatment-refractory or relapsed B cell malignancies including diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic leukaemia (B-ALL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and multiple myeloma (MM). T cell-based anti-inflammatory therapies are also under development which employ the unique anti-inflammatory and regenerative characteristics of regulatory T (Treg) cells. The efficacy of cell therapy relies upon the maintenance and long-term survival of engineered lymphocytes. For example, persistence of CAR T cells is critical to their durable function and antitumour efficacy. Long-term maintenance of lymphocyte responses is dependent upon maintenance of a pool of lymphocytes with a stem cell-like / memory phenotype which are long-lived and self-renew but remain functionally quiescent and display greatly reduced effector functions. In the context of acute infections, stem-like or memory cells are generated through weak interactions between the T cell receptor and cognate peptide-MHC complex. In the context of cell therapy, stem-like or memory T cell differentiation may be antagonised by the chronic nature of targeted antigens and the fixed, often high-affinity antigen binding and signalling architecture of synthetic CARs. This depletes stem-like or memory cells within the pool of therapeutic T cells, limiting the long-term functionality that is required for maximally durable and efficacious therapeutic responses. In the context of acute CD8+T cells responses, maintenance depends upon long-lived central / effector memory T cells which outlive shorter-lived terminally differentiated effector cells to establish immunological memory. Similarly, during chronic antigen exposure, maintenance depends upon progenitor-exhausted T (TPEx) cells , characterised by expression of the transcription factor TCF1 and the cell surface receptor Slamf6, which form a self-renewing population while giving rise to shorter-lived terminally-exhausted T (TTEx) cells, characterised by expression of cell surface receptors TIM-3 and CD69. These parallel differentiation hierarchies highlight the essential role of quiescent memory / progenitor exhausted states in maintaining physiological acute and chronic T cell responses. Thus, the long-term efficacy of existing cell therapies is limited by the poor maintenance and poor long-term survival of engineered cells, resulting in relapse and clinical failure. Moreover, many types of existing cell therapies remain restricted to the treatment of blood cancers, and impaired persistence of transferred cells severely limits their efficacy in solid cancers. There is an urgent and unmet therapeutic need for lymphocytes which achieve improved maintenance and long-term cell survival, as compared to existing cell therapies. SUMMARY OF THE INVENTION The inventors have identified for the first time that lymphocytes which overexpress a therapeutically effective amount of maintenance factor(s) retain the ability to produce effector cytokines in response to immune stimulation and exhibit improved therapeutic efficacy as compared to lymphocytes which do not overexpress said maintenance factor(s) or lymphocytes engineered for conventional high level overexpression of said maintenance factor(s). Lymphocytes which overexpress a therapeutically effective amount of maintenance factor(s) as described herein exhibit enhanced stem-like or memory phenotype as compared to lymphocytes which do not overexpress said maintenance factor(s). Importantly, these properties enable the lymphocytes of the invention to achieve improved maintenance and long-term survival in vivo leading to improved therapeutic efficacy. The invention provides a lymphocyte genetically engineered to overexpress one or more maintenance factor(s), wherein the lymphocyte exhibits a comparable or greater level of one or more effector functions in response to immune stimulation and / or a comparable or greater level of proliferation as compared to a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s). In one embodiment, the one or more maintenance factor(s) are selected from one or more of BACH2, F0X01, TCF1, MYB, EOMES, BCL6, STAT3, ZEB1, LEF1, F0XP1, KLF2, SATB1, FLU, RUNX2, RUNX3, S0X4, BHLHE40, KMT2A, SMARCA4, JUN, STAT5A, STAT5B, and S0CS1. In one embodiment, the lymphocyte is selected from a T cell, a natural killer (NK) cell, a B cell, an innate lymphoid cell (ILC), and a tumour-infiltrating lymphocyte (TIL). In one embodiment, the T cell is selected from a CD8+ T cell, a CD4+ T cell and a gamma-delta T cell, optionally wherein the CD4+ T cell is selected from a regulatory T (Treg) cell, a T helper (Th)l cell, a Th2 cell, a Thl7 cell, a Follicular Helper T (Tfh) cell, and a Th9 cell. In one embodiment, the lymphocyte is engineered to express a chimeric antigen receptor (CAR), a T cell receptor (TCR), an antibody-TCR, a TCR-based CAR, a T cell antigen coupler (TAC), a synthetic T cell receptor and antigen receptor (STAR), and / or a TCR fusion construct (TRuC). In one embodiment, immune stimulation comprises exposing the lymphocyte to one or more cytokines, optionally wherein the one or more cytokines comprises CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CX3CL1, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, IL-la, IL-ip, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, IFNa, IFNp, IFNy, TGFp, TNF, TNFp, XCL1, and XCL2. In one embodiment, immune stimulation comprises exposing the lymphocyte to an antigen. In one embodiment, the one or more effector functions comprises production of one or more effector molecules. In one embodiment, the one or more effector molecules comprise one or more effector cytokines, optionally wherein the one or more effector cytokines are selected from IFN-y, TNF, IL-2, Granzyme-B, Perforin, and CD103. In one embodiment, the one or more effector functions comprise cytotoxic activity. In one embodiment, the lymphocyte overexpresses a level of one or more maintenance factor(s) that is at least 2-fold higher than the level of said one or more maintenance factor(s) expressed by a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s), optionally wherein the lymphocyte overexpresses a level of said one or more maintenance factor(s) that is at least 100-fold, at least 500-fold, at least 1000-fold or at least 2000-fold higher than the level of said one or more maintenance factor(s) expressed by a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s). In one embodiment, the lymphocyte overexpresses a level of said one or more maintenance factor(s) that is between 5-fold and 1000-fold lower than the level of said one or more maintenance factor(s) expressed by a corresponding lymphocyte which is engineered to overexpress said one or more maintenance factor(s) from a retroviral vector configured for LTR-driven expression of said one or more maintenance factor(s). In one embodiment, the lymphocyte comprises a nucleic acid sequence encoding said one or more maintenance factor(s) downstream of a STOP-translational readthrough motif (STOP-TRM) sequence and / or a frame-slip motif. In one embodiment, the STOP-TRM sequence is selected from: TGA-CTAGCA; TGA-CTAGGC; TGA-CAATTA; TAG-CAATTA; TAG-CTAGCA; TAG-CTAGGC; TAA-CTAGGC; TAA-CAATTA; TAA-GAGAGT; TAG-GAGAGT; TAG; TAA-CTAGCA; TAG-GAGAGT; TAA; TGATGA; and TGATGA-CTAGCA. In one embodiment, the lymphocyte comprises a nucleic acid sequence encoding said one or more maintenance factor(s) operably linked to a 2A element. In one embodiment, the lymphocyte comprises a nucleic acid sequence encoding said one or more maintenance factor(s) operably linked to an internal ribosome entry site (IRES) sequence. In one embodiment, the lymphocyte comprises a nucleic acid sequence encoding said one or more maintenance factor(s) operably linked to a promoter for driving weak expression of said one or more maintenance factor(s). In one embodiment, the promoter is a human UBC promoter or an inducible promoter. In one embodiment, the lymphocyte comprises a catalytically-inactive Cas protein or a nucleic acid encoding a catalytically-inactive Cas protein and a guide RNA or a nucleic acid encoding a guide RNA, wherein the guide RNA is capable of hybridizing to a nucleic acid encoding said one or more maintenance factor(s). In one embodiment, the lymphocyte comprises a nucleic acid sequence encoding said one or more maintenance factor(s) operably linked to endogenous regulatory mechanisms; optionally wherein the nucleic acid sequence is integrated into an endogenous locus of the genome of the lymphocyte. In one embodiment, the lymphocyte comprises an exogenously delivered messenger RNA (mRNA) molecule encoding one or more maintenance factor(s). In one embodiment, the one or more maintenance factor(s) are modified to exhibit reduced activity as compared to the corresponding wild-type maintenance factor(s). In one embodiment, the one or more modified maintenance factor(s) exhibit reduced stability, nuclear translocation, DNA binding affinity, and / or co-factor binding affinity relative to the corresponding wild-type maintenance factor(s). In one embodiment, the one or more maintenance factor(s) are operably linked to an inducible protein domain which functions to regulate activity of the one or more maintenance factor(s) in response to a signal; optionally wherein the signal is selected from a ligand and light. In one embodiment, the inducible protein domain functions to regulate the activity of the one or more maintenance factor(s) by inducing or preventing: (a) degradation of the one or more maintenance factor(s); (b) nuclear translocation of the one or more maintenance factor(s); and / or (c) DNA and / or co-factor binding by the one or more maintenance factor(s). The invention provides a composition comprising a population of lymphocytes of any preceding claim. The invention provides a composition comprising a vector for use in producing a lymphocyte of the invention, wherein the vector comprises a nucleic acid sequence encoding one or more maintenance factor(s). In one embodiment, the vector is a viral vector, optionally a lentiviral vector, a retroviral vector, or an AAV vector. In one embodiment, the vector is a non-viral vector, optionally a lipid nanoparticles vector. The invention also provides a composition of the invention for use in therapy. The invention also provides a composition of the invention for use in a method of treating or preventing cancer in a patient. In one embodiment, the cancer is selected from a haematological cancer and a solid cancer. In one embodiment, the cancer is selected from a treatment-refractory or relapsed B cell malignancy, optionally wherein the cancer is selected from diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic leukaemia (B-ALL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and multiple myeloma (MM). In one embodiment, the cancer is a solid cancer selected from breast cancer, lung cancer, brain cancer, colorectal cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, cervical cancer, testicular cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, head and neck cancer, renal cancer, and gastric cancer. In one embodiment, the cancer is a haematological cancer selected from Acute Myeloid Leukaemia (AML), Chronic Lymphocytic Leukaemia (CLL), Chronic Myelogenous Leukaemia (CML), Chronic Myelomonocytic Leukaemia (CMML) and Cutaneous T cell Lymphoma (CTCL The invention also provides a composition of the invention for use in a method of treating or preventing an autoimmune disease in a patient. In one embodiment, the autoimmune disease is selected from rheumatoid arthritis, lupus erythematosus, multiple sclerosis, type I diabetes, coeliac disease, Crohn's disease, myasthenia gravis, Sjogren syndrome, Graves' disease, Behget's syndrome, and Asthma. In one embodiment, the lymphocytes are derived from: (a) a sample obtained from the patient; and / or (b) a sample obtained from a donor. In one embodiment, the method comprises administering the lymphocytes in combination with an RNA interference molecule for downregulating expression of the one or more maintenance factor(s). In one embodiment, the one or more maintenance factor(s) is operably linked to an inducible protein domain which functions to regulate activity of the one or more maintenance factor(s) in response to a signal, and wherein the method comprises administering the signal to the patient; optionally wherein the signal is selected from a ligand and light. The invention also provides a method of determining whether a lymphocyte which has been genetically engineered to overexpress one or more maintenance factor(s) expresses a therapeutically effective amount of said one or more maintenance factor(s), the method comprising: (a) comparing the sternness of the genetically engineered lymphocyte to the sternness of a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s); (b) comparing the level of one or more effector functions in response to immune stimulation of the genetically engineered lymphocyte to the level of one or more effector functions of a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s); and (c) determining whether the genetically engineered lymphocyte expresses a therapeutically effective amount of said one or more maintenance factor(s) based on steps (a) and (b). The invention also provides a method for producing a lymphocyte expressing a therapeutically effective amount of one or more maintenance factor(s), the method comprising: (a) genetically engineering a lymphocyte to overexpress said one or more maintenance factor(s); (b) comparing the sternness of the genetically engineered lymphocyte to the sternness of a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s); (c) comparing the level of one or more effector functions in response to immune stimulation of the genetically engineered lymphocyte to the level of one or more effector functions of a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s); and (d) selecting a lymphocyte which exhibits: (i) enhanced sternness compared to the corresponding lymphocyte; and (ii) a comparable or greater level of one or more effector functions in response to immune stimulation compared to the corresponding lymphocyte. In one embodiment, the method further comprises comparing the level of proliferation of the genetically engineered lymphocyte to the level of proliferation of a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s). In one embodiment, the immune stimulation comprises: (a) exposing the lymphocyte to an antigen; and / or (b) exposing the lymphocyte to one or more cytokines and / or chemokines configured to induce activation of effector function by the lymphocyte. In one embodiment, exposing the lymphocyte to one or more cytokines and / or chemokines comprises exposing the lymphocyte to CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CX3CL1, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, IL-la, IL-ip, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, IFNa, IFNp, IFNy, TGFp, TNF, TNFp, XCL1, and XCL2. In one embodiment, the one or more effector functions comprises the production of one or more effector molecules, optionally wherein the one or more effector molecules comprises one or more effector cytokines, optionally selected from IFN-y, TNF, IL-2, Granzyme-B, Perforin, and CD103. In one embodiment, said one or more maintenance factor(s) are selected from one or more of BACH2, ID3, F0X01, TCF7, EGR2, MYB, EOMES, BCL6, STAT3, ZEB1, LEF1, F0XP1, KLF2, SATB1, FLU, RUNX2, RUNX3, SOX4, BHLHE40, KMT2A, and SMARCA4. In one embodiment, the lymphocyte is selected from a T cell, a natural killer (NK) cell, a B cell, an innate lymphoid cell (ILC), and a tumour-infiltrating lymphocyte (TIL). In one embodiment, the T cell is selected from a CD8+ T cell, a CD4+ T cell and a gamma-delta T cell, optionally wherein the CD4+ T cell is selected from a regulatory T (Treg) cell, a T helper (Th)l cell, a Th2 cell, a Thl7 cell, a Follicular Helper T (Tfh) cell, and a Th9 cell. In one embodiment, the lymphocyte is engineered to express a chimeric antigen receptor (CAR), T cell receptor (TCR), an antibody-TCR, a TCR-based CAR, a T cell antigen coupler (TAC), a synthetic T cell receptor and antigen receptor (STAR), and / or a TCR fusion construct (TRuC). DESCRIPTION OF THE FIGURES Figure 1. High-level maintenance factor overexpression in tumour-reactive CD8+ T cells does not enhance anti-tumour efficacy, a-b, Mice bearing B16-OVA tumours (dl2 post-implantation) were administered 1x10s OT-I CD8+ T cells transduced with either Empty or conventional BACH2-expressing retroviral vectors. Experimental schema (a) and tumour growth kinetics (b) are shown, c, Expression of indicated molecules by transferred retrovirally transduced (Thyl.l+) cells within tumours of mice, d, Intracellular cytokine staining of indicated effector cytokines within retrovirally transduced (Thyl.l+) cells isolated from tumours of treated mice. P values; unpaired two-tailed Student's t-test. Error bars indicate mean ± SEM. Figure 2. Schematic representation of selected maintenance factor dosed expression vectors. A series of retroviral vectors enabling expression of BACH2 at a range of reduced doses relative to conventional overexpression vectors. Insertion upstream of a BACH2 open reading frame of a STOP codon followed by a series of translational readthrough motif (TRM) variants suppress the termination of translation to different extents, yielding different levels of expression. Figure 3. Dosed expression of maintenance factor maintains CD8+ T cells with a stem / memory phenotype with preserved effector function after chronic stimulation in vitro, a, Experimental schema showing in vitro chronic stimulation assay, b-c, Flow cytometric measurement of indicated molecules in transduced (Thyl.l+) CD8+T cells retrovirally transduced with indicated retroviral vectors and subjected to chronic stimulation as in a. n = 2-3 technical replicates and representative of two independent experiments. Bars and error are mean and SEM. *, P<0.05; **, P<0.01; ***, P<0.005; ****, p<o.oO1. One-way ANOVA. Figure 4. Dosed expression of maintenance factor improves the persistence and anti- tumour efficacy of tumour-reactive CD8+ T cells, a-b, Mice bearing B16-OVA tumours were administered 1x10s OT-I CD8+ T cells transduced with the indicated retroviral vectors. Tumour growth measurements (a) and representative photographs at day 17 after T cell transfer (b). c, Frequency of adoptively transferred retrovirally transduced (Thyl.l+) CD8+ T cells within tumours of mice in (a), d, Flow cytometry analysis of the expression of indicated molecules by transferred retrovirally transduced (Thyl.l+) T cells within tumours of treated mice, e, Intracellular cytokine staining analysis of the expression of indicated effector molecules after brief ex vivo restimulation of transferred retrovirally transduced (Thyl.T) T cells recovered from tumours of treated mice. *, P<0.05; **, P<0.01; ***, P<0.005; ****, P<0.001; One-way ANOVA. Figure 5. High level conventional overexpression of BACH2 promotes CD8+ sternness but compromises the acquisition of effector functions. a-b, Percentage of Slamf6+ TCF1+ (a) and TIM-3+ (b) cells in transduced intratumoral OT-I T cells and representative flow cytometry plots, c, Median fluorescence intensity (MFI) of CCR7, CD62L, CD44and PD-1 in transduced intratumoral OT-I T cells, and representative flow cytometry histograms, d-e, Percentage of IFN-y + TNF+ (d) and Granzyme B+ (e) cells in transduced intratumoral OT-I T cells following ex vivo stimulation with phorbol myristate acetate (PMA) + ionomycin and representative flow cytometry plots, f, Tumour measurements of mice injected with B16-OVA and receiving either Hanks' balanced salt solution HBSS (no cells) or OT-I T cells transduced with EV or BACH2oEas detailed in Example 2. Data are representative of two independent experiments with five to eight mice per group, ns, non-significant (P > 0.05); *, P < 0.05; **, P < 0.01; ****, P < 0.0001. Unpaired two-tailed Student's ttest. Bars and error indicate mean ± SEM. Figure 6. Intermediate levels of BACH2 expression can be mimicked by dosed transgene expression. a, BACH2oe and BACH2 dosed expression (BACH2De) vector design. All vectors contained Thyl.l as a transduction reporter, followed by a glycine-serine-glycine (GSG) linker, a T2A ribosomal skip motif and the Bach2 open reading frame (CCDS51135.1) tagged N-terminally with a 3xFLAG (3xFLAGBACH2). A STOP-TRMs was inserted into BACH2De vectors prior to the GSG linker to achieve lower levels of Bach2 expression relative to BACH2oe- b, MFI of 3xFLAGBACH2 expression on OT-I cells transduced with the indicated vectors and representative flow cytometry histograms. Data are representative of two independent experiments, ns, non-significant (P > 0.05); *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Multiple unpaired two-tailed Student's t test with Bonferroni correction (b). Bars or lines and error indicate mean ± SEM. Figure 7. Low-dose expression of BACH2 preserves a stem-like phenotype without compromising effector functions in vitro. a-b, Percentage of PD-l+TIM-3+ chronically stimulated (a) or IFN-y+TNF+ acutely stimulated following 4-hour of anti-CD3 restimulation in the presence of brefeldin-A and monensin (b) from OT-I T cells transduced with the indicated vectors at day 4 and representative flow cytometry plots, c, FSC-A of acutely stimulated OT-I T cells transduced with the indicated vectors at day 4 and representative flow cytometry histograms, d, PCA plot of chronically stimulated transduced OT-I cells at day 6. e, Comparison between EV and BACH2oe, BACH2De-io% or BACH2De-s% in chronically stimulated transduced OT-I cells at day 6 using gene set enrichment analysis (GSEA) with signatures derived from terminally exhausted or progenitor exhausted SHNFEKL-reactive CD8+ TILs from B16-OVA tumours (Miller, B.C., et al. (2019). Subsets of exhausted CD8(+) T cells differentially mediate tumour control and respond to checkpoint blockade. Nat Immunol 20, 326-336. 