Gene therapy

Abstract

A product comprising: (a) a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte comprising a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine; and (b) a T cell or NK cell, wherein the T cell or NK cell expresses an orthogonal receptor.

Description

[0001]GENE THERAPY FIELD OF THE INVENTION The present invention relates to products comprising a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte comprising a vector that expresses a cytokine, and a T cell or NK cell, wherein the T cell or NK cell expresses a cytokine receptor, and methods for the use thereof, for example in the treatment and prevention of cancer. BACKGROUND TO THE INVENTION Adoptive cell therapy (ACT) with genetically modified T cell receptors (TCRs) or chimeric antigen receptor (CAR)-transduced T cells (CARTs) has emerged as a promising immunotherapy strategy, for example against cancer. CARs are synthetic receptors that may comprise an extracellular antibody-like domain that recognises an antigen, such as a tumour- associated antigen (TAA), a hinge region, a transmembrane domain and one or more intracellular signaling domains. The efficacy of CARTs in clinical trials for hematological malignancies, especially of B cell origin, has already led to the approval of several treatments for B cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma and multiple myeloma. These advances promoted broader testing of CARTs for the treatment of solid tumours, which, however, has shown limited therapeutic potential in different clinical trials. A major hurdle for effective CART cell therapies in solid tumours is represented by the immunosuppressive tumour microenvironment (TME). As tumour cells co-evolve with their TME they interact through direct physical interaction or by local diffusion of soluble molecules leading to increased tumour cell survival and invasion, while at the same time, suppressing protective responses of immune effectors. Major roadblocks to CARTs in the TME that may need to be addressed to increase their efficacy are: (i) limited homing and trafficking into the tumour, (ii) limited persistence and local proliferation, and (iii) induced dysfunction and exhaustion. Cytokines with pleiotropic immune stimulatory activities might be used to counteract the immunosuppressive TME of solid tumours and support T cell function. This approach, however, is hampered by the severe toxicity associated with their systemic administration. To overcome this hurdle and deliver cytokines selectively at the tumour site advantage has previously been taken of a population of tumour-associated monocytes / macrophages expressing the TIE2 receptor (TEMs) that naturally infiltrating the TME to establish a tumour- targeted cytokine gene therapy strategy. Under this approach, hematopoietic stem cells (HSCs), for example, may be transduced with a lentiviral vector (LV) expressing the cytokine under positive regulation of the Tie2 enhancer / promoter and negative regulation of HSC- specific miRNAs recognising complementary target sequences in the vector (mirT) (De Palma et al. (2005) Cancer Cell 8: 211–226; Gentner et al. (2010) Sci. Transl. Med. 2: 58ra84- 58ra84). Among the cytokines that can potentiate ACT against solid tumours, interleukin-2 (IL-2) may play a major role given its action in promoting T cell proliferation, activation and function. For these reasons, IL-2 is used for ex vivo culture of CARTs, and it has also been applied in vivo to activate T cells in the TME of solid tumours. However, its use is severely constrained by both systemic, potentially lethal toxicities and its detrimental side activity in enhancing T regulatory cell (Treg) function. Orthogonal IL-2 cytokine / beta-receptor pairs (ortho-IL-2 / IL2Rβ) have been developed both in murine and human forms (Sockolosky et al. (2018) Science 359: 1037-1042; Aspuria et al. (2021) Sci. Transl. Med.13: eabg7565; Zhang et al. (2021) Sci. Transl. Med.13: eabg6986). Through the insertion of specific mutations both in IL-2 and IL-2Rβ receptor, the orthogonal pairs are endowed with the ability to bind preferentially to their mutant counterpart with limited to nearly abrogated cross-reactivity to the wild-type forms. However, systemic administration of ortho-IL-2 led to off-tumour activation of orthogonal CARTs and non-specific activation of the wild-type IL2Rβ causing toxicities spanning from weight loss to cytopenia and mice death. Accordingly, there remains a significant unmet need for effective immunotherapies, in particular therapies that enable CART-based treatments of cancers, particularly solid tumours. SUMMARY OF THE INVENTION The inventors have generated a TEM-related gene delivery platform coupled with CARTs expressing the ortho-IL2Rβ ^ and established a tumour-directed synthetic circuit for private and exogenously operated crosstalk to selectively enhance CART function within the TME of cancers such as glioblastoma multiforme (GBM), avoiding systemic side effects and counter regulatory responses. In particular, the inventors have developed a strategy for the safe and effective delivery of ortho-IL-2 and CARTs bearing the ortho-IL2Rβ to achieve improved anti-tumour activity. The ortho-IL-2 transgene is delivered, for example, by lentiviral vectors to HSCs under transcriptional control of Tie2 enhancer / promoter sequences and post-transcriptional negative regulation of HSC-specific miRNAs recognising complementary target sequences in the vector (e.g. miRT126 / 130). In this way, the TIE2-expressing myeloid progeny, preferentially recruited at tumour sites, release the ortho-IL-2 cytokine and locally activate adoptive T cells engineered to co-express a CAR and the ortho-IL2Rβ, which may be injected systemically and / or intratumourally. This approach avoids major toxicities observed with systemic, uncontrolled administration of the cytokine and allows full anti-tumour activity. The inventors have further developed the approach combining the use of an orthogonal cytokine