10.1038 / s41590-019-0312-6). Data are representative of three independent experiments with three to five samples per experimental group, ns, non-significant (P > 0.05); *, P < 0.05; **, P < 0.01; ****, P < 0.0001. One-way ANOVA with Dunnett's multiple comparison correction. Horizontal lines and error indicate mean ± SEM. Figure 8. BACH2 dosing enhances anti-tumour T cell therapy responses. a, Tumour volume of B16-OVA-bearing mice following sublethal irradiation with 3.5 Gy and adoptive transfer of 0.5x10s OT-I T cells transduced with indicated vectors, b, Tumour volumes at days 15-17 after T cell transfer and representative images of B16-OVA tumours, c, Number of tumour-infiltrating transduced OT-I T cells per gram of tumour for indicated T cell phenotypes and sample groups, d, Quantification of TCF1 and TIM-3 frequency of expression in tumour-infiltrating transduced PD-1+ OT-I T cells and representative flow cytometry plots. Significance represents difference in frequency of TCF1+ TIM-3- cells with that of the EV population, e, Absolute difference in the frequency of tumourinfiltrating transduced OT-I T cells expressing the indicated number of effector molecules (IFN-y, TNF, granzyme B, IL-2) upon 4-hour ex vivo anti-CD3 stimulation normalised to EV. Pie charts represent the average proportion of cells from each condition (co-)expressing the indicated number of effector molecules, f, Quantification of the absolute number of tumour-infiltrating transduced OT-I T cells per gram of tumour expressing the indicated effector molecule normalised to EV. Data are representative of three independent experiments. Data in (e-f) were pooled from two independent experiments, ns, non-significant (P > 0.05); *, P < 0.05; **, P < 0.01; ****, P < 0.0001. One-way ANOVA with Dunnett's multiple comparison correction. Bars and error indicate mean ± SEM. Figure 9. BACH2 dosing enhances anti-tumor T cell therapy responses in MC38-OVA tumor-bearing mice. a, Tumor volume of MC38-OVA-bearing mice following sublethal irradiation with 2.5 Gy and adoptive transfer of 0.5x10s OT-I T cells transduced with indicated vectors, b, Tumor volumes at day 21 after T cell transfer, ns, non-significant (P > 0.05); *, P < 0.05; **, P < 0.01; ****, P < 0.0001. One-way ANOVA with Dunnett's multiple comparison correction. Horizontal lines and error indicate mean ± SEM. Figure 10. Low-dose of F0X01AAA preserves a stem-like phenotype without compromising effector functions in vitro. a-b, Percentage of TCF1+TIM-3- chronically stimulated (a) or IFN-y+TNF+ acutely stimulated following 4-hour of PMA and ionomycin restimulation in the presence of brefeldin-A and monensin (b) from OT-I T cells transduced with the indicated vectors at day 4 and representative flow cytometry plots, ns, non-significant (P > 0.05); *, P < 0.05; **, P < 0.01; ****, P < 0.0001. One-way ANOVA with Dunnett's multiple comparison correction. Horizontal lines and error indicate mean ± SEM. DETAILED DESCRIPTION OF THE INVENTION The efficacy of cell therapy relies upon the maintenance and long-term survival of lymphocytes. Differentiation of stem-like or memory cells is regulated by the activity of transcription factors (TFs). KeyTFs regulate the transition between lymphocyte cell states by binding to DNAand controlling gene expression programmes. Factors which promote functional maintenance of lymphocytes in physiological and therapeutic responses (e.g. functional quiescence), referred to herein as maintenance factors, have previously been shown to be important in the induction of a stem-like or memory phenotype in lymphocytes. The inventors sought to determine whether overexpression of maintenance factors could promote maintenance and long-term survival of lymphocytes. Surprisingly, although conventional high-level overexpression of maintenance factors was found to promote the induction of a stem-like or memory phenotype in transduced cells, those cells exhibited significantly reduced therapeutic efficacy as compared to lymphocytes which were not engineered to overexpress maintenance factor. Prior to the present invention, the exploitation of maintenance factors in the context of cell therapy was severely limited and presented a considerable therapeutic challenge. As demonstrated herein, the inventors have discovered that conventional high-level overexpression of maintenance factors locks lymphocytes in a functionally quiescent state in which they display greatly reduced effector functions in response to immune stimulation and reduced proliferation as compared to lymphocytes which are not engineered to overexpress maintenance factor. The inventors have unexpectedly discovered that lymphocytes which are engineered to overexpress maintenance factor to a lower expression level than conventional high-level overexpression exhibit enhanced stem-like or memory phenotypes and comparative or higher levels of effector function and proliferation as compared to lymphocytes which do not overexpress maintenance factors. Herein, such lymphocytes are said to express a therapeutically effective amount of maintenance factor. Prior to the present invention, to the best of the inventors' knowledge, it was not known in the technical field that lymphocytes can be engineered to overexpress maintenance factors to enhance stem-like or memory phenotype without compromising their ability to engage in effector functions in response to immune stimulation or to proliferate. The present invention provides a remarkable contribution to the technical field which significantly increases the clinical utility of lymphocytes in cell therapies. Advantageously, lymphocytes which are engineered to express a therapeutically effective amount of maintenance factor exhibit enhanced therapeutic efficacy as compared to lymphocytes which do not overexpress maintenance factor or lymphocytes engineered for conventional high-level overexpression of maintenance factor. Importantly, the inventors demonstrate herein that expression of a therapeutically effective amount of maintenance factor markedly enhances the anti-tumour activity of lymphocytes and leads to greater survival and expansion in vivo as compared to lymphocytes which do not overexpress maintenance factor and lymphocytes engineered for conventional high-level overexpression of maintenance factors. Enhanced survival and expansion provide improved maintenance and long-term survival of lymphocytes in vivo which drastically improves the efficacy of lymphocyte-based therapies in a range of conditions, including both haematological and solid cancers. The invention provides a lymphocyte engineered to overexpress a maintenance factor, wherein the lymphocyte exhibits one or more effector functions in response to immune stimulation and is capable of proliferation. A lymphocyte of the invention expresses a therapeutically effective amount of maintenance factor. As used herein, a therapeutically effective amount of maintenance factor is an amount of maintenance factor that, when expressed in a lymphocyte, promotes a stem-like or memory phenotype without significantly reducing the ability of the lymphocyte to engage in effector functions in response to immune stimulation or to proliferate. In some embodiments, the invention provides a population of lymphocytes wherein the population of lymphocytes expresses a therapeutically effective amount of maintenance factor. As used herein, a population of lymphocytes which express a therapeutically effective amount of maintenance factor exhibits increased stem-like or memory phenotype as compared to a corresponding population of lymphocytes which do not overexpress maintenance factor. In some embodiments, increased stemlike or memory phenotype corresponds to increased survival of lymphocytes exhibiting a stem-like or memory phenotype. In addition, a population of lymphocytes which express a therapeutically effective amount of maintenance factor exhibit a comparable or greater level of effector function in response to immune stimulation and a comparable or greater level of proliferation as compared to a corresponding population of lymphocytes which do not overexpress maintenance factor. In some embodiments, a population of lymphocytes which exhibit a comparable or greater level of effector function exhibits at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 100%, at least 105%, at least 110%, at least 115%, at least 120%, at least 130%, at least 140%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250%, at least 275%, at least 300%, at least 350%, at least 400%, at least 450%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% of the level of effector function exhibited by a corresponding population of lymphocytes which do not overexpress maintenance factor. In some embodiments, a population of lymphocytes which exhibit a comparable or greater level of proliferation exhibits at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 100%, at least 105%, at least 110%, at least 115%, or at least 120%, at least 130%, at least 140%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250%, at least 275%, at least 300%, at least 350%, at least 400%, at least 450%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% of the level of proliferation exhibited by a corresponding population of lymphocytes which do not overexpress maintenance factor. It will be readily understood that reference herein to "the lymphocyte" embraces a population of lymphocytes of the invention unless expressly defined otherwise. In some embodiments, stem-like or memory phenotype, effector function in response to immune stimulation, and / or proliferation are measured in vitro as described herein. In some embodiments, a population of lymphocytes which express a therapeutically effective amount of maintenance factor exhibit enhanced survival in vivo as compared to a corresponding population of lymphocytes which do not overexpress maintenance factor. As used herein, a "corresponding lymphocyte" is typically a lymphocyte which differs from a lymphocyte of the invention only in that it is not engineered to overexpress maintenance factor. As used herein, a "corresponding population of lymphocytes" is typically a population of lymphocytes which differs from the population of lymphocytes of the invention only in that the lymphocytes in the population are not engineered to overexpress maintenance factor. For the comparisons referred to herein, a corresponding population of lymphocytes will typically have the same starting cell density as a population of lymphocytes of the invention. It will be readily understood that the therapeutically effective amount of maintenance factor may vary between different maintenance factors and between different types and subsets of lymphocytes, e.g. between lymphocytes having varying levels of maturity. A therapeutically effective amount of maintenance factor may also be referred to herein as a therapeutically effective level or a therapeutically effective dose of maintenance factor. A lymphocyte expressing a therapeutically effective amount of maintenance factor may also be said to express a dose-optimised level of maintenance factor. As used herein, lymphocytes which overexpress maintenance factor express a sufficient level of maintenance factor to promote a stem-like or memory phenotype. As used herein, a lymphocyte which overexpresses maintenance factor expresses a greater level of maintenance factor than the level of maintenance factor expressed in a corresponding lymphocyte which is not engineered to overexpress maintenance factor when assayed under the same culture conditions. As used herein, maintenance factors are proteins which promote a stem-like or memory phenotype in the cells in which they are expressed. Advantageously, maintenance factors promote long-term maintenance of the population size and / or function of lymphocytes in physiological and therapeutic responses. In some embodiments, maintenance factors induce a functionally quiescent state on the cells in which they are expressed. Maintenance factors have previously been shown to play a crucial role in the differentiation of stem-like populations of T cells. Importantly, the biology of maintenance factors is conserved among lymphocytes and so it will be understood that, unless expressly defined otherwise, discussion herein in respect of one type of lymphocyte is equally applicable to other types of lymphocyte which are known to express the same maintenance factor(s). In some embodiments, the invention employs one or more maintenance factor(s). In some embodiments, reference to "a maintenance factor" or "the maintenance factor" embraces one type of maintenance factor. In some embodiments, reference to "a maintenance factor" or "the maintenance factor" embraces two or more types of maintenance factors (e.g. 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more etc.). In some embodiments, a lymphocyte of the invention is engineered to overexpress one type of maintenance factor. In some embodiments, the maintenance factor is selected from BACH2 (Uniprot: Q9BYV9, NCBI Gene ID: 60468), ID3 (Uniprot: Q02535, NCBI Gene ID: 3399), F0X01 (Uniprot: Q12778, NCBI Gene ID: 2308), TCF1 (Uniprot: P36402, NCBI Gene ID: 6932), EGR2 (Uniprot: P11161, NCBI Gene ID: 1959), MYB (Uniprot: P10242, NCBI Gene ID: 4602), EOMES (Uniprot: 095936, NCBI Gene ID: 8320), BCL6 (Uniprot: P41182, NCBI Gene ID: 604), STAT3 (Uniprot: P40763, NCBI Gene ID: 6774), ZEB1 (Uniprot: P37275, NCBI Gene ID: 6935), LEF1 (Uniprot: Q9UJU2, NCBI Gene ID: 51176), FOXPl(Uniprot: Q9H334, NCBI Gene ID: 27086), KLF2 (Uniprot: Q9Y5W3, NCBI Gene ID: 10365), SATB1 (Uniprot: 0.01826, NCBI Gene ID: 6304), FLU (Uniprot: Q01543, NCBI Gene ID: 2313), RUNX2 (Uniprot: Q13950, NCBI Gene ID: 860), RUNX3 (Uniprot: Q13761, NCBI Gene ID: 864), S0X4 (Uniprot: Q06945, NCBI Gene ID: 6659), BHLHE40 (Uniprot: 014503, NCBI Gene ID: 8553), KMT2A (Uniprot: Q03164, NCBI Gene ID: 4297), SMARCA4 (Uniprot: P51532, NCBI Gene ID: 6597), JUN (Uniprot: P05412, NCBI Gene ID: 3725), STAT5A (Uniprot: P42229, NCBI Gene ID: 6776), STAT5B (Uniprot: P51692, NCBI Gene ID: 6777), and S0CS1 (Uniprot: 015524, NCBI Gene ID: 8651). In some embodiments, a lymphocyte of the invention is engineered to overexpress two or more types of maintenance factors. In some embodiments, a lymphocyte of the invention is engineered to overexpress two or more (e.g. 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, or 25) of BACH2, ID3, F0X01, TCF1, EGR2, MYB, EOMES, BCL6, STAT3, ZEB1, LEF1, F0XP1, KLF2, SATB1, FLU, RUNX2, RUNX3, S0X4, BHLHE40, KMT2A, SMARCA4, JUN, STAT5A, STAT5B, and S0CS1. In some embodiments, the maintenance factor is a wild-type maintenance factor. In some embodiments, the maintenance factor is a modified maintenance factor. It will be understood that a modified maintenance factor is typically modified as compared to the endogenous or wild-type maintenance factor expressed by the lymphocyte. In some embodiments, the maintenance factor is modified to alter stability and / or activity. In some embodiments, the maintenance factor is modified to be constitutively active. In some embodiments, the maintenance factor is a modified maintenance factor having at least 70% sequence identity to the amino acid sequence of a wild-type maintenance factor. In some embodiments, the modified maintenance factor has at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of a wild-type maintenance factor. In some embodiments, the wild-type maintenance factor is selected from BACH2 (Uniprot: Q9BYV9), ID3 (Uniprot: Q02535), F0X01 (Uniprot: Q12778), TCF1 (Uniprot: P36402), EGR2 (Uniprot: P11161), MYB (Uniprot: P10242), EOMES (Uniprot: 095936), BCL6 (Uniprot: P41182), STAT3 (Uniprot: P40763), ZEB1 (Uniprot: P37275), LEF1 (Uniprot: Q9UJU2), FOXPl(Uniprot: Q9H334), KLF2 (Uniprot: Q9Y5W3), SATB1 (Uniprot: Q01826), FLU (Uniprot: Q01543), RUNX2 (Uniprot: Q13950, NCBI Gene ID: 860), RUNX3 (Uniprot: Q13761), S0X4 (Uniprot: Q06945, NCBI Gene ID: 6659), and BHLHE40 (Uniprot: 014503, NCBI Gene ID: 8553), KMT2A (Uniprot: Q03164), SMARCA4 (Uniprot: P51532), JUN (Uniprot: P05412, NCBI Gene ID: 3725), STAT5A (Uniprot: P42229, NCBI Gene ID: 6776), STAT5B (Uniprot: P51692, NCBI Gene ID: 6777), or S0CS1 (Uniprot: 015524, NCBI Gene ID: 8651). In some embodiments, the maintenance factor is BACH2. Through the common bZip domain, BACH2 competes downstream of TCR signalling with AP-1 factors for binding TPA-response elements (TRE) thereby antagonising TCR-mediated activation and terminal differentiation. BACH2 expression is typically downregulated in cells receiving high levels of stimulation, including within tumours. BACH2 plays a critical role in the induction of stem / memory phenotypes and durable T cell responses. In some embodiments, the maintenance factor is ID3. Inhibitor of DNA-binding protein 3 (ID3) is a transcriptional regulator which lacks DNA-binding capacity. Rather, ID3 forms heterodimers with basic helix-loop-helix (bHLH) transcription factors to prevent DNA binding and negatively regulate the activity of bHLH E Protein TFs. Expression of ID3 has been shown to correlate positively with T cell maintenance and formation of memory. In some embodiments, the maintenance factor is F0X01. Via positive transcriptional regulation of numerous memory-associated genes, including BACH2, CCR7 and TCF7, F0X01 is a critical regulatory of memory differentiation and long-term T cell maintenance. Similarly, F0X01 has demonstrated ability to repress AP-1 signalling cascades, thereby antagonising terminal differentiation and senescence. In some embodiments, the maintenance factor is TCF1. T cell factor 1 (TCF1; encoded by TCF7) doubles as a prominent marker and key regulator of T cell sternness and long-term potential, used to identify the precursor-exhausted T cell subset which respond to checkpoint blockade. TCF1 belongs to the TCF / LEF family of transcription factors, which bind DNA through the shared HMG-box domain to regulate their target genes. In some embodiments, the maintenance factor is EGR2. Belonging to the EGR zinc finger transcription factor family, EGR2 directly promotes the expression of the memory-associated genes MYB, BCL6 and IDS whilst repressing genes associated with effector differentiation, including ZEB2. EGR2 has an further established role in regulating T cell anergy. In some embodiments, the maintenance factor is MYB. Also known as c-MYB, MYB is a transcriptional activator which promotes the expression of genes associated with long-term survival and memory T cell responses, including TCF7, SLAMF6, and KLF2. Studies involving knockout of c-Myb in murine T cells have demonstrated heightened terminal effector differentiation and loss of memory recall response capacity upon repeat immune challenge, highlighting the critical role of Myb in promoting T cell memory phenotypes. In some embodiments, the maintenance factor is EOMES. Eomesodermin (EOMES; encoded by EOMES) is a member of the T-Box transcription factor family with well-established roles in regulating T cell differentiation towards memory fates, demonstrated through the ablated memory T cell pool in T cells lacking EOMES. In some embodiments, the maintenance factor is BCL6. A transcriptional repressor, BCL6 antagonises the expression of terminal differentiation-promoting transcriptional regulatory, Blimp-1. Previous studies have revealed that BCL6 represses expression of target genes involved in glycolysis, including SLC2A1 and HK2. In some embodiments, the maintenance factor is STAT3. The IL-10-STAT3 signalling axis antagonises T cell exhaustion to support maintenance of T cell populations having a stem-like / memory phenotype (said T cell populations may be referred to as progenitor exhausted T (TPEx) populations), reducing expression of exhaustion-associated transcripts. Memory-associated genes regulated by STAT3 homodimers include BCL2 and FOXO1. In some embodiments, the memory factor is ZEB1. Zinc-finger E-box-binding homeobox 1 (ZEB1) supports maintenance and generation of memory T cells. T cells lacking ZEB1 display reduced expression of memory-associated markers CD62Land EOMES. In some embodiments, the memory factor is LEF1. Belonging to the same family as TCF1, LEF1 has an established role in promoting memory differentiation through modulating global chromatin architecture in T cells. Loss of LEF1 restricts memory T cell responses, favouring effector differentiation. In some embodiments, the memory factor is F0XP1. Forkhead box protein 1 (F0XP1) promotes quiescence and restricts terminal differentiation through directly repressing expression of ID2 and STAT6. In some embodiments, the memory factor is KLF2. Knockout of T cell KLF2 promotes the expression of terminal and exhaustion-related proteins, TOX and PD-1, and reduces expression of the memory marker CD62L. In some embodiments, the memory factor is SATB1. Special AT-rich sequence-binding protein 1 (SATB1) is responsible for directly repressing PD1 expression in antigen-experienced T cells. In some embodiments, the maintenance factor is FLU. Genetic deletion of FLU has been shown to increase effector differentiation over memory T cell fates. Similarly, overexpression of FLU induces Lyl08 and TCF-l-expressing T cell populations. In some embodiments, the maintenance factor is RUNX2. RUNX2 has been shown to be required for the generation and long-term maintenance of memory CD8 populations following acute viral infection. In some embodiments, the maintenance factor is RUNX3. The transcription factor RUNX3 restricts expression of T-bet to limit terminal effector differentiation in T cells and promote the formation of long-lived memory populations. In some embodiments, the maintenance factor is SOX4. SRY-Box Transcription Factor 4 (SOX4) promotes memory recall responses in T cells. In some embodiments, the maintenance factor is BHLHE40. Critical for maintaining tumour-infiltrating lymphocyte fitness, BHLHE40 maintains mitochondrial function and OXPHOS under conditions of stress. In some embodiments, the maintenance factor is KMT2A. MML1, which encodes KMT2A, has been shown to play a critical role in the establishment of a long-lived population of memory and stem-like CD8 T cells following TCR stimulation. In some embodiments, the maintenance factor is SMARCA4. A