and orthogonal cytokine receptor with the delivery of a second cytokine, for example IFNα. The combined use of the orthogonal cytokine and second cytokine further improved survival in a mouse model system. In one aspect, the invention provides a product comprising: (a) a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte comprising a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte- committed progenitor cell, wherein the transgene encodes an orthogonal cytokine; and (b) a T cell or NK cell, wherein the T cell or NK cell expresses an orthogonal receptor. In preferred embodiments, the T cell or NK cell is a T cell. In one aspect, the invention provides a product comprising: (a) a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte comprising a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte- committed progenitor cell, wherein the transgene encodes an orthogonal cytokine; and (b) a tumour associated antigen (TAA)-specific T cell, wherein the TAA-specific T cell expresses an orthogonal receptor. In some embodiments, the product is a composition or a kit. In one aspect, the invention provides a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte for use in therapy, wherein the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte- committed progenitor cell, wherein the transgene encodes an orthogonal cytokine, wherein the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte is used in combination with a T cell or NK cell, wherein the T cell or NK cell expresses an orthogonal receptor. In one aspect, the invention provides a T cell for use in therapy, wherein the T cell expresses an orthogonal receptor, wherein the T cell is used in combination with a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte, wherein the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine. In one aspect, the invention provides an NK cell for use in therapy, wherein the NK cell expresses an orthogonal receptor, wherein the NK cell is used in combination with a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte- committed progenitor cell, a macrophage or a monocyte, wherein the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine. In preferred embodiments, the therapy is treatment or prevention of cancer. In some embodiments, the therapy may be treatment of an autoimmune or inflammatory disorder, or cardiac fibrosis (e.g. following acute injury). In one aspect, the invention provides a method for treating or preventing cancer, comprising administering to a subject (a) a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte, wherein the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine; and (b) a T cell or NK cell, wherein the T cell or NK cell expresses an orthogonal receptor. The HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte may be, for example, administered simultaneously, sequentially or separately in combination with the T cell or NK cell. In one aspect, the invention provides a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte for use in treating or preventing cancer, wherein the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine, wherein the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte is used in combination with a tumour associated antigen (TAA)- specific T cell, wherein the TAA-specific T cell expresses an orthogonal receptor. In one aspect, the invention provides a tumour associated antigen (TAA)-specific T cell for use in treating or preventing cancer, wherein the TAA-specific T cell expresses an orthogonal receptor, wherein the TAA-specific T cell is used in combination with a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte, wherein the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine. In one aspect, the invention provides a method for treating or preventing cancer, comprising administering to a subject (a) a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte, wherein the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine; and (b) a tumour associated antigen (TAA)-specific T cell, wherein the TAA-specific T cell expresses an orthogonal receptor. The HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte may be, for example, administered simultaneously, sequentially or separately in combination with the TAA-specific T cell. In one aspect, the invention provides a product comprising: (a) a hematopoietic stem cell (HSC) comprising a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, wherein the transgene encodes an orthogonal cytokine; and (b) a T cell or NK cell, wherein the T cell or NK cell expresses an orthogonal receptor. In one aspect, the invention provides a hematopoietic stem cell (HSC) for use in therapy, wherein the HSC comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, wherein the transgene encodes an orthogonal cytokine, wherein the HSC is used in combination with a T cell or NK cell, wherein the T cell or NK cell expresses an orthogonal receptor. In preferred embodiments, the T cell or NK cell is a T cell. In one aspect, the invention provides a T cell for use in therapy, wherein the T cell expresses an orthogonal receptor, wherein the T cell is used in combination with a hematopoietic stem cell (HSC), wherein the HSC comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, wherein the transgene encodes an orthogonal cytokine. In one aspect, the invention provides an NK cell for use in therapy, wherein the NK cell expresses an orthogonal receptor, wherein the NK cell is used in combination with a hematopoietic stem cell (HSC), wherein the HSC comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, wherein the transgene encodes an orthogonal cytokine. In one aspect, the invention provides a method for treating or preventing cancer, comprising administering to a subject (a) a hematopoietic stem cell (HSC), wherein the HSC comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, wherein the transgene encodes an orthogonal cytokine; and (b) a T cell or NK cell, wherein the T cell or NK cell expresses an orthogonal receptor. The HSC may be, for example, administered simultaneously, sequentially or separately in combination with the T cell or NK cell. In one aspect, the invention provides a product comprising: (a) a hematopoietic stem cell (HSC) comprising a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, wherein the transgene encodes an orthogonal cytokine; and (b) a tumour associated antigen (TAA)-specific T cell, wherein the TAA-specific T cell expresses an orthogonal receptor. In one aspect, the invention provides a hematopoietic stem cell (HSC) for use in treating or preventing cancer, wherein the HSC comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, wherein the transgene encodes an orthogonal cytokine, wherein the HSC is used in combination with a tumour associated antigen (TAA)-specific T cell, wherein the TAA-specific T cell expresses an orthogonal receptor. In one aspect, the invention provides a tumour associated antigen (TAA)-specific T cell for use in treating or preventing cancer, wherein the TAA-specific T cell expresses an orthogonal receptor, wherein the TAA-specific T cell is used in combination with a hematopoietic stem cell (HSC), wherein the HSC comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, wherein the transgene encodes an orthogonal cytokine. In one aspect, the invention provides a method for treating or preventing cancer, comprising administering to a subject (a) a hematopoietic stem cell (HSC), wherein the HSC comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, wherein the transgene encodes an orthogonal cytokine; and (b) a tumour associated antigen (TAA)-specific T cell, wherein the TAA-specific T cell expresses an orthogonal receptor. The HSC may be, for example, administered simultaneously, sequentially or separately in combination with the TAA-specific T cell. In one aspect, the invention provides a product comprising: (a) a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC) or a myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine; and (b) a T cell or NK cell, wherein the T cell or NK cell expresses an orthogonal receptor. In one aspect, the invention provides a vector for use in therapy, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC) or a myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine, wherein the vector is used in combination with a T cell or NK cell, wherein the T cell or NK cell expresses an orthogonal receptor. In one aspect, the invention provides a T cell for use in therapy, wherein the T cell expresses an orthogonal receptor, wherein the T cell is used in combination with a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC) or a myeloid / monocyte- committed progenitor cell, wherein the transgene encodes an orthogonal cytokine. In one aspect, the invention provides an NK cell for use in therapy, wherein the NK cell expresses an orthogonal receptor, wherein the NK cell is used in combination with a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC) or a myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine. In one aspect, the invention provides a method for treating or preventing cancer, comprising administering to a subject (a) a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC) or a myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine; and (b) a T cell or NK cell, wherein the T cell or NK cell expresses an orthogonal receptor. The vector may be, for example, administered simultaneously, sequentially or separately in combination with the T cell or NK cell. In one aspect, the invention provides a product comprising: (a) a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC) or a myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine; and (b) a tumour associated antigen (TAA)-specific T cell, wherein the TAA-specific T cell expresses an orthogonal receptor. In one aspect, the invention provides a vector for use in treating or preventing cancer, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC) or a myeloid / monocyte- committed progenitor cell, wherein the transgene encodes an orthogonal cytokine, wherein the vector is used in combination with a tumour associated antigen (TAA)-specific T cell, wherein the TAA-specific T cell expresses an orthogonal receptor. In one aspect, the invention provides a tumour associated antigen (TAA)-specific T cell for use in treating or preventing cancer, wherein the TAA-specific T cell expresses an orthogonal receptor, wherein the TAA-specific T cell is used in combination with a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC) or a myeloid / monocyte- committed progenitor cell, wherein the transgene encodes an orthogonal cytokine. In one aspect, the invention provides a method for treating or preventing cancer, comprising administering to a subject (a) a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC) or a myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine; and (b) a tumour associated antigen (TAA)-specific T cell, wherein the TAA-specific T cell expresses an orthogonal receptor. The vector may be, for example, administered simultaneously, sequentially or separately in combination with the TAA-specific T cell. In some embodiments, the orthogonal cytokine substantially does not bind to its native receptor. In some embodiments, the orthogonal cytokine binds to and activates the orthogonal receptor. In some embodiments, the orthogonal receptor substantially does not bind to its native ligand. In some embodiments, the orthogonal cytokine does not bind to its native receptor. In some embodiments, the orthogonal cytokine binds to and activates the orthogonal receptor. In some embodiments, the orthogonal receptor does not bind to its native ligand. In some embodiments, the orthogonal cytokine substantially does not bind to its native receptor; the orthogonal cytokine binds to and activates the orthogonal receptor; and the orthogonal receptor substantially does not bind to its native ligand. In some embodiments, the orthogonal cytokine does not bind to its native