subunit of SWI / SNF chromatin remodelling complex with ATPase activity, SMARCA4 has previously been shown to restrict T cell exhaustion in CRISPR screens. In some embodiments, the maintenance factor is JUN. Overexpression of c-Jun has demonstrated capability to prevent exhaustion in CAR-T cells. In some embodiments, the maintenance factor is STAT5A. One component of functional STAT5, STAT5A potentiates IL-2 signalling cascades in T cells to promote durable function and memory formation in vivo. In some embodiments, the maintenance factor is STAT5B. Along with STAT5A, STAT5B potentiates IL-2 signalling cascades in T cells to promote durable function and memory formation in vivo. In some embodiments, the maintenance factor is S0CS1. Deficiency of S0CS1 results in unrestrained effector differentiation of T cells through inability to control cytokine signalling responses. As noted, the biology of maintenance factors is conserved among lymphocytes and so it will be understood that the present invention is not limited to a particular type of lymphocyte. Advantageously, the present invention is compatible with existing lymphocyte-based cell therapies and can be used to improve the therapeutic efficacy of said existing cell therapies. In some embodiments, the lymphocyte is selected from a T cell, a natural killer (NK) cell, an innate lymphoid cell (ILC), and a B cell. In some embodiments, the lymphocyte is a tumour-infiltrating lymphocyte (TIL). In some embodiments, the lymphocyte is engineered to express a receptor capable of inducing lymphocyte stimulation in response to a particular antigen. The receptor may be a natural or a synthetic receptor. In some embodiments, the lymphocyte is engineered to express a chimeric antigen receptor (CAR). CARs combine antigen-binding and lymphocyte activating functions into a single or dual receptor and provide lymphocytes with the ability to target a specific antigen. CARs typically recognise and bind to specific antigens on the surface of cells, e.g. the surface of cancer cells. In some embodiments, the lymphocyte is engineered to express a T-cell receptor (TCR). TCRs are typically naturally occurring receptors found on the surface of T cells which recognise antigens (e.g. antigenic fragments) presented by major histocompatibility complex (MHC) molecules. In some embodiments, the lymphocyte is engineered to express an antibody-TCR. An antibody-TCR receptor is a synthetic immunoreceptor that combines elements of both antibody-based recognition and TCR signalling mechanisms. This type of receptor is designed to harness the specificity of antibodies for antigen recognition, alongside the natural T cell signalling and activation provided by TCR components. The extracellular part of the receptor uses the variable regions of an antibody (typically a single-chain variable fragment or scFv) to recognize specific antigens. The intracellular part of the receptor includes components of the TCR signalling complex, such as the CD3^. Antibody-TCRs allow T cells to bind to antigens with the high specificity and affinity characteristics of antibodies, including those not presented by MHC molecules, while ensuring a robust T cell activation, proliferation, and effector function response, similar to natural TCR engagement. In some embodiments, the lymphocyte is engineered to express a TCR-based CAR. TCR-based CARs allow lymphocytes to recognise antigens in a similar way as TCRs and subsequently activate the lymphocytes via the stimulatory domains typically associated with CARs. The TCR-CAR approach aims to leverage the advantages of both TCR and CAR systems. It involves the use of a TCR-like recognition domain to target peptides presented by MHC molecules, combined with the signalling domains typical of CAR constructs. This allows TCR-CAR engineered T cells to recognize a wider range of antigens, including those derived from intracellular proteins, with the potent activation and effector functions provided by CAR signalling domains. In some embodiments, the lymphocyte is engineered to express a T cell antigen coupler (TAC). ATAC receptor comprises three different domains: an antigen-binding domain, a CD3-binding domain, and a CD4- or CD8-based co-receptor (hinge, transmembrane and intracellular regions). When a TAC-engineered T cell binds to a tumour-associated antigen through its antigen-binding domain, the coupling between the antigen-binding fragment and the T cell's signalling components - particularly the CD3^ chain integral to the TCR complex - triggers a cascade of intracellular signals similar to that occurring during TCR stimulation. In some embodiments, the lymphocyte is engineered to express a synthetic? cell receptor and antigen receptor (STAR). In a STAR receptor, antibody-based single-chain variable fragment replace the TCR native variable regions. This allows the receptor to recognise antigens not presented by MHC molecules with high specificity and affinity, while retaining the native mechanisms of TCR-induced stimulation. In some embodiments, the lymphocyte is engineered to express a TCR fusion construct (TRuC). In a TRuC receptor, an antigen-binding domain is fused directly to a TCR. This allows the receptor to recognise antigens not presented by MHC molecules with high specificity and affinity, while retaining the native mechanisms of TCR-induced stimulation. In some embodiments, the lymphocyte is a T cell. In some embodiments, the lymphocyte is selected from a CD8+ T cell, a CD4+ T cell and a gamma-delta T cell. In some embodiments, the CD4+ T cell is selected from a regulatory T (Treg) cell, a T helper (Th) 1 cell, a Th2 cell, a Thl7 cell, a Follicular Helper T (Tfh) cell, and a Th9 cell. In some embodiments, the lymphocyte is a CAR-T cell or a TCR-T cell, optionally a CAR-Treg cell or a TCR-Treg cell. In some embodiments, the lymphocyte is a NK cell. In some embodiments, the lymphocyte is a CAR-NKcell or a TCR-NK cell. In some embodiments, the lymphocyte is a therapeutic lymphocyte. As used herein, a therapeutic lymphocyte is a lymphocyte which is known or expected to have efficacy in treating or preventing a disease or condition. In some embodiments, the therapeutic lymphocyte is known or expected to exhibit anti-cancer properties. In some embodiments, the therapeutic lymphocyte is known or expected to exhibit anti-inflammatory properties. In some embodiments, the therapeutic lymphocyte is for use in cell therapy, e.g. adoptive cell therapy. In some embodiments, the lymphocyte is engineered to introduce and / or to enhance therapeutic properties. In some embodiments, the lymphocyte is engineered to introduce and / or to enhance anti-cancer properties. In some embodiments, the lymphocyte is engineered to introduce and / or to enhance anti-inflammatory properties. Importantly, lymphocytes which express a therapeutically effective amount of maintenance factor exhibit comparable or greater levels of effector function in response to immune stimulation as compared to lymphocytes which are not engineered to overexpress maintenance factor. It will be readily understood that the one or more effector functions will vary depending on the type of lymphocyte and the immune stimulation applied. Lymphocytes of the invention typically exhibit comparable or greater levels of effector function(s) in response to immune stimulation as compared to corresponding lymphocytes which have not been engineered to overexpress maintenance factor. In some embodiments, lymphocytes which exhibit comparable or greater levels of effector function exhibit at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 100%, at least 105%, at least 110%, at least 115%, at least 120%, at least 130%, at least 140%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250%, at least 275%, at least 300%, at least 350%, at least 400%, at least 450%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% of the level of effector function in response to immune stimulation exhibited by corresponding lymphocytes which are not engineered to overexpress maintenance factor. In some embodiments, immune stimulation comprises exposing the lymphocyte to one or more cytokines and / or chemokines. In some embodiments, immune stimulation comprises exposing the lymphocyte to a cytokine and / or chemokine selected from CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CX3CL1, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, IL-la, IL-1P, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, interferon-alpha (IFNa), interferon-beta (IFNP), interferongamma (IFNy), transforming growth factor beta (TGFP), tumour necrosis factor alpha (TNF), tumour necrosis factor beta (TNFP), XCL1, and XCL2. In some embodiments, immune stimulation comprises exposing the lymphocyte to one or more antigens. In some embodiments, the lymphocyte comprises an antigen receptor, and immune stimulation comprises exposing the lymphocyte to one or more antigens capable of interacting with and activating said antigen receptor. In some embodiments, wherein the lymphocyte comprises a receptor (e.g. CAR or TCR), immune stimulation comprises exposing the lymphocyte to one or more antigens capable of interacting with and activating said receptor. In some embodiments, wherein the lymphocyte is a T cell, immune stimulation comprises exposing the T cell to a cytokine and / or chemokine selected from CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CX3CL1, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, IL-la, IL-1P, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, interferon-alpha (IFNa), interferon-beta (IFNP), interferongamma (IFNy), transforming growth factor beta (TGFP), tumour necrosis factor alpha (TNF), tumour necrosis factor beta (TNFP), XCL1, and XCL2. In some embodiments, wherein the lymphocyte is a B cell, immune stimulation comprises exposing the B cell to a cytokine and / or chemokine selected from CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CX3CL1, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, IL-la, IL-1P, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, interferon-alpha (IFNa), interferon-beta (IFNP), interferongamma (IFNy), transforming growth factor beta (TGFP), tumour necrosis factor alpha (TNF), tumour necrosis factor beta (TNFP), XCL1, and XCL2. In some embodiments, wherein the lymphocyte is a natural killer (NK) cell, immune stimulation comprises exposing the NK cell to a cytokine and / or chemokine selected from CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CX3CL1, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, IL-la, IL-ip, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, interferon-alpha (IFNa), interferon-beta (IFNP), interferon-gamma (IFNy), transforming growth factor beta (TGFP), tumour necrosis factor alpha (TNF), tumour necrosis factor beta (TNFP), XCL1, and XCL2. In some embodiments, the one or more effector functions comprise production of one or more effector molecules. In some embodiments, the one or more effector molecules are selected from Tumour Necrosis Factor (TNF), Interferon gamma (IFNy), IL-2, Granzyme-B, Perforin, and CD103. Production of effector molecules (e.g. effector cytokines and / or chemokines) may be measured using any suitable method known in the art. For example, production of effector molecules may be determined by immunoassay, e.g. flow cytometry, mass cytometry, semi-quantitative or quantitative Western blot or ELISA. Production of effector molecules may be measured using surface marker staining and / or intracellular staining, e.g. intracellular cytokine staining. Production of effector molecules, e.g. effector cytokines and / or chemokines, may be measured by transcriptional profiling. In some embodiments, the one or more effector functions comprise cytotoxic function. Cytotoxic function may be measured using any suitable method known in the art, e.g. by assaying the ability of lymphocytes to target and kill target cells (e.g. tumour cells) in vitro. Cytotoxicity may be measured by determining the number of target cells killed or remaining in culture, e.g. by flow cytometry or microscopy. The ability of lymphocytes to proliferate may be measured using any suitable method known in the art. Suitable methods may be based on detecting DNA synthesis, cellular metabolism, proliferation-related proteins, proliferative dye dilution and / or transcriptional profiling. For example, lymphocyte proliferation may be measured by measuring expression of proteins indicating proliferative capacity (e.g. Ki-67); by measuring BrdU incorporation (e.g. measured by ELISA, flow cytometry or Western blot); and / or by measuring dilution of a cell permeable dye by flow cytometry wherein the quantity of dye is halved with each cell division (suitable dyes include Cell Trace dyes and carboxyfluorescein succinimidyl ester (CFSE)). Advantageously, a population of lymphocytes of the invention exhibit reduced cell exhaustion and enhanced sternness as compared to a population of lymphocytes which are not engineered to overexpress maintenance factor. As used herein, enhanced sternness means a population of lymphocytes of the invention exhibit a greater level of stem cell-like / memory phenotype than a corresponding population of lymphocytes which are not engineered to overexpress maintenance factor. As used herein, reduced cell exhaustion means a population of lymphocytes of the invention exhibits a reduced level of cell exhaustion phenotype as compared to a population of lymphocytes which do not overexpress maintenance factor. Cellular phenotype, e.g. whether the cells exhibits a stem-like or memory, or exhaustion phenotype, may be determined by surface marker staining and / or effector molecule assays (e.g. intracellular cytokine staining). Cell markers associated with a stem-like or memory phenotype include T cell factor 1 (TCF1), CD62L, SLAMF6, BACH2, ID3, F0X01, EGR2, MYB, EOMES, BCL6, STAT3, ZEB1, LEF1, F0XP1, KLF2, SATB1, FLU, RUNX2, RUNX3, SOX4, BHLHE40, KMT2A, or SMARCA4. Cell markers associated with cell exhaustion include T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), killer cell lectin-like receptor G1 (KLRG1), CD39, PD-1, TIGIT, TOX, and CXCR5. As noted, a lymphocyte of the invention overexpresses maintenance factor as compared to a corresponding lymphocyte which is not engineered to overexpress maintenance factor when assayed under the same culture conditions. The corresponding lymphocyte is typically a lymphocyte which differs from a lymphocyte of the invention only in that it is not engineered to overexpress maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses a level of maintenance factor that is at least 2-fold higher than the level of maintenance factor expressed by a corresponding lymphocyte which is not engineered to overexpress maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses a level of maintenance factor that is at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100fold, at least 150-fold, at least 200-fold, at least 250-fold, at least 300-fold, at least 350-fold, at least 400-fold, at least 450-fold, at least 500-fold, at least 1000-fold, at least 1500-fold, at least 2000-fold, at least 2500-fold, at least 3000-fold, at least 3500-fold, at least 4000-fold, at least 4500-fold, or at least 5000-fold higher than the level of maintenance factor expressed by a corresponding lymphocyte which is not engineered to overexpress maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses a level of maintenance factor that is between 2-fold and 5000-fold higher than the level of maintenance factor expressed by a corresponding lymphocyte which is not engineered to overexpress maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is between 2-fold and 4500-fold, 2-fold and 4000-fold, 2-fold and 3500-fold, 2-fold and 3000-fold, 2-fold and 2500-fold, 2-fold and 2000-fold, 2-fold and 1750-fold, 2-fold and 1500-fold, 2-fold and 1250-fold, 2-fold and 1000-fold, 2-fold and 900-fold, 2-fold and 800-fold, 2-fold and 700-fold, 2-fold and 600fold, 2-fold and 500-fold, 2-fold and 400-fold, 2-fold and 300-fold, 2-fold and 200-fold, 2-fold and 100fold, 2-fold and 50-fold, 50-fold and 5000-fold, 100-fold and 5000-fold, 200-fold and 5000-fold, 300fold and 5000-fold, 400-fold and 5000-fold, 500-fold and 5000-fold, 600-fold and 5000-fold, 700-fold and 5000-fold, 800-fold and 5000-fold, 900-fold and 5000-fold, 1000-fold and 5000-fold, 1250-fold and 5000-fold, 1500-fold and 5000-fold, 1750-fold and 5000-fold, 2000-fold and 5000-fold, 2500-fold and 5000-fold, 3000-fold and 5000-fold, 3500-fold and 5000-fold, 4000-fold and 5000-fold, and 4500- fold and 5000-fold higher than the level of maintenance factor expressed by a corresponding lymphocyte which is not engineered to overexpress maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses a level of maintenance factor that is at least 5% higher than the level of maintenance factor expressed by a corresponding lymphocyte which is not engineered to overexpress maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses a level of maintenance factor that is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, at least 200%, at least 225%, at least 250%, at least 275%, at least 300%, at least 325%, at least 350%, at least 375%, at least 400%, at least 425%, at least 450%, at least 475%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% higher than the level of maintenance factor expressed by a corresponding lymphocyte which is not engineered to overexpress maintenance factor. As noted, lymphocytes which are engineered to exhibit conventional high-level overexpression of maintenance factor do not achieve the advantageous properties demonstrated by the lymphocytes of the present invention. As used herein, a lymphocyte which is engineered for conventional high-level overexpression of maintenance factor is a lymphocyte which (i) expresses a greater level of maintenance factor than a corresponding lymphocyte which is not engineered to overexpress maintenance (e.g. quiescence) factor and (ii) exhibits reduced levels of effector function in response to immune stimulation and / or reduced levels of proliferation as compared to a corresponding lymphocyte which is not engineered to overexpress maintenance factor. In some embodiments, a population of lymphocytes which are engineered for conventional high-level overexpression of maintenance factor exhibits less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% the level of proliferation and / or effector function of a corresponding population of lymphocytes which are not engineered to overexpress maintenance factor. Thus, a lymphocyte which is engineered for conventional high-level overexpression of maintenance factor does not express a therapeutically effective amount of maintenance factor as described herein. A lymphocyte which is engineered for conventional high-level overexpression of maintenance factor may comprise a vector known in the art to provide conventional high-level overexpression of a protein of interest. For example, a lymphocyte which is engineered for conventional high-level overexpression of maintenance factor may comprise a retroviral vector configured for LTR-driven expression of maintenance factor. In another example, a lymphocyte which is engineered for conventional high-level overexpression of maintenance factor may comprise a murine stem cell virus (MSCV) retrovirus expression system vector encoding a maintenance factor, such as the MSCV retrovirus expression system described in Roychoudhuri etal., Nature Immunology, 2016. It will be readily understood that overexpression of a gene of interest may be achieved by integrating a DNA sequence containing said gene (which may also be preceded or followed by other sequences including promoters or enhancers) into the genome of a cell of interest, e.g. using viral vectors, such as MSCV retroviruses; transposable elements, such as the Sleeping Beauty transposon system; or CRISPR-based homology-directed recombination (HDR). Viral vectors are engineered viruses used to deliver genetic material into cells. These methods typically use the virus's natural ability to infect and insert its DNA into a host cell. For gene overexpression purposes, the viral genome is modified to carry the gene of interest instead of its viral genes, ensuring it does not replicate or cause disease. Transposon systems utilise DNA sequences which can change their position within the genome. This method involves a cut-and-paste mechanism, where a transposase enzyme recognizes specific sequences in the transposon DNA, excises it, and integrates it into a new genomic location. The gene of interest is inserted into a transposon vector, and the transposase is supplied, either in plasmid form or as mRNA, to catalyse the integration of the transposon into the host genome resulting in stable gene overexpression. CRISPR-Cas9 technology can be used for homology-directed repair (HDR), a process that introduces specific changes to the genome by exploiting the cell's natural DNA repair mechanisms. To achieve gene overexpression, a DNA repair template containing the gene of interest flanked by sequences homologous to the target site is introduced into cells along with the CRISPR-Cas9 components. The Cas9 protein creates a double-strand break at a specific genomic location guided by a designed RNA molecule. The cell repairs this break using the supplied DNA template through HDR, integrating the gene of interest at a precise location. Overexpression of a gene of interest can also be achieved via delivery of mRNA encoding said gene. The mRNA may also be modified to include specific untranslated regions (UTRs) for regulating elements such as the stability, efficiency of translation or location of the mRNA. A gene of interest can also be overexpressed by utilising nuclease-dead Cas9 (dCas9) fused with a transcriptional activation domain and targeted by specific single guide (sg)RNAs specific towards said gene. A lymphocyte of the invention exhibits a lower level of maintenance factor activity than a corresponding lymphocyte which is engineered for conventional high-level overexpression of maintenance factor. It will be readily