receptor; the orthogonal cytokine binds to and activates the orthogonal receptor; and the orthogonal receptor does not bind to its native ligand. In some embodiments, the orthogonal receptor is an IL-2 receptor or an IL-9 receptor. In preferred embodiments, the orthogonal receptor is an IL-2 receptor. In some embodiments, the orthogonal receptor is an IL-9 receptor. In some embodiments, the orthogonal receptor is an IL2Rβ. In some embodiments, the orthogonal cytokine is an IL-2, IL-15 or IL-9. In some embodiments, the orthogonal cytokine is an IL-2 or IL-15. In preferred embodiments, the orthogonal cytokine is an IL-2. In preferred embodiments, the orthogonal receptor is an IL-2 receptor (e.g. IL2Rβ) and the orthogonal cytokine is an IL-2. In some embodiments, the orthogonal receptor is human IL2Rβ modified at H133 and / or Y134, wherein the amino acids are numbered with reference to SEQ ID NO: 2. In some embodiments, the orthogonal receptor is human IL2Rβ modified at H133 and Y134, wherein the amino acids are numbered with reference to SEQ ID NO: 2. In some embodiments, the orthogonal receptor is human IL2Rβ comprising: (a) a D at the position corresponding to amino acid 133; and / or (b) an F at the position corresponding to amino acid 134, wherein the amino acids are numbered with reference to SEQ ID NO: 2. In some embodiments, the orthogonal receptor is human IL2Rβ comprising: (a) a D at the position corresponding to amino acid 133; and (b) an F at the position corresponding to amino acid 134, wherein the amino acids are numbered with reference to SEQ ID NO: 2. In some embodiments, the orthogonal receptor comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5, and comprises: (a) a D at the position corresponding to amino acid 133; and / or (b) an F at the position corresponding to amino acid 134, wherein the amino acids are numbered with reference to SEQ ID NO: 5. In some embodiments, the orthogonal receptor comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5, and comprises: (a) a D at the position corresponding to amino acid 133; and (b) an F at the position corresponding to amino acid 134, wherein the amino acids are numbered with reference to SEQ ID NO: 5. In some embodiments, the orthogonal cytokine is human IL-2 modified at Q13, L14, E15, H16, L19, D20, Q22, M23, G27, R81 and / or N88, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 modified at H16, L19, D20, Q22, M23 and / or G27, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 modified at H16, L19, D20, Q22, M23 and G27, wherein the amino acids are numbered with reference to SEQ ID NO: 1. The modification may be, for example, amino acid substitution. In some embodiments, the orthogonal cytokine is human IL-2 with one or more of the following amino acid substitutions: E15S, E15T, E15Q, or E15H; H16Q; L19V, or L19I; D20T, D20S, D20M, or D20L; Q22K, or Q22N; and / or M23L, M23S, M23V, or M23T, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations E15S, H16Q, L19V, D20T, Q22K, and M23L wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations E15S, H16Q, L19V, D20S, Q22K, and M23L wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations E15S, H16Q, L19V, D20M, Q22K, and M23L wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations E15S, H16Q, L19V, D20T, Q22K, and M23S wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations E15S, H16Q, L19V, D20S, Q22K, and M23S wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations E15S, H16Q, L19V, D20M, Q22K, and M23S wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations: E15S, H16Q, L19V, D20L, and M23Q, and optionally Q22K, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations: E15S, H16Q, L19V, D20L, and M23A, and optionally Q22K, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 with one or more of the following sets of amino acid substitutions: [E15S; H16Q; L19V, D20T; Q22K, M23L]; [E15S; H16Q; L19V, D20T; Q22K, M23S]; [E15S; H16Q; L19V, D20S; Q22K, M23L]; [E15S; H16Q; L19V, D20S; Q22K, M23S]; [E15S; H16Q; L19I; D20S; Q22K; M23L]; [E15S; L19V; D20M; Q22K; M23S]; [E15T; H16Q; L19V; D20S; M23S]; [E15Q; L19V; D20M; Q22K; M23S]; [E15Q; H16Q; L19V; D20T; Q22K; M23V]; [E15H; H16Q; L19I; D20S; Q22K; M23L]; [E15H; H16Q; L19I; D20L; Q22K; M23T]; [L19V; D20M; Q22N; M23S]; [E15S, H16Q, L19V, D20L, M23Q, R81D, T51I], [E15S, H16Q, L19V, D20L, M23Q, R81Y], [E15S, H16Q, L19V, D20L, Q22K, M23A], [E15S, H16Q, L19V, D20L, M23A], wherein the amino acids are numbered with reference to mature peptide in SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 comprising: (a) a N at the position corresponding to amino acid 16; (b) a V at the position corresponding to amino acid 19; (c) an L at the position corresponding to amino acid 20; (d) a T at the position corresponding to amino acid 22; (e) an H at the position corresponding to amino acid 23; and / or (f) a K at the position corresponding to amino acid 27, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 comprising: (a) a N at the position corresponding to amino acid 16; (b) a V at the position corresponding to amino acid 19; (c) an L at the position corresponding to amino acid 20; (d) a T at the position corresponding to amino acid 22; (e) an H at the position corresponding to amino acid 23; and (f) a K at the position corresponding to amino acid 27, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6, and comprises: (a) a N at the position corresponding to amino acid 16; (b) a V at the position corresponding to amino acid 19; (c) an L at the position corresponding to amino acid 20; (d) a T at the position corresponding to amino acid 22; (e) an H at the position corresponding to amino acid 23; and / or (f) a K at the position corresponding to amino acid 27, wherein the amino acids are numbered with reference to SEQ ID NO: 6. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6, and comprises: (a) a N at the position corresponding to amino acid 16; (b) a V at the position corresponding to amino acid 19; (c) an L at the position corresponding to amino acid 20; (d) a T at the position corresponding to amino acid 22; (e) an H at the position corresponding to amino acid 23; and (f) a K at the position corresponding to amino acid 27, wherein the amino acids are numbered with reference to SEQ ID NO: 6. In some embodiments, the orthogonal cytokine is human IL-2 modified at E15, H16, L19, D20, Q22 and / or M23, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 modified at E15, H16, L19, D20, Q22 and M23, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 comprising: (a) a D at the position corresponding to amino acid 15; (b) a N at the position corresponding to amino acid 16; (c) an V at the position corresponding to amino acid 19; (d) a L at the position corresponding to amino acid 20; (e) a K at the position corresponding to amino acid 22; and / or (f) an A at the position corresponding to amino acid 23, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL- 2 comprising: (a) a D at the position corresponding to amino acid 15; (b) a N at the position corresponding to amino acid 16; (c) an V at the position corresponding to amino acid 19; (d) a L at the position corresponding to amino acid 20; (e) a K at the position corresponding to amino acid 22; and (f) an A at the position corresponding to amino acid 23, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7, and comprises: (a) a D at the position corresponding to amino acid 15; (b) a N at the position corresponding to amino acid 16; (c) an V at the position corresponding to amino acid 19; (d) a L at the position corresponding to amino acid 20; (e) a K at the position corresponding to amino acid 22; and / or (f) an A at the position corresponding to amino acid 23, wherein the amino acids are numbered with reference to SEQ ID NO: 7. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7, and comprises: (a) a D at the position corresponding to amino acid 15; (b) a N at the position corresponding to amino acid 16; (c) an V at the position corresponding to amino acid 19; (d) a L at the position corresponding to amino acid 20; (e) a K at the position corresponding to amino acid 22; and (f) an A at the position corresponding to amino acid 23, wherein the amino acids are numbered with reference to SEQ ID NO: 7. In some embodiments, the orthogonal receptor is mouse IL2Rβ modified at H134 and / or Y135, wherein the amino acids are numbered with reference to SEQ ID NO: 4. In some embodiments, the orthogonal receptor is mouse IL2Rβ modified at H134 and Y135, wherein the amino acids are numbered with reference to SEQ ID NO: 4. In some embodiments, the orthogonal receptor is mouse IL2Rβ comprising: (a) a D at the position corresponding to amino acid 134; and / or (b) an F at the position corresponding to amino acid 135, wherein the amino acids are numbered with reference to SEQ ID NO: 4. In some embodiments, the orthogonal receptor is mouse IL2Rβ comprising: (a) a D at the position corresponding to amino acid 134; and (b) an F at the position corresponding to amino acid 135, wherein the amino acids are numbered with reference to SEQ ID NO: 4. In some embodiments, the orthogonal receptor comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 8, and comprises: (a) a D at the position corresponding to amino acid 134; and / or (b) an F at the position corresponding to amino acid 135, wherein the amino acids are numbered with reference to SEQ ID NO: 8. In some embodiments, the orthogonal receptor comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 8, and comprises: (a) a D at the position corresponding to amino acid 134; and (b) an F at the position corresponding to amino acid 135, wherein the amino acids are numbered with reference to SEQ ID NO: 8. In some embodiments, the orthogonal cytokine is mouse IL-2 modified at Q30, M33, D34, Q36, E37 and / or R41, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine is mouse IL-2 modified at Q30, M33, D34, Q36, E37 and R41, wherein the amino acids are numbered with reference to SEQ ID NO: 3 In some embodiments, the orthogonal cytokine is mouse IL-2 comprising: (a) a N at the position corresponding to amino acid 30; (b) a V at the position corresponding to amino acid 33; (c) an L at the position corresponding to amino acid 34; (d) a T at the position corresponding to amino acid 36; (e) an H at the position corresponding to amino acid 37; and / or (f) a K at the position corresponding to amino acid 41, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine is mouse IL-2 comprising: (a) a N at the position corresponding to amino acid 30; (b) a V at the position corresponding to amino acid 33; (c) an L at the position corresponding to amino acid 34; (d) a T at the position corresponding to amino acid 36; (e) an H at the position corresponding to amino acid 37; and (f) a K at the position corresponding to amino acid 41, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 9, and comprises: (a) a N at the position corresponding to amino acid 30; (b) a V at the position corresponding to amino acid 33; (c) an L at the position corresponding to amino acid 34; (d) a T at the position corresponding to amino acid 36; (e) an H at the position corresponding to amino acid 37; and / or (f) a K at the position corresponding to amino acid 41, wherein the amino acids are numbered with reference to SEQ ID NO: 9. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 9, and comprises: (a) a N at the position corresponding to amino acid 30; (b) a V at the position corresponding to amino acid 33; (c) an L at the position corresponding to amino acid 34; (d) a T at the position corresponding to amino acid 36; (e) an H at the position corresponding to amino acid 37; and (f) a K at the position corresponding to amino acid 41, wherein the amino acids are numbered with reference to SEQ ID NO: 9. In some embodiments, the orthogonal cytokine is mouse IL-2 modified at E29, Q30, M33, D34, Q36 and / or E37, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine is mouse IL-2 modified at E29, Q30, M33, D34, Q36 and E37, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine is mouse IL-2 comprising: (a) a D at the position corresponding to amino acid 29; (b) a N at the position corresponding to amino acid 30; (c) an V at the position corresponding to amino acid 33; (d) a L at the position corresponding to amino acid 34; (e) a K at the position corresponding to amino acid 36; and / or (f) an A at the position corresponding to amino acid 37, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine is mouse IL- 2 comprising: (a) a D at the position corresponding to amino acid 29; (b) a N at the position corresponding to amino acid 30; (c) an V at the position corresponding to amino acid 33; (d) a L at the position corresponding to amino acid 34; (e) a K at the position corresponding to amino acid 36; and (f) an A at the position corresponding to amino acid 37, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 10, and comprises: (a) a D at the position corresponding to amino acid 29; (b) a N at the position corresponding to amino acid 30; (c) an V at the position corresponding to amino acid 33; (d) a L at the position corresponding to amino acid 34; (e) a K at the position corresponding to amino acid 36; and / or (f) an A at the position corresponding to amino acid 37, wherein the amino acids are numbered with reference to SEQ ID NO: 10. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 10, and comprises: (a) a D at the position corresponding to amino acid 29; (b) a N at the position corresponding to amino acid 30; (c) an V at the position corresponding to amino acid 33; (d) a L at the position corresponding to amino acid 34; (e) a K at the position corresponding to amino acid 36; and (f) an A at the position corresponding to amino acid 37, wherein the amino acids are numbered with reference to SEQ ID NO: 10. In some embodiments, the transgene further encodes a second cytokine. In some embodiments, the second cytokine is selected from the group consisting of IFNα, IL- 15, IL-9, IL-1β, IL-7, IL-12, IFNβ, IFNγ, TNFα, CXCL10 and CXCL9. In preferred embodiments, the second cytokine is IFNα. In some embodiments, the miRNA target sequence prevents or reduces expression of the transgene in HSCs. In some embodiments, the miRNA target sequence is a miR-130a and / or miR-126 target sequence. In some embodiments, the miRNA target sequence is a miR-130a target sequence. In some embodiments, the miRNA target sequence is a miR-126 target sequence. In some embodiments, the miRNA target sequence comprises at least one miR-130a target sequence and at least one miR-126 target sequence. In some embodiments, the miRNA target sequence comprises two miR-130a target sequences and two miR-126 target sequences. In some embodiments, the transgene is operably linked to a tissue-specific promoter. In some embodiments, the tissue-specific promoter is a TEK (Tie2) promoter. In some embodiments, the hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte is a HSC. In some embodiments, the vector is a viral vector. In preferred embodiments, the vector is a lentiviral vector. In some embodiments, the vector is a VSV-G pseudotyped lentiviral vector. In some embodiments, the T cell expresses a chimeric antigen receptor (CAR) and / or a transgenic T cell receptor (TCR). In preferred embodiments, the T cell expresses a chimeric antigen receptor (CAR). In some embodiments, the T cell expresses a transgenic T cell receptor (TCR). In some embodiments, the NK cell expresses a chimeric antigen receptor (CAR). In preferred embodiments, the T cell or NK cell is a CAR-T cell. In some embodiments, the TAA-specific T-cell expresses a chimeric antigen receptor (CAR) and / or a transgenic T cell receptor (TCR). In preferred embodiments, the TAA-specific T-cell expresses a chimeric antigen receptor (CAR). In some embodiments, the TAA-specific T-cell expresses a transgenic T cell receptor (TCR). In some embodiments, the TAA is selected from the group consisting of B7-H3, carcinoembryonic antigen (CEA), estrogen receptor, progesterone receptor, ephrinB2, ephrinA2, ROR1, mesothelin, c-Met, GD-2, MAGE A3 TCR, 4-1BB, adenocarcinoma antigen, alpha-fetoprotein, BAFF, B-lymphoma cell, C242 antigen, carbonic anhydrase 9 (CA-IX), CCR4, CD152, CD200, CD22, CD19, CD22, CD123, CD133, CD221, CD23 (IgE receptor), CD28, CD4, CD40, CD44, CD44 v6, CD51, CD52, CD56, CD74, CD80, CS-1, CNT0888, CTLA-4, DR5, EpCAM, CD3, fibronectin extra domain-B, folate receptor 1, glycoprotein 75, GPNMB, HGF, human scatter factor receptor kinase, IGF-1 receptor, IGF-I, IgGl, L1-CAM, IL- 13, IL-13 receptor α2, IL-6, insulin-like growth factor I receptor, integrin α5β1, integrin αvβ3, MORAb-009, MS4A1, mucin CanAg, N-glycolylneuraminic acid, NPC-1C, PDGF-Rα, PDL192, phosphatidylserine, prostatic carcinoma cells, RANKL, RON, SCH 900105, SDC1, SLAMF7, tenascin C, TGF beta 2, TGF-β, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, Vascular endothelial growth, factor (VEGF), VEGF-A, VEGFR-1, VEGFR2, vimentin, 5T4, CD5, CD19, CD20, CD21, CD25, CD37, CD30, CD33, CD45, CAMPATH-1 (CDw52), HLA-DR, Anti- idiotype, TAG-72, Ep-CAM, MUC1, Folate-binding protein, A33, G250, Prostate-specific membrane antigen, (PSMA), Prostate specific antigen (PSA), Ferritin, Gangliosides (e.g. GD2, GD3, GM2), Ley, CA-125, CA19-9, Epidermal growth factor receptor (EGFR), p185HER2, IL- 2 receptor, de2-7 EGFR, EGFR variant III, Fibroblast activation protein (FAP), Glypican 3 (GPC3), CSPG4, Tenascin, metalloproteinases, Endosialin, Carbonic anhydrase, Galectin 9, Aldolase A, eIFγ4, Tyrosinase, Galectin 4, HERKV-K10, p53, NY-LU-12, Restin, NY-CO-38, MAGE-1, MAGE-4a, SSX2, NY-ESO-1, SCP-1, 707-AP, AFP, ART-4, BAGE, b-catenin / m, Bcr-abl, CAMEL, CAP-1, CASP-8, CDC27m, CDK4 / m, CT, Cyp-B, DAM-6 (MAGE-B2) and DAM-10 (MAGE-B1), ELF2M, ETV6-AML1, G250, GAGE, GnT-V, Gp100, HAGE, HER-2 / neu, HLA-A*0201-R170I, HPV-E7, HSP70-2M, HST-2, hTERT (hTRT), iCE, KIAA0205, LAGE, LDLR / FUT, MAGE, MART-1 / Melan-A, MC1R, Myosin / m, MUC1, MUM-1, MUM-2, MUM-3, NA88-A, NY-ESO-1, P15, p190 minor bcr-abl, Pml / RARa, PRAME, RAGE, RU1, RU2, SAGE, SART-1, SART-3, TEL / AML1, TPI / m, TRP-1, protein 1, gp75, TRP-2, TRP-2 / INT2 and WT1. In some embodiments, the TAA is B7-H3. In some embodiments, the TAA-specific T-cell expresses a B7-H3-specific CAR. In some embodiments, the T cell or NK cell comprises a polynucleotide comprising a nucleotide sequence encoding the CAR and / or a polynucleotide comprising a nucleotide sequence encoding the transgenic TCR. In preferred embodiments, the T cell or NK cell comprises a polynucleotide comprising a nucleotide sequence encoding the CAR. In some embodiments, the T cell comprises a polynucleotide comprising a nucleotide sequence encoding the transgenic TCR. In some embodiments, the TAA-specific T-cell comprises a polynucleotide comprising a nucleotide sequence encoding the CAR and / or a polynucleotide comprising a nucleotide sequence encoding the transgenic TCR. In preferred embodiments, the TAA-specific T-cell comprises a polynucleotide comprising a nucleotide sequence encoding the CAR. In some embodiments, the TAA-specific T-cell comprises a polynucleotide comprising a nucleotide sequence encoding the transgenic TCR. In some embodiments, the nucleotide sequence encoding the CAR is operably linked to a promoter. In some embodiments, the promoter is a phosphoglycerate kinase (PGK) promoter. In some embodiments, the nucleotide sequence encoding the transgenic TCR is operably linked to a promoter. In some embodiments, the promoter is a phosphoglycerate kinase (PGK) promoter. In some embodiments, the T cell or NK cell (e.g. the TAA-specific T-cell) comprises a polynucleotide comprising a nucleotide sequence encoding the orthogonal receptor. In some embodiments, the nucleotide sequence encoding the orthogonal receptor is operably linked to a promoter. In some embodiments, the promoter is a CMV promoter. In some embodiments, the T cell or NK cell (e.g. the TAA-specific T cell) is derived from a cell isolated from a subject. In some embodiments, the T cell or NK cell (e.g. the TAA-specific T cell) is an adoptive T cell or NK cell (e.g. adoptive TAA-specific T cell). In some embodiments, the T cell or NK cell (e.g. the TAA-specific T cell) is autologous or allogeneic. In some embodiments, the T cell or NK cell (e.g. the TAA-specific T cell) is autologous. In some embodiments, the T cell or NK cell (e.g. the TAA-specific T cell) is allogeneic. In some embodiments, the T cell or NK cell (e.g. the TAA-specific T-cell) has been engineered to disrupt at least one endogenous gene. In some embodiments, the T cell or NK cell (e.g. the TAA-specific T-cell) has been engineered to disrupt at least one endogenous gene, wherein the at least one endogenous gene is selected from an endogenous gene encoding a TCR α chain, a TCR β chain and a major histocompatibility complex (MHC). In some embodiments, the cancer is a hematological malignancy or a solid tumour. In some embodiments, the cancer is a solid tumour. In some embodiments, the solid tumour is selected from the group consisting of glioblastoma, malignant CNS tumor, lung cancer, breast cancer, oesophageal cancer, gastric cancer, colon cancer, cholangiocarcinoma, pancreatic cancer, ovarian cancer, head and neck cancers, synovial sarcoma, angiosarcoma, osteosarcoma, thyroid cancer, endometrial cancer, neuroblastoma, rabdomyosarcoma, liver cancer, melanoma, prostate cancer, renal cancer, soft tissue sarcoma, urothelial cancer, biliary cancer, cervical cancer, colorectal cancer, and non-melanoma skin cancer. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the hematological malignancy is selected from the group consisting of acute myeloid leukemia (AML), lymphoblastic leukemia, acute lymphoblastic leukemia (ALL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), primary myelofibrosis, essential thrombocythemia, polycythemia vera, atypical chronic myeloid leukemia, chronic myeloid leukemia (CML), chronic lymphoid leukemia (CLL), lymphoma, multiple myeloma, non Hodgkin lymphoma and Hodgkin lymphoma. In some embodiments, the cancer is a metastasis from a primary tumor. In some embodiments, the T cell or NK cell (e.g. the TAA-specific T cell) is administered to a subject systemically and / or intratumourally. In some embodiments, the T cell or NK cell (e.g. the TAA-specific T cell) is administered to a subject in a first administration and a second administration; wherein the first administration is a systemic administration and the second administration is an intratumoural administration. In one aspect, the invention provides a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte comprising a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine. In one aspect, the invention provides a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in a HSC, HPC and / or myeloid / monocyte- committed progenitor cell, wherein the transgene encodes an orthogonal cytokine. DESCRIPTION OF THE DRAWINGS Figure 1 Tumour-specific orthogonal IL-2 delivery is well tolerated and potentiates CARB7H3T cells in an in vivo model. A. Schematic representation of CARB7H3 / CARhCD19-orthoIL2Rβ BdLV constructs. B. Flow cytometry evaluation of B7-H3 expression by GL261-Luc cells. C. Schematic representation of experiment. B6 albino mice were orthotopically injected with glioma cells (luciferase-expressing GL261, GL261-Luc) unmodified (WT) or expressing ortho- IL-2 1G12 (SEQ ID NO: 9) / 3A10 (SEQ ID NO: 10). Tumour growth was monitored by bioluminescence imaging. D. In vivo bioluminescence imaging of mice from C expressing tumour growth as total flux of photons per second (Kruskal-Wallis test with post-hoc Dunn’s analysis at last timepoint, * 1G12 vs wt p=0.0140; 1G12 vs 3A10 p=0.0301). E. Experimental outline for ortho-pair evaluation in vivo. B6 albino mice were orthotopically injected with GL261-Luc expressing ortho-IL-21G12. After 4 days, CARhCD19 or CARB7H3 T cells, with or without ortho-IL2Rβ (oRec, SEQ ID NO: 8) were