understood that a lower level of maintenance factor activity may be achieved by reducing the level of overexpression of maintenance factor and / or by modulating the activity of overexpressed maintenance factor. The level of maintenance factor activity may be determined by any suitable method known in the art. As described herein, maintenance factor activity may be determined by comparing the phenotype of a population of lymphocytes expressing the maintenance factor to a population of lymphocytes expressing a known level of maintenance factor, e.g. by comparing the level of sternness or exhaustion exhibited by a population of lymphocytes. Maintenance factor activity may also be determined by comparing the level of effector function and / or proliferation of a population of lymphocytes expressing the maintenance factor to a population of lymphocytes expressing a known level of maintenance factor as described herein. The level of maintenance factor activity may also be determined by measuring the expression of one or more target genes which are known to be associated with maintenance factor activity. The target gene may be an endogenous gene known to be regulated by the maintenance factor. The target gene may alternatively be a recombinant gene which is engineered to be regulated by the maintenance factor, for example, the recombinant gene may be a gene encoding a reporter protein (e.g. a fluorescent protein). In some embodiments, a lymphocyte of the invention overexpresses a lower level of maintenance factor than a lymphocyte which is engineered for conventional high-level overexpression of maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is at least two-fold lower than the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 13fold, at least 14-fold, at least 15-fold, at least 16-fold, at least 17-fold, at least 18-fold, at least 19-fold, at least 20-fold, at least 21-fold, at least 22-fold, at least 23-fold, at least 24-fold, at least 25-fold, at least 26-fold, at least 27-fold, at least 28-fold, at least 29-fold, at least 30-fold, at least 35-fold, at least 40-fold, at least 45-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90fold, at least 100-fold, at least 150-fold, at least 200-fold, at least 250-fold, at least 300-fold, at least 350-fold, at least 400-fold, at least 450-fold, at least 500-fold, at least 550-fold, at least 600-fold, at least 650-fold, at least 700-fold, at least 750-fold, at least 800-fold, at least 850-fold, at least 900-fold, at least 950-fold, or at least 1000-fold lower than the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is at least 5-fold lower than the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is at least 15-fold lower than the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is between 2-fold and 1000-fold lower than the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is between 2-fold and 1000-fold, 5-fold and 1000-fold, 10-fold and 1000-fold, 15-fold and 1000-fold, 20-fold and 1000-fold, 25-fold and 1000-fold, 30-fold and 1000-fold, 35-fold and 1000-fold, 40-fold and 1000-fold, 45-fold and 1000-fold, 50-fold and 1000-fold, 60-fold and 1000-fold, 70-fold and 1000-fold, 80-fold and 1000-fold, 90-fold and 1000-fold, 100-fold and 1000-fold, 150-fold and 1000-fold, 200-fold and 1000-fold, 250-fold and 1000-fold, 300-fold and 1000-fold, 350-fold and 1000fold, 400-fold and 1000-fold, 450-fold and 1000-fold, 500-fold and 1000-fold, 600-fold and 1000-fold, 700-fold and 1000-fold, 800-fold and 1000-fold, or 900-fold and 1000-fold lower than the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is between 2-fold and 20-fold lower than the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is between 2-fold and 20-fold, between 3-fold and 20-fold, between 4-fold and 20-fold, between 5-fold and 20-fold, between 6-fold and 20-fold, between 7-fold and 20-fold, between 8-fold and 20-fold, between 9-fold and 20-fold, between 10-fold and 20-fold, between 2-fold and 19-fold, between 2-fold and 18-fold, between 2-fold and 17-fold, between 2-fold and 16-fold, or between 2fold and 15-fold lower than the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is between 5-fold and 15-fold lower than the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is up to 50% of the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is up to 45%, up to 40%, up to 35%, up to 30%, up to 25%, up to 20%, up to 15%, up to 10%, up to 9%, up to 8%, up to 7%, up to 6%, up to 5%, up to 4%, up to 3%, up to 2%, up to 1%, up to 0.9%, up to 0.8%, up to 0.7%, up to 0.6%, up to 0.5%, up to 0.4%, up to 0.3%, up to 0.2%, or up to 0.1% of the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is up to 5% the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is between 0.1% and 50% of the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is between 0.1% and 45%, between 0.1% and 30%, between 0.1% and 35%, between 0.1% and 30%, between 0.1% and 25%, between 0.1% and 20%, between 0.1% and 15%, between 0.1% and 10%, between 0.1% and 5%, between 0.5% and 50%, between 1% and 50%, between 2% and 50%, between 3% and 50%, between 4% and 50%, between 5% and 50%, between 6% and 50%, between 7% and 50%, between 8% and 50%, between 9% and 50%, between 10% and 50%, and between 15% and 50% of the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is between 5% and 15% of the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. In some embodiments, a lymphocyte of the invention overexpresses maintenance factor at a level that is between 5% and 20% of the level of maintenance factor expressed by a lymphocyte which is engineered for conventional high-level overexpression of the maintenance factor. The level of maintenance factor expression may be determined by any suitable method known in the art. For example, the level of maintenance factor expression may be determined by immunoassay, e.g. semi-quantitative or quantitative Western blot or ELISA or flow cytometry. A lower level of maintenance factor overexpression as compared to the level of expression provided by conventional high-level overexpression vectors can be achieved using various methods which are known in the art to regulate gene expression. Several strategies for regulating gene expression are described below. In some embodiments, a lymphocyte of the invention comprises a nucleic acid sequence encoding a maintenance factor downstream of a STOP-translational readthrough motif (TRM) sequence. A TRM is a sequence or structure within an mRNA that signals the ribosome to continue translation beyond a termination (or STOP) codon, resulting in the synthesis of a longer protein product. This phenomenon allows for the production of extended or alternative protein isoforms by allowing ribosomes to ignore the stop codon and continue translating along the mRNA molecule, often generating proteins with additional functional domains or altered properties. By manipulating the sequence of the TRM, graded control over the level of readthrough can be achieved. Weaker or stronger TRMs can modulate the frequency of readthrough events, thereby allowing for fine-tuning of gene expression to desired levels. Lymphocytes comprising a nucleic acid sequence encoding the maintenance factor downstream of a STOP-TRM sequence exhibit reduced expression of maintenance factor as compared to a corresponding lymphocyte comprising a nucleic acid sequence encoding the maintenance factor which is not downstream of a STOP-TRM sequence. Suitable STOP-TRM sequences are known in the art, see e.g. WO 2021 / 229218. In some embodiments, the nucleic acid sequence encoding a maintenance factor is downstream of a STOP-TRM sequence selected from: TGA-CTAGCA; TGA-CTAGGC; TGA-CAATTA; TAG-CAATTA; TAG-CTAGCA; TAG-CTAGGC; TAA-CTAGGC; TAA-CAATTA; TAA-GAGAGT; TAG-GAGAGT; TAG; TAA-CTAGCA; TAG-GAGAGT; TAA; TGATGA; and TGATGA-CTAGCA. In some embodiments, the STOP-TRM sequence is upstream of a glycine-serine-glycine (GSG) linker. In some embodiments, the GSG linker comprises the nucleic acid sequence GGAAGCGGA. In some embodiments, the STOP-TRM sequence is TGACTAGCA and the lymphocyte overexpresses maintenance factor at a level that is at least 5-fold lower than the level of maintenance factor overexpressed by a corresponding lymphocyte wherein the nucleic acid encoding the maintenance factor is not downstream of a STOP-TRM sequence. In some embodiments, the STOP-TRM sequence is TGACAATTA and the lymphocyte overexpresses maintenance factor at a level that is at least 15-fold lower than the level of maintenance factor overexpressed by a corresponding lymphocyte wherein the nucleic acid encoding the maintenance factor is not downstream of a STOP-TRM sequence. In some embodiments, the STOP-TRM sequence is TAGCTAGCA and the lymphocyte overexpresses maintenance factor at a level that is at least 50-fold lower than the level of maintenance factor overexpressed by a corresponding lymphocyte wherein the nucleic acid encoding the maintenance factor is not downstream of a STOP-TRM sequence. In some embodiments, the STOP-TRM sequence isTAAGAGAGT and the lymphocyte overexpresses maintenance factor at a level that is at least 100fold lower than the level of maintenance factor overexpressed by a corresponding lymphocyte wherein the nucleic acid encoding the maintenance factor is not downstream of a STOP-TRM sequence. In some embodiments, the STOP-TRM sequence is TGACTAGCA and the lymphocyte overexpresses maintenance factor at a level that is at least 10-fold lower than the level of maintenance factor overexpressed by a corresponding lymphocyte wherein the nucleic acid encoding the maintenance factor is not downstream of a STOP-TRM sequence. In some embodiments, the STOP-TRM sequence is TGACTAGCA and is upstream of a GSG linker having the sequence GGAAGCGGA. In some embodiments, the STOP-TRM sequence is TGACAATTA and the lymphocyte overexpresses maintenance factor at a level that is at least 20-fold lower than the level of maintenance factor overexpressed by a corresponding lymphocyte wherein the nucleic acid encoding the maintenance factor is not downstream of a STOP-TRM sequence. In some embodiments, the STOP-TRM sequence is TGACAATTA and is upstream of a GSG linker having the sequence GGAAGCGGA. In some embodiments, a lymphocyte of the invention comprises a nucleic acid sequence encoding a maintenance factor downstream of a frame-slip motif (FSM). A FSM is a sequence or structure within an mRNA comprising a hepta-repeat of thymine, guanine or uracil bases. In some embodiment, the FSM sequence comprises a STOP codon. A FSM causes the ribosome to shift its reading frame during protein translation, commonly backward (-1), but potentially also forward (+1). Frameshifting of a ribosome may lead to lower levels of expression of downstream genetic elements. In some embodiments, a lymphocyte of the invention comprises a retroviral vector comprising the nucleic acid sequence encoding a maintenance factor downstream of a STOP-TRM sequence. In some embodiments, the retroviral vector is a murine stem cell virus (MSCV) vector. In some embodiments, the vector is a MMLV (Moloney Murine Leukemia Virus) retroviral vector. In some embodiments, the retroviral vector is derived from MSCV-IRES-Thyl.l DEST (Addgene, Plasmid #17442). In some embodiments, a lymphocyte of the invention comprises a nucleic acid sequence encoding a maintenance factor, wherein the nucleic acid encoding a maintenance factor is operably linked to a 2A element. 2A (or 'self-cleavage') peptide sequences are short peptides derived from viruses which induce a ribosome-skipping event during translation. 2A peptide sequences enable the production of multiple proteins from a single mRNA by causing a temporary interruption in translation, leading to the release of separate protein products from the same transcript. Protein produced from the gene downstream of the 2A sequence is generally expressed at lower levels compared to the protein produced from the gene upstream of the 2A sequence. By controlling the number and type of 2A peptides, fine-tuning of gene expression to desired levels may be achieved. In some embodiments, a lymphocyte of the invention comprises a nucleic acid sequence encoding a maintenance factor, wherein the nucleic acid encoding a maintenance factor is operably linked to an internal ribosome entry site (IRES) sequence. IRES sequences are RNA elements found in some viral and cellular messenger RNAs. IRES sequences allow for cap-independent initiation of protein synthesis, enabling the recruitment of ribosomes to start protein production internally, bypassing the typical 5' cap-dependent mechanism. IRES sequences are typically utilized in molecular biology to enable the expression of multiple proteins from a single mRNA transcript or for the design of specialized expression vectors in biotechnology and gene therapy. In some embodiments, the IRES sequence is a modified IRES sequence, wherein the modified IRES sequences comprises one or more mutations which result in reduced expression of a gene which is operably linked thereto as compared to the expression of the same gene when operably linked to the wild-type IRES sequence under the same conditions. Mutant libraries of IRES sequences can be generated using methods known in the art and screened to identify variants which lead to optimal levels of protein expression. Using this approach, an IRES mutant can be selected to provide a therapeutically effective level of maintenance factor expression. Modified IRES sequences are known in the art, see e.g. \NO 2015 / 016786. In some embodiments, a lymphocyte of the invention comprises a nucleic acid sequence encoding a maintenance factor operably linked to a promoter for driving expression of therapeutically effective level of maintenance factor. Promoters may be routinely selected to achieve a desired strength of expression. As such, promoter(s) may routinely be selected to regulate the level of maintenance factor expression. Differing levels of expression may be achieved by using promoters of different strengths. In some embodiments, the nucleic acid sequence encoding the maintenance factor is operably linked to a weak promoter. Weak promoters are known in the art and include, for example, human UBC promoter. Differing levels of expression may also be achieved by using engineered promoters, e.g. promoters which have been modified to alter promoter strength. Promoters with a desired strength may be identified by screening a library of promoters to identify promoters which achieve the desired level of expression. In some embodiments, a lymphocyte of the invention comprises a nucleic acid sequence encoding a maintenance factor operably linked to an inducible promoter. In some embodiments, the inducible promoter is a ligand-responsive promoter. Ligand-responsive promoters regulate gene expression in response to a particular ligand, such as a drug or chemical compound. As used herein, the term "operably linked" means that a nucleic acid sequence encoding the maintenance factor and an expression control sequence (e.g. a 2A element, IRES sequence, and / or a promoter) are positioned in such a way that the expression control sequence regulates the expression of the gene of interest. In some embodiments, a lymphocyte of the invention comprises a catalytically-inactive Cas protein or a nucleic acid encoding a catalytically-inactive Cas protein and a guide RNA or a nucleic acid encoding a guide RNA, wherein the guide RNA is capable of hybridizing to a nucleic acid encoding the maintenance factor. Expression of a therapeutically effective amount of maintenance factor may also be achieved using CRISPR interference (CRISPRi-) and / or CRISPR activation (CRISPRa)-mediated regulation of expression. CRISPRi- and / or CRISPRa-mediated regulation of expression employs a catalytically-inactive Cas protein together with activator or repressor domains to regulate the level of expression of a gene of interest. In CRISPRi, the guide RNA targets a catalytically-inactive Cas protein to a target locus when it represses transcription by blocking transcriptional initiation and / or elongation. The level of repression can be regulated by altering the position and strand to which the guide RNA binds. In some embodiments, a lymphocyte of the invention comprises a nucleic acid sequence encoding a maintenance factor, wherein the nucleic acid encoding a maintenance factor is integrated into an endogenous locus. By integrating the nucleic acid sequence encoding the maintenance factor, expression of the maintenance factor is controlled by endogenous regulatory mechanisms. Thus, by integrating the nucleic acid sequence into an endogenous locus which is known to exhibit the desired expression level, a therapeutically effective amount of maintenance factor expression can be achieved. In some embodiments, a lymphocyte of the invention comprises an exogenously delivered messenger RNA (mRNA) molecule encoding a maintenance factor. The exogenously delivered mRNA may be modified to control its stability, abundance, or efficiency of translation. In some embodiments, a lymphocyte of the invention comprises a nucleic acid sequence encoding a maintenance factor and a riboswitch, wherein transcription of the nucleic acid sequence results in production of a messenger RNA (mRNA) comprising the maintenance factor coding region linked to the riboswitch. Riboswitches typically comprise a ligand-sensing aptamer domain which regulates gene expression in response to ligand binding. In some embodiments, wherein expression of the maintenance factor is linked to the presence or absence of a ligand, the lymphocyte further comprises a nucleic acid encoding the ligand. In some embodiments, a lymphocyte of the invention exhibits reduced maintenance factor activity as compared to a lymphocyte which is engineered for conventional high-level overexpression of maintenance factor. Maintenance factor activity may be modulated by altering the stability, binding affinity and / or cellular localisation of the maintenance factor. In some embodiments, a lymphocyte of the invention expresses one or more modified maintenance factors. As used herein, a modified maintenance factor is a maintenance factor which is modified as compared to the endogenous or wild-type maintenance factor expressed by the lymphocyte. As used herein, a modified maintenance factor typically exhibits reduced activity as compared to the endogenous maintenance factor. In some embodiments, the modified maintenance factor exhibits reduced stability relative to the endogenous maintenance factor. A maintenance factor having reduced stability may be more susceptible to degradation and / or may exhibit reduced DNA binding affinity to a maintenance factor binding site of a target gene as compared to the endogenous maintenance factor. In some embodiments, the modified maintenance factor exhibits reduced binding affinity to a maintenance factor binding site of a target gene and / or to a co-factor as compared to the endogenous maintenance factor. In some embodiments, the modified maintenance factor comprises one or more mutations in a DNA binding domain, wherein the one or more mutations reduce the DNA binding affinity of the maintenance factor relative to the wild-type maintenance factor. In some embodiments, the modified maintenance factor comprises one or more mutations in a functional domain, wherein the one or more mutations alters the interaction of the maintenance factor with a co-factor, e.g. a co-activator or co-repressor. In some embodiments, the modified maintenance factor exhibits reduced nuclear translocation as compared to the endogenous maintenance factor. In some embodiments, the modified maintenance factor comprises one or more mutations in a nuclear localisation signal (NLS) and / or a nuclear export signal (NES). In some embodiments, the modified maintenance factor is engineered to contain one or more nuclear export signals (NES). NLS is a specific sequence of amino acids typically found within proteins that serve as a signal for their transport from the cytoplasm into the cell nucleus. Proteins containing a functional NLS are recognized by nuclear transport machinery, such as importins, which facilitate their translocation through the nuclear pore complexes, allowing them to enter the nucleus and perform their specific functions, such as gene regulation. Similarly, NES is a sequence of amino acids that directs the export of proteins from the nucleus to the cytoplasm. Proteins containing NES sequences are recognized by exportins, which bind to the NES-containing proteins and facilitate their transport out of the nucleus through the nuclear pore complexes, controlling their localization and regulating their activity outside the nucleus. By manipulating the nuclear localization signals through mutations or by adding nuclear export signals, precise control over the subcellular distribution of a maintenance factor can be achieved. This modulation in localization directly influences the maintenance factors activity and its ability to regulate gene expression, allowing fine-tuning of maintenance factor activity. In some embodiments, the modified maintenance factor comprises an inducible protein domain which functions to regulate activity of the maintenance factor. In some embodiments, the inducible protein domain functions to regulate activity of the maintenance factor in response to an inducer. In some embodiments, the inducer is a ligand configured to interact with the inducible protein domain. In some embodiments, the ligand is a drug or chemical compound. In some embodiments, the inducible protein domain is a light-sensitive domain and the inducer is application of light. It will be understood that, depending on the inducible protein domain used, activation may occur in the presence or the absence of the inducer. In some embodiments, activation of the inducible protein domain promotes activity of the maintenance factor. In some embodiments, activation of the inducible protein domain inhibits activity of the maintenance factor. In some embodiments, the inducible protein domain regulates degradation of the maintenance factor. In some embodiments, the inducible protein domain regulates nuclear translocation of the maintenance factor. In some embodiments, the inducible protein domain regulates DNA and / or co-factor binding by the maintenance factor. In some embodiments, the maintenance factor is a maintenance factor-ligand receptor fusion protein. In some embodiments, the maintenance factor is a maintenance factor-estrogen receptor (ER) fusion protein. In some embodiments, the maintenance factor is a maintenance factor-ER fusion protein and the ligand is tamoxifen. In some embodiments, the lymphocyte is genetically modified using a vector comprising a nucleic acid encoding a maintenance factor as described herein. Suitable vectors are known in the art and include, but are not limited to, retroviral vectors, lentiviral vectors, adenoviral vectors, and adeno-associated viral (AAV) vectors. In some embodiments, the vector is a MSCV (Murine Stem Cell Virus) retroviral vector. In some embodiments, the vector is a MMLV (Moloney Murine Leukemia Virus) retroviral vector. In some embodiments, the vector is a low copy number vector. In some embodiments, the lymphocytes is edited by adding a nucleic acid encoding a maintenance factor through CRISPR-mediated homology-directed repair (HDR). CRISPR-mediated HDR is a precise genome editing technique that utilizes the CRISPR-Cas9 system. In this method, after CRISPR-Cas9 makes a targeted cut in the DNA, the cell's HDR mechanism is used to repair the cut using a provided DNA template that contains the desired genetic changes. This template has sequences similar to those around the cut site, allowing for accurate insertion or modification of specific DNA sequences. In some embodiments, the lymphocyte of the invention is generated by in vivo generation. Methods of in vivo generation of modified lymphocytes are known in the art. Unlike traditional methods of generating modified lymphocytes by genetically modifying extracted cells and then reinfusing them into a subject (typically referred to as ex vivo modification), in vivo generation of modified lymphocytes involves modifying cells within the body. In some embodiments, lymphocytes of the invention are generated by delivering genetic material for modifying the lymphocytes directly to the subject. The genetic material may be configured to induce overexpression of a therapeutically effective amount of maintenance factor in transduced cells. In some embodiments, lymphocytes of the invention are generated by delivering a vector comprising genetic material for modifying the lymphocyte directly to the subject. Delivery of genetic material may be achieved using viral or non-viral delivery systems. In some embodiments, the vector is a viral vector. Viral vectors (e.g. lentiviral vectors, retroviral vectors, and adeno-associated viral (AAV) vectors) are common due to their high efficiency in gene delivery. In some embodiments, the vector is a non-viral vector. Non-viral methods may include lipid nanoparticles which have been successfully used e.g. for mRNA vaccines. The invention provides a vector for use in producing a lymphocyte of the invention, wherein the vector comprises a nucleic acid sequence encoding a maintenance factor. The invention also provides a composition comprising a vector of the invention. The vector of the invention may be used to generate lymphocytes of the invention in v / vo.The vector of the invention maycomprisea nucleic acid sequence encoding a maintenance factor as described herein. In some embodiments, the vector comprises a nucleic acid sequence encoding a modified maintenance factor as described herein. It will be readily understood that descriptions herein relating to nucleic acid sequences / elements and modified maintenance factors in the context of lymphocytes of the invention apply equally to vectors of the invention which comprise said nucleic acid sequences / elements or which comprise a nucleic acid sequence encoding said modified maintenance factor. In some embodiments, the vector is a viral vector, optionally a lentiviral vector, a retroviral vector, or an AAV vector. In some embodiments, the vector is a non-viral vector, optionally a lipid nanoparticles vector. In some embodiments, the vector comprises a nucleic acid sequence encoding a maintenance factor downstream of a STOP-translational readthrough motif (TRM) sequence. In some embodiments, the nucleic acid sequence encoding a maintenance factor is downstream of a STOP-TRM sequence selected from: TGA-CTAGCA; TGA-CTAGGC; TGA-CAATTA; TAG-CAATTA; TAG-CTAGCA; TAG-CTAGGC; TAA-CTAGGC; TAA-CAATTA; TAA-GAGAGT; TAG-GAGAGT; TAG; TAA-CTAGCA; TAG-GAGAGT; TAA; TGATGA; and TGATGA-CTAGCA. In some embodiments, the STOP-TRM sequence is upstream of a glycine-serine-glycine (GSG) linker. In some embodiments, the GSG linker comprises the nucleic acid sequence GGAAGCGGA. In some embodiments, the vector comprises a nucleic acid sequence encoding a maintenance factor downstream of a frame-slip motif (FSM). In some embodiments, the vector comprises a nucleic acid sequence encoding a maintenance factor operably linked to a 2A element. In some embodiments, the vector comprises a nucleic acid sequence encoding a maintenance factor operably linked to an internal ribosome entry site (IRES) sequence. In some embodiments, the vector comprises a nucleic acid sequence encoding a maintenance factor operably linked to a promoter for driving expression of therapeutically effective level of maintenance factor, optionally wherein the promoter is an inducible promoter and / or a weak promoter. In some embodiments, the vector comprises a nucleic acid sequence encoding a maintenance factor and a riboswitch. The invention also provides a composition comprising a population of lymphocytes of the invention. The population of lymphocytes of the invention exhibit enhanced stem-like or memory phenotype as compared to a population of lymphocytes which are not engineered to overexpress maintenance factor. In some embodiments, increased stem-like or memory phenotype corresponds to increased survival of lymphocytes exhibiting a stem-like or memory phenotype. The invention also provides a composition comprising a population of lymphocytes of the invention for use in therapy. In some embodiments, the composition is for use in cell therapy. The invention also provides an adoptive cell therapy method comprising administering to a patient a population of lymphocytes of the invention. The invention also provides a composition comprising a vector of the invention for use in therapy, wherein the therapy comprises in vivo generation of a lymphocyte of the invention. The invention also provides a composition comprising a population of lymphocytes of the invention for use in a method of treating or preventing cancer in a patient. The invention also provides a method of treating cancer in a patient, the method comprising administering to the patient a population of lymphocytes of the invention. The invention also provides a composition comprising a vector of the invention for use in a method of treating or preventing cancer in a patient, wherein the method comprises in vivo generation of a lymphocyte of the invention. The invention also provides a method of treating cancer in a patient, the method comprising administering to the patient a vector for use in in vivo generation of a lymphocyte of the invention. In some embodiments, the composition is for use in tumour-infiltrating lymphocytes (TIL) therapy. In some embodiments, the cancer is selected from a haematological cancer and a solid cancer. In some embodiments, the cancer is selected from a treatment-refractory or relapsed B cell malignancy, optionally selected from diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic leukaemia (B-ALL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and multiple myeloma (MM). In some embodiments, the cancer is a solid cancer selected from breast cancer, lung cancer, brain cancer, colorectal cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, cervical cancer, testicular cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, head and neck cancer, renal cancer, and gastric cancer. In some embodiments, the cancer is a haematological cancer selected from Acute Myeloid Leukaemia (AML), Chronic Lymphocytic Leukaemia (CLL), Chronic Myelogenous Leukaemia (CML), Chronic Myelomonocytic Leukaemia (CMML) and Cutaneous T cell Lymphoma (CTCL). In some embodiments, the cancer is selected from adrenocortical carcinoma, bladder urothelial carcinoma, brain lower grade glioma, breast invasive carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, cholangiocarcinoma, chronic myelogenous leukaemia, colon adenocarcinoma, oesophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma and paraganglioma, prostate adenocarcinoma, rectum adenocarcinoma, sarcoma, skin cutaneous melanoma, stomach adenocarcinoma, testicular germ cell tumours, thymoma, thyroid carcinoma, uterine carcinosarcoma, uterine corpus endometrial carcinoma, and uveal melanoma. The invention also provides a composition comprising a population of lymphocytes of the invention for use in a method of treating or preventing an autoimmune disease in a patient. The invention also provides a method of treating an autoimmune disease in a patient, the method comprising administering to the patient a population of lymphocytes of the invention. The invention also provides a composition comprising a vector of the invention for use in a method of treating or preventing an autoimmune disease in a patient, wherein the method comprises in vivo generation of a lymphocyte of the invention. The invention also provides a method of treating an autoimmune disease in a patient, the method comprising administering to the patient a vector for use in in vivo generation of a lymphocyte of the invention. In some embodiments, the autoimmune disease is selected from rheumatoid arthritis, lupus erythematosus, multiple sclerosis, type I diabetes, coeliac disease, Crohn's disease, myasthenia gravis, Sjogren syndrome, Graves' disease, Behget's syndrome, and Asthma. In some embodiments, the lymphocytes are derived from a sample obtained from the patient. In some embodiments, the lymphocytes are derived from a sample obtained from a donor. In some embodiments, the lymphocytes are derived from multiple samples obtained from two or more donors. In some embodiments, the lymphocytes are generated in vivo as described herein. In some embodiments, the therapeutic methods described herein comprise administering the lymphocytes in combination with an RNA interference (RNAi) molecule for downregulating expression of the overexpressed maintenance factor. By administering lymphocytes in combination with an RNAi molecule, the level of maintenance factor expression can be regulated to ensure lymphocytes express a therapeutically effective amount of maintenance factor. As used herein, an RNAi molecule is an agent which inhibits expression of a target gene by RNA interference. In some embodiments, the RNAi molecule is selected from a short interfering RNA, a small hairpin RNA, and a microRNA. In some embodiments, wherein expression and / or activity of the maintenance factor is dependent on an inducer, the therapeutic method further comprises administering the inducer to the patient. In some embodiments, the inducer is light and the method comprises targeted delivery of light to the patient. In some embodiments, the inducer is a ligand. In some embodiments, the ligand is administered directly. In some embodiments, the ligand is administered in the form of a substance that is metabolised to produce the ligand. In some embodiments, the ligand is a drug. In some embodiments, the ligand is tamoxifen. In some embodiments, the therapeutic methods described herein comprise administering the composition intravenously, intraperitoneally, subcutaneously, intradermally, intratumourally and / or intramuscularly. It will be readily understood that the dose of lymphocytes administered will depend on the type of lymphocyte used and the condition or disease being treated. Advantageously, by improving the maintenance and long-term survival of lymphocytes in vivo, the present invention may enable the use of lower doses of lymphocytes and / or a lower number of repeated doses to be administered, as compared to existing cell therapies, without reducing therapeutic efficacy. In some embodiments, the method comprises administering a dose of lxl03to lxlO10 lymphocytes per kg of body weight to the patient, optionally wherein the method comprises administering a dose of lxlO3 to lxlO9, lxlO3 to lxlO8, lxlO3 to lxlO7, lxlO3 to 1x10s, lxlO3 to lxlO5, lxlO4 to lxlO10, lxlO5 to lxlO10, 1x10s to lxlO10, lxlO7 to lxlO10, lxlO8 to lxlO10 or lxlO9 to lxlO10 lymphocytes per kg of body weight to the patient. In some embodiments, the method comprises administering a dose of 0.5xl03 to 5xlO10 lymphocytes per kg of body weight to the patient, optionally wherein the method comprises administering a dose of 0.5xl03 to 5xl09, 0.5xl03 to 5xl08, 0.5xl03 to 5xl07, 0.5xl03 to 5x10s, 0.5xl03 to 5xl05, 0.5xl04 to 5xlO10, 0.5xl05 to 5xlO10, 0.5x10s to 5xlO10, 0.5xl07 to 5xlO10, 0.5xl08 to 5xlO10 or O.5xio9 to 5xlO10 lymphocytes per kg of body weight to the patient. As used herein, the term "treatment" or "treating" embraces therapeutic measures. Treatment of a condition may be characterised by a reduction or elimination of disease symptoms. As used herein, the term "preventing" includes preventing the onset and / or the progression of a condition. As used herein, the term "patient" refers to an animal or any living organism including, but not limited to, members of the human, primate, equine, porcine, bovine, murine, rattus, canine and feline species. In one embodiment, the patient is a mammal. In one embodiment, the patient is a human. The patient may have been diagnosed with cancer or with an autoimmune disease. The invention also provides a method for determining whether a lymphocyte which has been genetically engineered to overexpress maintenance factor expresses a therapeutically effective amount of maintenance factor, the method comprising: (a) comparing the sternness of the genetically engineered lymphocyte to the sternness of a corresponding lymphocyte which is not engineered to overexpress maintenance factor; (b) comparing the level of one or more effector functions in response to immune stimulation of the genetically engineered lymphocyte to the level of one or more effector functions of a corresponding lymphocyte which is not engineered to overexpress maintenance factor; and (c) determining whether the genetically engineered lymphocyte expresses a therapeutically effective amount of maintenance factor based on steps (a) and (b). A genetically engineered lymphocyte which exhibits: (i) enhanced sternness compared to the corresponding lymphocyte; and (ii) a comparable or greater level of one or more effector functions in response to immune stimulation compared to the corresponding lymphocyte is identified as expressing a therapeutically effective amount of maintenance factor. In some embodiments, the method comprises comparing the sternness of a population of genetically engineered lymphocytes to the sternness of a corresponding population of lymphocytes which are not engineered to overexpress maintenance factor. In some embodiments, the method comprises comparing the level of one or more effector functions of a population of genetically engineered lymphocytes to the level of one or more effector functions of a corresponding population of lymphocytes which are not engineered to overexpress maintenance factor. The invention also provides a method for producing a lymphocyte expressing a therapeutically effective amount of maintenance factor, the method comprising: (a) genetically engineering a lymphocyte to overexpress maintenance factor; (b) comparing the sternness of the genetically engineered lymphocyte to the sternness of a corresponding lymphocyte which is not engineered to overexpress maintenance factor; (c) comparing the level of one or more effector functions in response to immune stimulation of the genetically engineered lymphocyte to the level of one or more effector functions of a corresponding lymphocyte which is not engineered to overexpress maintenance factor; and (d) selecting a lymphocyte which exhibits: (i) enhanced sternness compared to the corresponding lymphocyte; and (ii) a comparable or greater level of one or more effector functions in response to immune stimulation as compared to the corresponding lymphocyte. In some embodiments, the method is a method of producing a population of lymphocytes expressing a therapeutically effective amount of maintenance factor and the method comprises selecting a population of lymphocytes which exhibit: (i) enhanced sternness compared to a corresponding population of lymphocytes which are not engineered to overexpress maintenance factor; and (ii) a comparable or greater level of one or more effector functions in response to immune stimulation as compared to a corresponding population of lymphocytes which are not engineered to overexpress maintenance factor. In some embodiments, a comparable or greater level of one or more effector functions comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 100%, at least 105%, at least 110%, at least 115%, at least 120%, at least 130%, at least 140%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250%, at least 275%, at least 300%, at least 350%, at least 400%, at least 450%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% of the level of the one or more effector functions exhibited by a corresponding lymphocyte or population of lymphocytes which do not overexpress maintenance factor. The methods described herein are ideally suited to high-throughput screening of lymphocytes comprising different levels of overexpression of maintenance factor. In some embodiments, the method further comprises screening two or more lymphocytes which exhibit different levels of maintenance factor activity. In some embodiments, the two or more lymphocytes have been engineered to overexpress different levels of maintenance factor. In some embodiments, the two or more lymphocytes exhibit different levels of activity of overexpressed maintenance factor. In some embodiments, the method further comprises screening three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, or 25 or more lymphocytes which have been engineered to overexpress different levels of maintenance factor. Lymphocytes expressing distinct levels of maintenance factor activity can be generated using one or more of the methods described herein. Lymphocytes used in said assays typically differ only in that they express distinct levels of maintenance factor. In some embodiments, the method further comprises identifying the lymphocyte expressing the optimal level of maintenance factor, wherein the lymphocyte expressing the optimal level of maintenance factor exhibits (i) the highest degree of sternness and / or (ii) the highest degree of effector function(s) out of the lymphocytes screened. In some embodiments, comparing the sternness comprises detecting the presence of one or more cell markers associated with a stem-like or memory phenotype. In some embodiments, the lymphocyte is identified as exhibiting enhanced sternness if the level of expression of one or more cell markers associated with a stem-like or memory phenotype in the lymphocyte is higher than in the corresponding lymphocyte. In some embodiments, the one or more cell markers associated with a stem-like or memory phenotype comprise TCF1, CD62L, SLAMF6, BACH2, ID3, F0X01, EGR2, MYB, EOMES, BCL6, STAT3, ZEB1, LEF1, F0XP1, KLF2, SATB1, FLU, RUNX2, RUNX3, SOX4, BHLHE40, KMT2A, and SMARCA4. As used herein, a genetically engineered lymphocyte is a lymphocyte which is genetically engineered to overexpress maintenance factor. As used herein, the corresponding lymphocyte typically differs from the genetically engineered lymphocyte(s) only in that it is not engineered to overexpress maintenance factor. It will be understood that the genetically engineered lymphocyte and the corresponding lymphocyte may also be genetically engineered to introduce and / or modulate other proteins and / or functions (e.g. addition of a CAR). In some embodiments, the lymphocyte is identified as exhibiting enhanced sternness if the level of expression of one or more cell markers associated with a stem-like or memory phenotype is at least 5% higher in the lymphocyte than in the corresponding lymphocyte. In some embodiments, the lymphocyte is identified as exhibiting enhanced sternness if the level of expression of one or more cell markers associated with a stem-like or memory phenotype is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, at least 1000%, at least 1500%, at least 2000%, at least 2500%, at least 3000%, at least 3500%, at least 4000%, at least 4500%, at least 5000%, at least 6000%, at least 7000%, at least 8000%, at least 9000%, or at least 10000% higher in the lymphocyte than in the corresponding lymphocyte. In some embodiments, the method comprises comparing the level of cellular exhaustion of the genetically engineered lymphocyte to the level of cellular exhaustion of a corresponding lymphocyte which is not engineered to overexpress maintenance factor. In some embodiments, the method further comprises comparing the level of cellular exhaustion of a population of genetically engineered lymphocytes to the level of cellular exhaustion of a corresponding population of lymphocytes which are not engineered to overexpress maintenance factor. In some embodiments, the method comprises comparing the cellular exhaustion of the genetically engineered lymphocytes instead of comparing the sternness of the genetically engineered lymphocytes. Reduced cell exhaustion indicates that the genetically engineered lymphocyte expresses a therapeutically effective amount of maintenance factor. In some embodiments, comparing the level of cell exhaustion comprises detecting the presence of one or more cell markers associated with cell exhaustion. In some embodiments, the lymphocyte is identified as exhibiting reduced cell exhaustion if the level of expression of one or more cell markers associated with cell exhaustion is lower in the genetically engineered lymphocyte than in the corresponding lymphocyte. In some embodiments, the one or more cell markers associated with a cell exhaustion comprise TIM-3, KLRG1, CD39, PD-1, TIGIT, TOX, and / or CXCR5. In some embodiments, the lymphocyte is identified as exhibiting reduced cell exhaustion if the level of expression of one or more cell markers associated with cell exhaustion is at least 5% lower in the genetically engineered lymphocyte than in the corresponding lymphocyte. In some embodiments, the lymphocyte is identified as exhibiting reduced cell exhaustion if the level of expression of one or more cell markers associated with cell exhaustion is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% lower in the genetically engineered lymphocyte than in the corresponding lymphocyte. In some embodiments, determining whether the lymphocyte exhibits a comparable or greater level of one or more effector functions in response to immune stimulation comprises determining the level of one or more effector molecules, e.g. effector cytokines and / or chemokines, produced in response to immune stimulation. In some embodiments, the one or more effector molecules comprise TNF, IFNy, IL-2, Granzyme-B, Perforin, and CD103. In some embodiments, the lymphocyte is identified as expressing a therapeutically effective amount of maintenance factor if the lymphocyte produces a comparable or greater level of the one or more effector molecules (e.g. effector cytokines) as a corresponding lymphocyte which is not engineered to overexpress maintenance factor. In some embodiments, the lymphocyte is identified as expressing a therapeutically effective amount of maintenance factor if the lymphocyte produces at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 100%, at least 105%, at least 110%, at least 115%, at least 120%, at least 130%, at least 140%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250%, at least 275%, at least 300%, at least 350%, at least 400%, at least 450%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% of the level of one or more effector molecules produced by the corresponding lymphocyte. In some embodiments, the lymphocyte is identified as expressing a therapeutically effective amount of maintenance factor if the lymphocyte produces at least 100% of the level of one or more effector cytokines produced by the corresponding lymphocyte. In some embodiments, immune stimulation comprises exposing the lymphocyte to one or more cytokines and / or chemokines. In some embodiments, immune stimulation comprises exposing the lymphocyte to CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CX3CL1, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, IL-la, IL-ip, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, IFNa, IFNp, IFNy, TGFP, TNF, TNFp, XCL1, and / or XCL2. In some embodiments, wherein the lymphocyte comprises an antigen receptor, immune stimulation comprises exposing the lymphocyte to one or more antigens capable of interacting with and activating said antigen receptor. In some embodiments, the method further comprises comparing the level of proliferation of the genetically engineered lymphocyte to a corresponding lymphocyte which does not overexpress maintenance factor. A comparable or greater level of proliferation as compared to the corresponding lymphocyte indicates that the genetically engineered lymphocyte expresses a therapeutically effective amount of maintenance factor. The level of proliferation may be determined by measuring DNA synthesis, cellular metabolism, and / or proliferation proteins. In some embodiments, determining the level of proliferation comprises measuring expression of proteins indicative of proliferative capacity (e.g. Ki-67); measuring BrdU incorporation (e.g. measured by ELISA, flow cytometry or Western blot); and / or measuring dilution of a cell permeable dye by flow cytometry wherein the quantity of dye is halved with each cell division (suitable dyes include Cell Trace dyes and CFSE). In some embodiments, the method further comprises comparing the level of proliferation of a population of genetically engineered lymphocytes to the level of proliferation of a corresponding population of lymphocytes which are not engineered to overexpress maintenance factor. In some embodiments, the lymphocyte or population of lymphocytes is identified as expressing a therapeutically effective amount of maintenance factor if the lymphocyte or population of lymphocytes exhibits a level of proliferation that is at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 100%, at least 105%, at least 110%, at least 115%, at least 120%, at least 130%, at least 140%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250%, at least 275%, at least 300%, at least 350%, at least 400%, at least 450%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% of the level of proliferation exhibited by a corresponding lymphocyte or corresponding population of lymphocytes which are not engineered to overexpress maintenance factor. In some embodiments, a lymphocyte of the invention may be identified and / or produced by a method of the invention. EXAMPLES The invention will be further clarified by the following examples, which are intended to be purely exemplary of the invention and are in no way limiting. Example 1 The inventors developed a technology which enhances the maintenance and efficacy of cell therapy through dose-optimised maintenance factor delivery to lymphocytes. The inventors employed BACH2 as a representative maintenance factor. Conventional high-level overexpression of BACH2 was found to drive acquisition of a stem / memory phenotype among transduced cells but locked those cells in a functionally quiescent state wherein they exhibited significantly reduced levels of proliferation and effector functions. The inventors therefore developed a gene expression system to enable dosed expression of BACH2 to CD8+ T cells which were employed as representative lymphocytes. T cells expressing dose-optimised BACH2 were found to not only exhibit increased stem / memory characteristics, but also to exhibit comparable or greater levels of proliferative capacity and effector cytokines production as lymphocytes which were not engineered to overexpress maintenance (e.g. quiescence) factor. Importantly, cells expressing dose-optimised BACH2 exhibited greater survival, expansion, and anti-tumour function in vivo in a pre-clinical solid tumour model. The optimised dose required to achieve these advantageous therapeutic effects is referred to herein as a therapeutically effective amount or dose. Results Conventional high level overexpression of maintenance factor fails to improve anti-tumour efficacy of adoptively transferred T cells To determine whether overexpression of BACH2 at high levels enhances anti-tumour efficacy, the inventors used a well-established murine pre-clinical cell therapy model. Syngeneic B16 melanoma tumour cells expressing a model antigen, chicken egg ovalbumin (VV-OVA; B16-OVA), were subcutaneously administered to C57BL / 6 mice and recognised by adoptively transferred OT-I TCR transgenic CD8+ T cells specific for the OVA257-264 epitope (Fig. la). The inventors generated retroviral vectors for conventional overexpression of BACH2 (BACH2-OE) and transduced OT-I cells with either empty or BACH2-OE vectors prior to adoptive transfer. Importantly, BACH2-OE cells did not exhibit superior efficacy to empty-vector transduced cells (Fig. lb). BACH2-OE-transduced cells displayed reduced frequencies of terminally exhausted (TIM-3+) cells and increased frequencies of stem-like (TCF-1+) cells (Fig. lc). However, conventional BACH2 overexpression limited the production of effector cytokines required forthe tumoricidal function of CD8+T cells (Fig. Id). Hence, despite limiting terminal differentiation and promoting desirable characteristics associated with long-lived T cells, high level overexpression of BACH2 did not lead to improved anti-tumour T cell responses in the context of adoptive cell therapy. Dose-optimised expression of maintenance factor enhances stem / memory differentiation without compromising effector function in vitro Bach2 mRNA is expressed at heterogeneous levels across physiological T cell subsets, with intermediate levels of expression in stem / memory CD8+ T cells compared to naive and terminally differentiated effector cells. This led the inventors to hypothesise that optimising the dose at which BACH2 is expressed in T cells may enable programming of long-lived memory-like characteristics while preserving the capacity for robust effector function and anti-tumour efficacy. To achieve precision dosing, the inventors leveraged a system which regulates payload expression at the level of protein translation through the use of a STOP codon followed by a translational read-through motif preceding the Bach2 gene. Insertion of a BACH2 open reading frame (ORF) upstream of specific STOP-TRM combinations enabled control over the delivery of BACH2 protein levels in transduced cells, thereby yielding different levels of dosed expression (Fig. 2). The inventors first established a dose-optimisation assay to define the optimal BACH2 expression level for induction of a stem / memory phenotype while minimally impacting proliferation and cytokine function. The inventors performed an in vitro repetitive stimulation assay to define an optimal dose of BACH2 expression in the context of chronic stimulation, measuring cellular phenotype using surface marker staining, cytokine function using intracellular cytokine staining and proliferation using Ki-67 (Fig. 3a). As predicted, high dose overexpression of BACH2 reduced the expression of exhaustion-related markers (TIM-3 and KLRG1), increased the expression of the stem / memory marker CD62L, and blunted the production of effector cytokines compared to empty vector-transduced cells (Fig. 3b-d). Importantly, dose-optimised BACH2, expressed at 5-fold and 15-fold lower levels than full overexpression, also reduced T cell exhaustion and enhanced sternness. Critically, however, cells expressing dose-optimised BACH2 retained the capacity for effector cytokine production, even displaying modestly enhanced production of IFN-y than empty vector-transduced cells (Fig. 3d). Collectively, these data indicate that an in vitro dose-optimisation assay can be used to define a therapeutically effective expression level of maintenance factor which maintains T cell sternness while retaining effector function and proliferation. Dose optimised maintenance factor improves the anti-tumour efficacy of adoptively transferred T cells Next, the inventors assessed whether dose-optimised BACH2 expression improves the efficacy of adoptive cell therapy in vivo. Again, the inventors leveraged the syngeneic B16-OVA solid tumour model and adoptively transferred T cells transduced with BACH2 expression vectors or empty vector control. Impressively, dose-optimised BACH2 expression markedly enhanced anti-tumour efficacy compared to either empty vector cells or cells expressing high dose BACH2 (Fig. 4a-b and 8a-b). Ex vivo flow cytometry analyses of tumour-infiltrating T cells revealed that dose-optimised BACH2 improved the persistence of tumour-infiltrating OT-1 T cells (Fig. 4c). In addition, consistent with prior in vitro experiments, dosed BACH2 led to reduced levels of terminal differentiation markers and increased levels of stemness / memory marker compared to control cells (Fig. 4d). Unlike high dose BACH2, dose-optimised expression did not compromise the effector function of adoptively transferred T cells (Fig. 4e). Crucially, as observed under chronic stimulation in vitro, dose-optimised BACH2-expressing T cells showed increased production of IFN-y and TNF compared to empty vector cells. These findings show that expression of a therapeutically effective amount of maintenance factors, such as BACH2, within T cells enhances persistence and sternness of T cells whilst maintaining anti-tumour effector function, resulting in highly effective and durable anti-tumour responses. Conclusion The inventors have demonstrated that T cells engineered to express a therapeutically effective amount of BACH2 exhibit enhanced T cell maintenance and function, resulting in improved antitumour responses in solid tumour models. Conversely, conventional high-level overexpression of BACH2 failed to enhance cell therapy responses. These findings suggest that the level of expression of maintenance factor payloads may produce qualitatively rather than merely quantitatively distinct functional outcomes, with major implications for how genetic payloads are delivered to cells in the context of cell therapy and other gene therapy applications. The inventors have demonstrated for the first time maintenance factors being used effectively to improve T cell-mediated antitumour responses. Without wishing to be bound by theory, the inventors believe that the continual expression of dosed maintenance factors might influence lymphocytes by facilitating the maintenance of a hybrid state with characteristics of both stem / memory and effector subsets. Alternatively, it could also be impacting the frequency at which cells differentiate between the two states. Importantly, the results demonstrated herein are applicable to both haematological and solid malignancies since terminal differentiation is a cell-intrinsic process agnostic of the type of CAR-T target. In addition, the conserved biology of maintenance factors, including BACH2, among cells of the lymphoid lineage indicates that this technology may be applied to other lymphocyte cell types, including CD4 T cells, Treg, NK and B cells - all of which experience analogous processes to that of CD8 terminal differentiation. Example 2 The inventors have demonstrated that quantitative control of the representative maintenance factor BACH2 dosage in representative CD8+ T cells establishes a continuum of physiological stem and effector states and enables engineering of synthetic cell states with enhanced persistence and antitumour efficacy dependent upon quiescence. Bach2 expression is precisely regulated in CD8+T cells, with intermediate expression in memory and progenitor-exhausted cells balancing sternness and effector functions. High-dose constitutive BACH2 expression locks cells in a quiescent progenitor state limiting effector functions and anti-tumour efficacy. Conversely, dose-optimised BACH2 expression enables terminally differentiated cells to retain features of stem-like cells without limiting effector function, resulting in enhanced persistence and anti-tumour efficacy. As demonstrated herein, quantitative control of BACH2 dosage in CD8+T cells establishes a continuum of stem and effector states and enables engineering of synthetic cell states with enhanced persistence and anti-tumour efficacy. Analysis of single cell RNA sequencing (scRNA-seq) data of tumourinfiltrating lymphocytes (TILs) and Bach2 reporter mice revealed that Bach2 expression is highest in naive CD8+T cells, and is progressively lost as cells differentiate into TPEx and Ttex cells, with TPEx subsets expressing intermediate levels of Bach2 mRNA. Constitutive high-dose BACH2 expression promoted acquisition of a progenitor-exhausted phenotype among CD8+T cells but limited their ability to engage effector functions, compromising anti-tumour efficacy. The inventors therefore developed a system to precisely regulate the level of BACH2 expression and found that constitutive low-dose BACH2 expression enables terminally differentiated cells to retain features of stem-like cells without limiting effector functions, enhancing persistence and anti-tumour efficacy. Importantly, the inventors also demonstrate that this principle is not restricted to the representative maintenance factor BACH2, but can also be applied to other maintenance factors, including FOXO1. These findings reveal dosage of maintenance factor regulation as a fundamental mechanism controlling T cell maintenance and provide a method for safe extension of T cell persistence. Results High level conventional overexpression of BACH2 locks CD8+ T cells in a stem-like state unable to engage effector functions The inventors utilised an adoptive cell therapy model whereby syngeneic B16 melanoma cells expressing the model antigen ovalbumin (B16-OVA) are recognised by OT-I TCR-transgenicCD8+T cells specific for the OVA257-264 epitope. OT-I T cells retrovirally transduced with a constitutive BACH2 overexpression vector (BACH2qE) or a control empty vector (EV) were adoptively transferred into sublethally irradiated B16-OVA tumour-bearing animals. BACH2 overexpression resulted in markedly increased frequencies of TCF1+ Slamf6+ TPEx cells, a nearcomplete absence of TIM-3 expression, higher levels of the lymphoid homing receptors CD62L and CCR7 whose expression is associated with naive and memory T cells, and diminished expression of the activation markers CD44 and PD-1 (Fig. 5a-c). Moreover, BACH2 overexpression vector (BACH2qE) severely curtailed production of effector molecules TNF, IFN-y, and granzyme B upon 4-hour restimulation ex vivo (Fig. 5d-e). Consequently, despite increased expression of markers associated with sternness and reduced levels of terminal differentiation, BACH2-overexpressing OT-I cells mediated impaired anti-tumour responses compared to control empty vector (EV)-transduced cells upon adoptive transfer (Fig. 5f). Collectively, these data confirm that constitutive high-dose overexpression of BACH2 promotes the differentiation of memory and progenitor-exhausted cells but simultaneously prevents acquisition of effector functions, blunting the anti-tumour efficacy of adoptively transferred CD8+T cells. Low-dose expression ofBACH2 induces a stem-like phenotype without compromising effector functions Using two different STOP-TRM mutants, the inventors achieved dosed expression of BACH2 (BACH2De) at median levels approximately 10% (BACH2De-io%) and 5% (BACH2De-5%) of those achieved by conventional retroviral overexpression, as determined using flow cytometric detection of a 3xFLAG tag at the N-terminus of the BACH2 ORF transgene (Fig. 6a-b). To determine the effect of BACH2De on the phenotype and function of CD8+ T cells, the inventors first performed chronic stimulation assays in vitro. Splenic CD8+T cells were stimulated, transduced with either BACH2oe, BACH2De-io%, BACH2De-5° / o or empty vectors, and maintained in media supplemented with IL-2 alone (acute stimulation) or IL-2 and anti-CD3 antibodies (chronic stimulation) replaced every two days. Chronic stimulation was sufficient to induce terminal exhaustion of a proportion of cultured cells, as indicated by co-induction of PD-1 and TIM-3 expression, and reduced cytokine production upon 4-hour restimulation. Using this assay, the inventors observed that both BACH2oe and BACH2De caused a substantial reduction in the frequency of TIM-3+ PD-1+ terminally exhausted cells after chronic stimulation (Fig. 7a). Both BACH2oe and BACH2De also caused higher levels of CD62L and TCF1 expression relative to EV. However, while BACH2oe caused decreased cytokine expression relative to EV upon 4-hour restimulation of acutely activated T cells, this was not observed in BACH2De-io% or BACH2DE-5%-transduced cells (Fig. 7b). BACH2De also resulted in similar or higher frequencies of polyfunctional cytokine-expressing cells compared to EV-transduced cells upon restimulation of chronically activated cells (Fig. 7d). In addition, BACH2oe cells were significantly smaller in size than EV cells (consistent with compromised levels of activation), but this was not the case with BACH2De-io% or BACH2De-5% (Fig. 7c). To investigate how BACH2De influences gene expression at the transcriptional level, we sorted transduced cells after 6 days of chronic stimulation and performed bulk RNA sequencing (RNA-seq). Principal component analysis (PCA) highlighted substantial differences between EV, BACH2oe and BACH2De groups, but a high degree of similarity among BACH2De-io% and BACH2De-5% (Fig. 7d). Gene set enrichment analysis (GSEA) showed that both BACH2oe and BACH2De cells exhibited a transcriptional signature that more closely aligned with that of stem-like T cells, while empty vector-transduced cells bore higher resemblance to the signature of terminally differentiated T cells (Fig. 7e). In summary, these data indicate that dosed expression of BACH2 induces qualitatively distinct changes to the phenotypic, functional and transcriptional profile of T cells when compared with conventional high-dose BACH2 overexpression, enabling retention of stem-like phenotypic features without compromising their ability to engage effector functions. Low-dose BACH2 expression enhances anti-tumour T cell therapy responses The ability of BACH2 dosing to promote the differentiation of stem-like T cells without compromising effector functions led the inventors to test whether this approach can be utilised to enhance adoptive T cell therapy responses in vivo. B16-OVA tumour-bearing mice were intravenously administered with OT-I T cells transduced with empty, BACH2oe or BACH2De vectors. While BACH2oe was unable to enhance the anti-tumour efficacy of adoptively transferred OT-I T cells compared with empty vector-transduced cells, BACH2De-io%- and BACH2DE-5%-transduced OT-I cells mediated substantially enhanced anti-tumour responses (Fig. 4a-b and 8a-b). Similar results were obtained with an OVA-expressing MC38 colorectal carcinoma T cell therapy model (MC38-OVA) (Fig. 9a-b). Notably, while BACH2oe led to an increase in the absolute number of TPEx cells but a decrease in Ttex cells relative to EV control, both BACH2De-io% or BACH2De-5% resulted in increased numbers of both T cell subsets (Fig. 8c). Consequently, BACH2oe resulted in a near-complete loss of terminally differentiated Ttex cells, while the overall frequency of stem-like and terminally differentiated cells remained minimally altered among BACH2DE-transduced cells (Fig. 8d). Evaluation of effector cytokine production upon 4-hour ex vivo restimulation revealed that BACH2oE-transduced cells displayed a significantly lower frequency of cells expressing effector molecules (IFN-y, TNF, granzyme B, IL-2), while this remained unchanged between BACH2De and empty vector control (Fig. 8e). Consistent with the observed expansion of both TPEx and Ttex subsets and preserved effector functions, mice receiving BACH2DE-transduced cells displayed a significantly increased number of cytokine-producing cells per gram of tumour (Fig. 8f). Collectively, these data indicate that BACH2De enhances the antitumour efficacy of CD8+ T cells by promoting persistence while allowing acquisition of effector functions. Low-dose FOXO1 expression enhances anti-tumour T cell therapy responses The inventors cloned vectors expressing a constitutively active triple-alanine mutant of the transcription factor FOXO1 (FOXO1AAA). Notably, FOXO1 is a maintenance factor required for maintenance of memory and progenitor-exhausted CD8+ T cells, and similar to BACH2 is more highly expressed in naive CD8+ T cells than in central memory and effector memory subsets. As with the previously designed BACH2 vectors (Fig. 6a), these vectors employ a STOP-TRM system enabling either conventional high-dose overexpression or dosed expression of F0X01AAA (FOXO1aaaoe, FOX01aaaDe-io%, and FOXO1aaade-5%)- Using the in vitro chronic stimulation assay, the inventors found that both high-and low-dose constitutive expression of FOXO1AAA led to a comparable increase in the frequency of TCF1+ TIM-3- cells relative to EV-transduced cells (Fig. 10a). However, FOXO1aaaoe impaired the production of IFN-y and TNF to a greater extent than FOX01aaaDe-io% and F0X01aaaDe-5% after 4-hour brief restimulation in vitro (Fig. 10b). These data suggest a generalizable principle that quantitative changes to the expression of maintenance factors (such as BACH2 and FOXO1AAA) induces qualitatively distinct changes to the phenotypic, functional and transcriptional profile of T cells when compared with conventional high dose overexpression of the same factors, enabling programming of stem-like phenotypic features without compromising their ability to engage effector functions. Conclusion The inventors have demonstrated that dosed expression of the maintenance factor BACH2 enhances the persistence and anti-tumour efficacy of adoptive T cell therapy. In contrast to approaches that maintain persistence through activation, maintenance factor dosing leverages a physiological mechanism of T cell maintenance, critical to both immunological memory and maintenance of T cell responses against chronic antigens. Rather than enforcing persistent activation, BACH2 restrains effector programs, promoting a state of regulated quiescence that more closely resembles physiological T cell maintenance. The known role of BACH2 as a tumour suppressor in the context of CAR T cell-derived lymphomas raises the potential that this approach may protect against therapy-induced lymphomagenesis rather than potentiating it, representing a safe strategy for enhancing T cell persistence in cellular immunotherapy. Moreover, the maintenance factor function of BACH2 may result in 'slower release' of effector cytokines, potentially reducing the possibility of cytokine release syndrome. Importantly, the inventors also demonstrated that these observations are applicable to other maintenance factors including FOXO1. In conclusion, the inventors have demonstrated that dosed expression of maintenance factor is critical for programming optimal T cell responses in the context of cellular immunotherapy. While conventional high-dose maintenance factor overexpression enforces a state of profound quiescence that restricts effector function, expression of maintenance factor at low levels enables enhanced T cell persistence while preserving anti-tumour functionality. These findings enable safe extension of T cell persistence and reveal that quantitative modulation of transcription factor expression can yield qualitatively distinct cellular outcomes, with important implications for cellular engineering approaches in immunotherapy. Methods - Example 1 Vector Synthesis In brief, an open reading frame containing sequences encoding Thyl.l and BACH2 separated by a T2A self-cleavage domain was introduced into a murine stem cell virus (MSCV) vector backbone. Preceding the BACH2 open reading frame, a stop codon followed by different translational readthrough motifs (TRMs), previously reported to suppress stop codon-induced termination of translation to differing extents, were introduced to yield different levels of maintenance factor expression (Sillibourne, J.E., et al. (2022). Biotechniques 72, 143-154). Splenocyte isolation and OT-I CD8 T cell expansion Spleens were mashed through a 40 pm nylon cell strainer and the resulting splenocyte suspension was washed in phosphate-buffered saline (PBS). Erythrocytes were lysed by resuspending the splenocytes in ammonium-chloride-potassium (ACK) lysing buffer (Gibco) for 1 minute at room temperature (RT). The cells were washed in PBS and resuspended in RPMI complete medium (CM) (RPMI 1640 medium (Gibco), 10% v / v heat-inactivated foetal bovine serum (FBS) (Sigma), 1% v / v GlutaMAX (Gibco), 1% v / v penicillin-streptomycin (Gibco), 1% v / v minimum essential medium non-essential amino acids solution (Gibco), 0.1% v / v 2-mercaptoethanol (Gibco), 0.1% v / v amphotericin B (Gibco), 0.1% v / v gentamycin (Gibco)). For expanding OT-I+ CD8 T cells, isolated splenocytes from OT-I mice were activated and expanded in RPMI CM in the presence of 5 ng / ml IL-2 and 10 pg / ml of soluble anti-CD3 (145-2C11, InVivoMab) and anti-CD28 (37.51, InVivoMab) at 37°C in a 5% CO2 incubator. Retroviral transduction Retroviral transductions were performed as described in Huang et al. (2019), Current Protocols in Immunology, 124. In brief, Platinum-E retroviral packaging cells (Cell Biolabs) grown in DMEM CM were plated in tissue culture-treated 24-well plates (Thermo Scientific). At 60-80% confluency, cells were co-transfected with 0.4 pg / well plasmid DNA of interest and 0.2 pg / well pCL-Eco retroviral packaging plasmid (Addgene cat. 12371) in 60 pl / well OptiMEM medium (Invitrogen) and 1.8 pl / well TranslT-293 transfection reagent (Mirus). 24 and 48 hours after transfection, viral supernatant (VSN) was collected, centrifuged to remove cell debris and stored at -80 °C, and fresh DMEM CM was added to the cells. OT-I+ CD8 T cells previously isolated and expanded for 24 hours with 10 mg / ml anti-CD3 and anti-CD28 were resuspended in VSN at 1x10s cells / ml and supplemented with 5 ng / ml rhlL-2 and 8 pg / ml polybrene. The cells were plated in a 24-well plate, centrifuged at 800 x g, for 2 hours at 37 °C and resuspended in RPMI CM supplemented with 5 ng / ml IL-2. The medium was replaced every 12 days and the cells were kept at 1-2 x 106 cells / ml. In vitro chronic stimulation assay For exhaustion assays, OT-I T cells were isolated and transduced as previously described. One day following transduction, and every two days thereafter until 8 days of culture, transduced T cells were resuspended at 1 x 106 cells / ml in RPMI CM supplemented with 5 ng / ml IL-2 and cultured on anti-CD3-coated plates. After 8 days of repeated stimulation, cells were harvested for flow cytometry analysis, or restimulated for 4 hours with phorbol myristate acetate (PMA) and ionomycin in the presence of 5 nM Brefeldin A (Biolegend) and 2 pM monensin (Biolegend) before undergoing intracellular cytokine staining. Adoptive cell therapy models 8-week-old female wild-type (WT) mice (C57BL / 6J background, CD45.2+) were purchased form Charles River and transferred to the University Biomedical Services animal facility. B16-OVA cells were grown in DMEM CM (DMEM (Gibco) supplemented with RPMI CM), and 1.25 x 105 cells / mouse were injected subcutaneously into the flank in 100 pl phenol-free DMEM. Tumour growth was measured using a digital calliper at indicated timepoints. For the adoptive T cell transfer, OT-I+ CD8 T cells were isolated from congenically distinct female mice (C57BL / 6J and B6SJL background, OT-I+, CD45.1+), transduced as previously described and cultured in RPMI CM supplemented with 5 ng / ml IL-2 for 36 hours. 11 days after B16-OVA injection, tumour-bearing animals were sublethally irradiated with 2.5 Gy radiation from an X-ray source. One day later, 0.5 x 106 OT-I+ CD8 T cells / mouse were injected intravenously in 100 pl HBSS to tumour-bearing mice. Tissue processing Tumours were dissected, cut into small fragments, and digested using DNase (20 pg / ml) and collagenase (1 mg / ml) for 30 minutes at 37 °C, 200 rpm. The resulting tumour suspension was mashed through a 40 pm nylon cell strainer and washed in PBS. An isotonic Percoll stock solution was prepared by mixing 9 volumes of Percoll (Sigma) with 1 volume of 1.5 M NaCI solution. The resulting stock was further diluted in PBS into a 37% (v / v) Percoll solution and used in a density gradient centrifugation to separate cells from fat and other contaminants (600 x g, 10 minutes, room temperature). The cells were washed in PBS and resuspended in RPMI CM. Flow cytometry Cells were washed in PBS and stained in PBS with surface antibodies and live / dead dye for 30 minutes at 4°C and protected from light. Cells were washed in fluorescence-activated cell sorting (FACS) buffer (PBS, 2% v / v heat-inactivated FBS (Sigma), 2 mM EDTA (Sigma), 0.6 g / l sodium azide (Sigma)) and stained for intracellular markers using the eBioscience Foxp3 / Transcription Factor Staining Buffer Set (Invitrogen) as per manufacturer's instructions. Cells were washed and resuspended in FACS buffer before analysis. Acquisition of data was performed using a Cytek Aurora. Data was analysed in FlowJo v.10.9.0 and statistical analyses were performed using GraphPad Prism 9. Vectors pMIT-FLAG-BACH2: vector for conventional overexpression of BACH2, composed by the pMIT backbone with the BACH2 gene (FLAG-tagged) cloned in. This vector has been used for initial studies of BACH2 function in T cells (Roychoudhuri et a!., Nature Immunology, 2016), and leads to high levels of BACH2 overexpression. pMIT-FLAG-BACH2 was used to generate the data in Figure 1. pMSCV-Thyl.l-T2A-FLAG-BACH2: MSCV-based vector with a Thyl.l-T2A-FLAG-BACH2 construct cloned in. This vector leads to overexpression of Thyl.l and FLAG-BACH2 as a single protein, which gets split into two separate protein units at the T2A self-cleavage sequence. This vector leads to high levels of BACH2 overexpression. pMSCV-Thyl.l-T2A-FLAG-BACH2 was used to generate the data for 'Conventional BACH2' in Figures 3 and 4. pMSCV-Thyl.l-[STOP-TRMl]T2A-FLAG-BACH2: this vector is identical to pMSCV-Thyl.l-T2A-FLAG-BACH2, except it incorporates a STOP codon followed by a translational readthrough motif (TRM) upstream of the T2A self-cleavage sequence. This vector is estimated to lead to a ~5-fold decrease in the level of expression of FLAG-BACH2 compared to pMSCV-Thyl.l-T2A-FLAG-BACH2 (based on Sillibourne et a!., 2022). pMSCV-Thyl.l-[STOP-TRMl]T2A-FLAG-BACH2 was used to generate the 'Dose 1' data in Figures 3 and 4. pMSCV-Thyl.l-[STOP-TRM2]T2A-FLAG-BACH2: identical to pMSCV-Thyl.l-[STOP-TRMl]T2A-FLAG-BACH2, except the TRM sequence in this vector leads to an estimated ~15-fold decrease in the level of expression of FLAG-BACH2 compared to pMSCV-Thyl.l-T2A-FLAG-BACH2. pMSCV-Thyl.l-[STOP-TRM2]T2A-FLAG-BACH2 was used to generate the 'Dose 2' data in Figures 3 and 4. pMSCV-Thyl.l-[STOP-TRM3]T2A-FLAG-BACH2: identical to pMSCV-Thyl.l-[STOP-TRMl]T2A-FLAG-BACH2, except the TRM sequence in this vector leads to an estimated ~50-fold decrease in the level of expression of FLAG-BACH2 compared to pMSCV-Thyl.l-T2A-FLAG-BACH2. pMSCV-Thyl.l-[STOP-TRM4]T2A-FLAG-BACH2: identical to pMSCV-Thyl.l-[STOP-TRMl]T2A-FLAG-BACH2, except the TRM sequence in this vector leads to an estimated ~100-fold decrease in the level of expression of FLAG-BACH2 compared to pMSCV-Thyl.l-T2A-FLAG-BACH2. Methods - Example 2 Mice OT-I and Ptprc3 (CD45.1) congenic mice were obtained from the Jackson Laboratory (Hogquist, K.A., et al. (1994). T cell receptor antagonist peptides induce positive selection. Cell 76,17-27. 10.1016 / 0092-8674(94)90169-4). Bach2tdRFP mice were generated as previously described (Herndler-Brandstetter, D., et al. (2018). KLRG1(+) Effector CD8(+) T Cells Lose KLRG1, Differentiate into All Memory T Cell Lineages, and Convey Enhanced Protective Immunity. Immunity 48, 716-729 e718. 10.1016 / j.immuni.2018.03.015). Wild-type C57BL / 6 mice were purchased from Charles River Laboratories (Wilmington, MA, USA). Experiments were performed with 8- to 12-week-old animals using age- and sex-matched experimental groups. Mice were housed at the University of Cambridge University Biomedical Services (UBS) Gurdon Institute Facility. Experiments were conducted in accordance with UK Home Office guidelines and were approved by the University of Cambridge Animal Welfare and Ethics Review Board. Genotyping was performed by Transnetyx (Memphis, TN, USA). Cell lines and reagents The B16-F10 murine melanoma cell line was purchased from American Type Culture Collection. The B78ChOVA-mCherry (B16-OVA) murine melanoma cell line was kindly provided by Matthew Krummel. Platinum-E retroviral ecotropic packaging cells (Plat-E) were purchased from Cell Biolabs. Cell lines were passaged in DMEM (Gibco) supplemented with 10% heat-inactivated fetal bovine serum (Sigma-Aldrich), 1 mM sodium pyruvate (Gibco), 0.1 mM non-essential amino acids (Gibco), 2 mM glutamine (Gibco), 100 U ml1 streptomycin and penicillin (Gibco). Murine-reactive anti-CD3 (Clone 145-2C11) and anti-CD28 (Clone 37.51) antibodies were purchased from BioLegend. Recombinant human IL-2 (rhlL-2) was purchased from PeproTech and stored at -80 °C until use. Processing of tumour, spleen and lymph nodes Spleens and lymph nodes were mechanically dissociated through 40 pM cell strainers. Red blood cells were lysed using ACK Lysing Buffer (Gibco). Tumours were digested in DMEM with 20 pg ml-1 DNase I (Roche) and 1 mg ml-1 collagenase (Sigma-Aldrich) for 30 minutes at 37°C. Digested tumours were mechanically dissociated through 40 pM cell strainers and washed twice with PBS. Tumour-infiltrating lymphocyte enrichment was performed using Lympholyte-M solution (Cedarlane Labs) according to the manufacturer's instructions. For assessing cytokine production, single-cell suspensions were resuspended in media containing 20 ng ml-1 phorbol myristate acetate (PMA) (Sigma) and 1 pg ml-1 ionomycin (Sigma), or 5 pg ml-1 anti-CD3, together with 5 pg ml-1 brefeldin A (Sigma) and 5 pg ml-1 monensin (Sigma) for 4 hours. Generation of retrovirus for murine T cell transduction Plasmids encoding murine stem cell virus (MSCV)-based vectors for expression of BACH2 (CCDS51135.1) or F0X01AAA with a 3xFLAG tag at the N-terminus were purchased from VectorBuilder. Three alanine mutations (T24A, S253Aand S316A) were introduced in the F0X01 (CCDS17343.1) open reading frame for generating F0X01AAA (Tang, E.D., et al. (1999). Negative regulation of the forkhead transcription factor FKHR by Akt. J Biol Chern 274, 16741-16746. 10.1074 / jbc.274.24.16741). At 7080% confluency in a T175 flask, Plat-E cells were co-transfected with 6.3 pg pCL-Eco retroviral packaging plasmid (Addgene #12371) and 28.5 pg retroviral vector plasmid DNA of interest in 3.17 ml OptiMEM medium (Gibco) and 95 pl TranslT-293 transfection reagent (Mirus Bio). Transfected Plat-E cells were cultured at 37 °C 5% CO2 and viral supernatant harvested at 48- and 72-hours posttransfection. viral supernatant was centrifuged at 400 x g for 5 minutes to remove cellular debris and stored at -80 °C until use. Primary murine T cell transduction CD45.1+ OT-I splenocytes were activated for 24 hours in complete RPMI media (RCM; Gibco) containing 100 IU ml-1 rhlL-2,10 pg ml-1 anti-CD3 and 5 pg ml-1 anti-CD28 antibodies. Activated T cells were resuspended at 1 x 106 cells ml-1 in viral supernatant containing 100 IU ml-1 rhlL-2 and 8 pg ml-1 polybrene transfection reagent (Merck). Cell suspensions were plated on non-tissue culture-treated plates and centrifuged at 2000 x g 32 °C for 2 hours with minimal acceleration and no brake. Following centrifugation, cell suspensions were cultured for 4 hours, then washed and maintained at 1.25 x 106 cells ml-1 in RCM containing 100 IU ml-1 rhlL-2 until use. Transduction efficiency was evaluated by flow cytometry 48 hours following transduction. Flow cytometry and cell sorting Single-cell suspensions were blocked with anti-mouse CD16 / 32 Fc block (BioXCell, 2.4G2) followed by live and dead cell discrimination with Fixable Viability Dye eFluor 780 (Thermo Fisher Scientific). Surface staining was performed for 30 minutes away from light at 4 °C. Intracellular staining of transcription factors and cytokines was performed overnight following fixation and permeabilization using the eBioscience Foxp3 / Transcription Factor Staining Buffer Kit (Invitrogen) and BD Cytofix / Cytoperm Fixation / Permeabilization Kit (BD Biosciences), respectively (Whyte, C.E., et al. (2022). Do more with Less: Improving High Parameter Cytometry Through Overnight Staining. Curr Protoc 2, e589. 10.1002 / cpzl.589). Cell counts were obtained using 123count eBeads (Invitrogen). Samples were acquired using Cytek Aurora cytometers and data analyzed using FlowJo vlO (Tree Star Inc.). For fluorescence activated cell sorting (FACS), single-cell suspensions were filtered resuspended in complete RPMI 1640 media before sorting. Cells were sorted into RPMI 1640 media supplemented with 50% FCS (Sigma) and kept cold throughout until subsequent use. Cell sorting was performed using BD Aria or MoFlo Astrios (Beckman Coulter) cell sorters. UMAP plots were generated using the CATALYST package as previously described (Nowicka, M., et al. (2017). CyTOF workflow: differential discovery in high-throughput high-dimensional cytometry datasets. FlOOORes 6, 748. 10.12688 / flOOOresearch.11622.3). Adoptive cell transfer C57BL / 6 mice were injected subcutaneously into the flank with 1.25 x 105 B16-OVA cells or 3 x 105 MC38-OVA cells 12-14 days prior to T cell transfer. Once established, tumour-bearing mice were selected and randomized into experimental groups. Tumour area was measured every 3-4 days thereafter using electronic calipers and volume calculated as length x width2. Mice received 2.5 Gy (MC38-OVA-bearing mice) or 3.5 Gy (B16-OVA-bearing mice) total body X-ray irradiation one day before adoptive transfer. 5 x 105 transduced OT-I cells were intravenously injected into tumourbearing mice. For analysis of tumour-infiltrating cells, mice were culled 17-21 days following T cell transfer. Staff performing intravenous injections and tumour measurements were blinded to the experimental groups. Assessment of endogenous BACH2 expression 1.25 x 105 B16-F10 cells were subcutaneously injected into the flanks of Bach2tdRFP / + or Bach2+ / + mice. Tumour and spleen samples were harvested after 16 days, processed as previously described and analysed by flow cytometry. In vitro chronic stimulation assay OT-I splenocytes were activated with anti-CD3 and anti-CD28 antibodies for 24 hours and retrovirally transduced as previously described. The following day (day 2), and again 48 hours later (day 4), transduced cells were passaged in complete RPMI media supplemented with 100 III ml-1 rhlL-2 and re-stimulated on plates coated with 5 pg ml-1 anti-CD3 antibody. Acutely stimulated cells were passaged every two days and maintained in complete RPMI media supplemented with 100 III ml-1 rhlL-2. Cells were analysed by flow cytometry on days 2, 4 and 6. Cytokine polyfunctionality was assessed by intracellular staining following 4-hour restimulation on anti-CD3 coated plates in the presence of 5 pg ml-1 brefeldin-A and 5 pg ml-1 monensin. scRNA sequencing analysis Published sc-RNAseq data of human TILs was sourced from a public repository (https: / / zenodo.org / records / 5461803) (Zheng, L., et al. (2021). Pan-cancer single-cell landscape of tumour-infiltrating T cells. Science 374, abe6474. 10.1126 / science.abe6474). Downstream analyses were performed using Seurat (v5.1.0) in R v4.3.2. Visualization was performed using Scanpy (v.1.9.1) in Python v3.11.1. Raw gene expression matrices were processed by first removing blacklisted genes as described by the authors (Zheng, L., et al. (2021). Pan-cancer single-cell landscape of tumourinfiltrating T cells. Science 374, abe6474. 10.1126 / science.abe6474). Counts were normalized, scaled and variable features found using the SCTransform workflow with regression of mitochondrial and cell cycle-related genes. UMAP plots were generated using the first 25 principal components and cluster annotation performed manually according to signature cluster genes. RNA sequencing and analysis Single-cell suspensions of tumour-infiltrating Slamf6+ and Slamf6“Thyl.l+ CD45.1+ OT-I cells from B16-OVA-bearing mice, and Thyl.l+ OT-I cells following in vitro chronic stimulation, were purified by FACS. All samples were stored in 40 pl RNA / ater Stabilization Solution (ThermoFisher) at -80 °C. Samples were processed using the QIAshredder kit (Qiagen) and RNA extracted using the RNeasy Plus Mini Kit (Qiagen) according to the manufacturer's instructions. RNA libraries were produced using the SMARTer Universal Low Input RNA Kit (Takara) and sequenced on an Illumina NovaSeq 6000 instrument. FASTQ files were quality-checked using FastQC and aligned to the GRCm38 Mus musculus genome assembly using STAR. DESeq2 (vl.42.0) (Love, M.L, Huber, W., and Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15, 550.10.1186 / sl3059-014-0550-8) was used to perform differential gene expression analysis. Further analysis and visualization were completed using R v4.2.2. PCA was performed using variance stabilizing transformed counts generated using DESeq2. Heatmaps of gene expression were created using the R package pheatmap (vl.0.12). GSEA was performed using the R package fgsea (vl.28.0) with statistical analyses derived from 10,000 permutations.

Claims

1. A lymphocyte genetically engineered to overexpress one or more maintenance factor(s), wherein the lymphocyte exhibits a comparable or greater level of one or more effector functions in response to immune stimulation and / or a comparable or greater level of proliferation as compared to a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s).

2. The lymphocyte of claim 1, wherein the one or more maintenance factor(s) are selected from one or more of BACH2, ID3, F0X01, TCF1, EGR2, MYB, EOMES, BCL6, STAT3, ZEB1, LEF1, F0XP1, KLF2, SATB1, FLU, RUNX2, RUNX3, S0X4, BHLHE40, KMT2A, SMARCA4, JUN, STAT5A, STAT5B, and S0CS1.

3. The lymphocyte of any preceding claim, wherein the lymphocyte is selected from a T cell, a natural killer (NK) cell, a B cell, an innate lymphoid cell (ILC), and a tumour-infiltrating lymphocyte (TIL).

4. The lymphocyte of claim 3, wherein the T cell is selected from a CD8+ T cell, a CD4+ T cell and a gamma-delta T cell, optionally wherein the CD4+ T cell is selected from a regulatory T (Treg) cell, a T helper (Th) 1 cell, a Th2 cell, a Thl7 cell, a Follicular Helper T (Tfh) cell, and a Th9 cell.

5. The lymphocyte of any preceding claim, wherein the lymphocyte is engineered to express a chimeric antigen receptor (CAR), a T cell receptor (TCR), an antibody-TCR, a TCR-based CAR, a T cell antigen coupler (TAC), a synthetic T cell receptor and antigen receptor (STAR), and / or a TCR fusion construct (TRuC).

6. The lymphocyte of any preceding claim, wherein immune stimulation comprises exposing the lymphocyte to one or more cytokines, optionally wherein the one or more cytokines comprises CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CX3CL1, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, IL-la, IL-ip, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, IFNa, IFNp, IFNy, TGFp, TNF, TNFP, XCL1, and XCL2.

7. The lymphocyte of any preceding claim, wherein immune stimulation comprises exposing the lymphocyte to an antigen.

8. The lymphocyte of any preceding claim, wherein the one or more effector functions comprises production of one or more effector molecules.

9. The lymphocyte of claim 8, wherein the one or more effector molecules comprise one or more effector cytokines, optionally wherein the one or more effector cytokines are selected from IFN-y, TNF, IL-2, Granzyme-B, Perforin, and CD103.

10. The lymphocyte of any preceding claim, wherein the one or more effector functions comprise cytotoxic activity.

11. The lymphocyte of any preceding claim, wherein the lymphocyte overexpresses a level of one or more maintenance factor(s) that is at least 2-fold higher than the level of said one or more maintenance factor(s) expressed by a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s), optionally wherein the lymphocyte overexpresses a level of said one or more maintenance factor(s) that is at least 100-fold, at least 500fold, at least 1000-fold or at least 2000-fold higher than the level of said one or more maintenance factor(s) expressed by a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s).

12. The lymphocyte of any preceding claim, wherein the lymphocyte overexpresses a level of said one or more maintenance factor(s) that is between 5-fold and 1000-fold lower than the level of said one or more maintenance factor(s) expressed by a corresponding lymphocyte which is engineered to overexpress said one or more maintenance factor(s) from a retroviral vector configured for LTR-driven expression of said one or more maintenance factor(s).

13. The lymphocyte of any preceding claim, wherein the lymphocyte comprises a nucleic acid sequence encoding said one or more maintenance factor(s) downstream of a STOP-translational readthrough motif (STOP-TRM) sequence and / or a frame-slip motif.

14. The lymphocyte of claim 13, wherein the STOP-TRM sequence is selected from: TGA-CTAGCA; TGA-CTAGGC; TGA-CAATTA; TAG-CAATTA; TAG-CTAGCA; TAG-CTAGGC; TAA-CTAGGC; TAA-CAATTA; TAA-GAGAGT; TAG-GAGAGT; TAG; TAA-CTAGCA; TAG-GAGAGT; TAA; TGATGA; and TGATGA-CTAGCA.

15. The lymphocyte of any preceding claim, wherein the lymphocyte comprises a nucleic acid sequence encoding said one or more maintenance factor(s) operably linked to a 2A element.

16. The lymphocyte of any preceding claim, wherein the lymphocyte comprises a nucleic acid sequence encoding said one or more maintenance factor(s) operably linked to an internal ribosome entry site (IRES) sequence.

17. The lymphocyte of any preceding claim, wherein the lymphocyte comprises a nucleic acid sequence encoding said one or more maintenance factor(s) operably linked to a promoter for driving weak expression of said one or more maintenance factor(s).

18. The lymphocyte of claim 17, wherein the promoter is a human UBC promoter or an inducible promoter.

19. The lymphocyte of any preceding claim, wherein the lymphocyte comprises a catalytically-inactive Cas protein or a nucleic acid encoding a catalytically-inactive Cas protein and a guide RNA or a nucleic acid encoding a guide RNA, wherein the guide RNA is capable of hybridizing to a nucleic acid encoding said one or more maintenance factor(s).

20. The lymphocyte of any preceding claim, wherein the lymphocyte comprises a nucleic acid sequence encoding said one or more maintenance factor(s) operably linked to endogenous regulatory mechanisms; optionally wherein the nucleic acid sequence is integrated into an endogenous locus of the genome of the lymphocyte.

21. The lymphocyte of any preceding claim, wherein the lymphocyte comprises an exogenously delivered messenger RNA (mRNA) molecule encoding one or more maintenance factor(s).

22. The lymphocyte of any preceding claim, wherein the one or more maintenance factor(s) are modified to exhibit reduced activity as compared to the corresponding wild-type maintenance factor(s).

23. The lymphocyte of claim 22, wherein the one or more modified maintenance factor(s) exhibit reduced stability, nuclear translocation, DNA binding affinity, and / or co-factor binding affinity relative to the corresponding wild-type maintenance factor(s).

24. The lymphocyte of any preceding claim, wherein the one or more maintenance factor(s) are operably linked to an inducible protein domain which functions to regulate activity of the one or more maintenance factor(s) in response to a signal; optionally wherein the signal is selected from a ligand and light.

25. The lymphocyte of claim 24, wherein the inducible protein domain functions to regulate the activity of the one or more maintenance factor(s) by inducing or preventing:(a) degradation of the one or more maintenance factor(s);(b) nuclear translocation of the one or more maintenance factor(s); and / or(c) DNA and / or co-factor binding by the one or more maintenance factor(s).

26. A composition comprising a population of lymphocytes of any preceding claim.

27. A composition comprising a vector for use in producing a lymphocyte of any of claims 1-25,wherein the vector comprises a nucleic acid sequence encoding one or more maintenance factor(s).

28. The composition of claim 27, wherein the vector is a viral vector, optionally a lentiviral vector, a retroviral vector, or an AAV vector.

29. The composition of claim 27, wherein the vector is a non-viral vector, optionally a lipid nanoparticles vector.

30. The composition of any of claims 26-29 for use in therapy.

31. The composition of any of claims 26-30 for use in a method of treating or preventing cancerin a patient.

32. The composition for use according to claim 31, wherein the cancer is selected from a haematological cancer and a solid cancer.

33. The composition for use according to claim 31 or claim 32, wherein the cancer is selected from a treatment-refractory or relapsed B cell malignancy, optionally wherein the cancer is selected from diffuse large B-cell lymphoma (DLBCL), B-cell acute lymphoblastic leukaemia (B-ALL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and multiple myeloma (MM).

34. The composition for use according to claim 32, wherein the cancer is a solid cancer selected from breast cancer, lung cancer, brain cancer, colorectal cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, cervical cancer, testicular cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, head and neck cancer, renal cancer, and gastric cancer.

35. The composition for use according to claim 32, wherein the cancer is a haematological cancer selected from Acute Myeloid Leukaemia (AML), Chronic Lymphocytic Leukaemia (CLL), Chronic Myelogenous Leukaemia (CML), Chronic Myelomonocytic Leukaemia (CMML) and Cutaneous T cell Lymphoma (CTCL36. The composition of any of claims 26-30 for use in a method of treating or preventing an autoimmune disease in a patient.

37. The composition for use according to claim 36, wherein the autoimmune disease is selected from rheumatoid arthritis, lupus erythematosus, multiple sclerosis, type I diabetes, coeliac disease, Crohn's disease, myasthenia gravis, Sjogren syndrome, Graves' disease, Behget's syndrome, and Asthma.

38. The composition for use according to any of claims 30-37, wherein the lymphocytes are derived from:(a) a sample obtained from the patient; and / or(b) a sample obtained from a donor.

39. The composition for use according to any of claims 30-38, wherein the method comprises administering the lymphocytes in combination with an RNA interference molecule for downregulating expression of the one or more maintenance factor(s).

40. The composition for use according to any of claims 30-39, wherein the one or more maintenance factor(s) is operably linked to an inducible protein domain which functions to regulate activity of the one or more maintenance factor(s) in response to a signal, and wherein the method comprises administering the signal to the patient; optionally wherein the signal is selected from a ligand and light.

41. A method of determining whether a lymphocyte which has been genetically engineered to overexpress one or more maintenance factor(s) expresses a therapeutically effective amount of said one or more maintenance factor(s), the method comprising:(a) comparing the sternness of the genetically engineered lymphocyte to the sternness of a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s);(b) comparing the level of one or more effector functions in response to immune stimulation of the genetically engineered lymphocyte to the level of one or more effector functions of a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s); and(c) determining whether the genetically engineered lymphocyte expresses a therapeutically effective amount of said one or more maintenance factor(s) based on steps (a) and (b).

42. A method for producing a lymphocyte expressing a therapeutically effective amount of one or more maintenance factor(s), the method comprising:(a) genetically engineering a lymphocyte to overexpress said one or more maintenance factor(s);(b) comparing the sternness of the genetically engineered lymphocyte to the sternness of a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s);(c) comparing the level of one or more effector functions in response to immune stimulation of the genetically engineered lymphocyte to the level of one or more effector functions of a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s); and(d) selecting a lymphocyte which exhibits:(i) enhanced sternness compared to the corresponding lymphocyte; and(ii) a comparable or greater level of one or more effector functions in response to immune stimulation compared to the corresponding lymphocyte.

43. The method of claim 41 or claim 42, wherein the method further comprises comparing the level of proliferation of the genetically engineered lymphocyte to the level of proliferation of a corresponding lymphocyte which is not engineered to overexpress said one or more maintenance factor(s).

44. The method of any of claims 41-43, wherein the immune stimulation comprises:(a) exposing the lymphocyte to an antigen; and / or(b) exposing the lymphocyte to one or more cytokines and / or chemokines configured to induce activation of effector function by the lymphocyte.

45. The method of claim 44, wherein exposing the lymphocyte to one or more cytokines and / or chemokines comprises exposing the lymphocyte to CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CX3CL1, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, IL-la, IL-ip, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-39, IL-40, IL-41, IFNa, IFNp, IFNy, TGFp, TNF, TNFp, XCL1, and XCL2.

46. The method of any of claims 41-45, wherein the one or more effector functions comprises the production of one or more effector molecules, optionally wherein the one or more effector molecules comprises one or more effector cytokines, optionally selected from IFN-y, TNF, IL-2, Granzyme-B, Perforin, and CD103.

47. The method of any of claims 41-46, wherein said one or more maintenance factor(s) are selected from one or more of BACH2, ID3, F0X01, TCF1, EGR2, MYB, EOMES, BCL6, STAT3, ZEB1, LEF1, F0XP1, KLF2, SATB1, FLU, RUNX2, RUNX3, S0X4, BHLHE40, KMT2A, SMARCA4, JUN, STAT5A, STAT5B, and S0CS1.

48. The method of any of claims 41-47, wherein the lymphocyte is selected from a T cell, a natural killer (NK) cell, a B cell, an innate lymphoid cell (ILC), and a tumour-infiltrating lymphocyte (TIL).

49. The method of claim 48, wherein the T cell is selected from a CD8+ T cell, a CD4+ T cell and a gamma-delta T cell, optionally wherein the CD4+ T cell is selected from a regulatory T (Treg) cell, a T helper (Th) 1 cell, a Th2 cell, a Thl7 cell, a Follicular Helper T (Tfh) cell, and a Th9 cell.

50. The method of any of claims 41-49, wherein the lymphocyte is engineered to express a chimeric antigen receptor (CAR), T cell receptor (TCR), an antibody-TCR, a TCR-based CAR, a T cell antigen coupler (TAC), a synthetic T cell receptor and antigen receptor (STAR), and / or a TCR fusion construct (TRuC).

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