injected intratumourally. Tumour growth was monitored by bioluminescence imaging. F. In vivo bioluminescence imaging of mice from D expressing tumour growth as total flux of photons per second (LLOD, lower limit of detection – grey box). Figure 2 Orthogonal IL-2 can be delivered with Tie2-based gene therapy without toxicities. A. Schematic representation of Tie2-orthoIL2-miRT and HSC transplant outline. B-M. Peripheral blood analyses at reconstitution (8 weeks) of mice transplanted with Empty or orthoIL-2 LV: engraftment of donor cells in total CD45+ cells (B) and percent variation of body weight from baseline (C), VCN on nucleated blood cells (D), IL-2 plasma concentration measured by ELISA (E), hemoglobin concentration (HGB), absolute counts of platelet (PLT) (G), white blood cells (WBC) (H), B cells (I), CD11b+ myeloid cells (J), T cells (K), CD4 T cells (L), and CD8 T cells (M). (Mann-Whitney test). Figure 3 Orthogonal IL-2 gene therapy improves activation of tumour-infiltrating orthogonal CAR T cells. A. Experimental outline. HSCs, transduced with empty or Tie2-ortho-IL2-mirT (oIL2) LVs, were transplanted and mGB2 cells injected orthotopically in the striatum. Mice received either CARhCD19or CARB7H3T cells with ortho-IL2Rβ (orthoCAR), intra-tumour. Mice were followed by MRI and euthanised for tumour infiltrate analysis at day 44. B. Tumour burden evaluation by MRI 42 days after tumour injection. C. Weight changes of mice 40 days after tumour challenge compared to baseline. D. Counts of adoptive T cells normalised on tumour weights. E. CD4 / CD8 composition of adoptive T cells in the tumour infiltrate. F-G. Percentage of Granzyme-B expressing CD4 (F) and CD8 (G) adoptive T cells. H. Percentage of PD-1 / LAG-3 co-expressing CD8 adoptive T cells. (Kruskal-Wallis test with post-hoc Dunn’s analysis) Figure 4 Endogenous tumour-infiltrating T cells are not impacted by orthogonal IL-2 gene therapy. A. Counts of endogenous T cells normalised on tumour weights. B. CD4 / CD8 composition of endogenous T cells in the tumour infiltrate of mice from Fig.3. C-D. Percentage of CD4 / CD25 (C) and CD4 / FoxP3 (D) co-expressing endogenous T cells. E. Percentage of B7-H3 expression on tumour cells (GFP+). (Kruskal-Wallis test with post-hoc Dunn’s analysis). Figure 5 TEM-mediated orthogonal IL-2 gene therapy combined to orthoCARB7H3 T cells inhibits tumour growth and prolongs survival. A. Experimental outline. HSC transplantation and mGB2 cells injection were performed as in Fig.3. B. Tumour burden evaluated by MRI 29 and 44 days after tumour injection in Empty and oIL-2 mice receiving intra-tumour CARB7H3 or orthoCARB7H3 T cells (Kruskal-Wallis test with post-hoc Dunn’s analysis at each time-point). C. Kaplan-Meier survival curves of the four experimental groups of mice (log-rank Mantel-Cox test with Bonferroni correction). D. Individual tumour burden changes from day 29 to 44 after tumour injections and relative median variation (Δ) of the four experimental groups of mice (Wilcoxon matched-pairs signed rank test). Figure 6 Double-route CAR T-cell administration achieves better anti-tumour activity. A. Experimental outline. HSC transplantation and mGB2 cells injection were performed as in Fig. 3. Empty mice received either CARhCD19 or CARB7H3 T cell intravenously (upon cyclophosphamide -CPA- conditioning) and, 12 days later, intratumourally. Mice were followed by MRI. B. Tumour burden evaluated by MRI 40 and 57 days after tumour injection (Mann- Whitney test at each time-point). C. Kaplan-Meier survival curves of the two experimental groups of mice (log-rank Mantel-Cox test). Figure 7 Orthogonal IL-2 gene therapy confers superior anti-tumour activity to double-route injected CAR T cells without signs of toxicities. A. Experimental outline. HSC transplantation, mGB2 cells injection and adoptive T cell transfer were performed as in Fig.6. B. Weight changes 42 days after tumour challenge compared to baseline. C. Tumour burden evaluation by MRI 45 days after tumour injection (Mann-Whitney test). C. Kaplan-Meier survival curves of the two experimental groups of mice (log-rank Mantel-Cox test). Figure 8 oIL2 and IFN-α codelivery does not impair hematopoietic reconstitution upon HSC transplant. A. Schematic representation of the Tie2-Ifna-P2A-oIL2-miRT LV. B. IFN-α and IL- 2 concentrations in the supernatants, normalized per VCN, of bEnd.3 cells transduced with Empty, Tie2-Ifna, Tie2-oIL2 or Tie2-Ifna-P2A-oIL2 LVs. C-E. Analyses at hematopoietic reconstitution of mice transplanted with HSCs transduced with Empty, Tie2-Ifna-miRT (IFN), Tie2-oIL2-miRT (oIL2) or Tie2-Ifna-P2A-oIL2-miRT (IFN+oIL2). The following data are reported: IFN-α and IL-2 plasma concentration measured by ELISA (C), VCN of total HIV sequences in PB nucleated cells (D), engraftment of donor cells in total CD45+cells (E), hemoglobin concentration (F), absolute counts of WBC (G), platelets (H), B cells (I), T cells (J), myeloid cells (K). Figure 9 Tumor-targeted IFN-α and oIL2 co-delivery potentiate CAR-Ts to achieve superior therapeutic efficacy. A. Experimental outline for treatment efficacy evaluation and systemic T-cell immune-phenotype analysis. B-C. Tumor burden assessment by MRI 44 days after tumor injection (B) and Kaplan-Meier survival curves of mGB2-bearing mice from the different treatment groups (C) (n=9, 9, 5 and 9 mice in Empty+oCARB7H3, IFN+oCARB7H3, oIL2+oCARB7H3, IFN+oIL2+oCARB7H3 groups, respectively; Kruskal-Wallis test with post-hoc Dunn’s analysis in B; Log-rank Mantel-Cox test in C). Figure 10 Rewiring of adoptive and endogenous T cells upon targeted cytokine delivery promotes anti-tumor effector function. A, C. Balloon plots showing the expression (frequency, Freq) and the median fluorescent intensity (MFI) of specific markers (columns) in discrete PhenoGraph clusters (rows) of adoptively transferred (A) and endogenous T cells (C) from multiple organs as indicated in Fig. 9A. Unbiased hierarchical meta clustering grouped markers with similar immune-phenotypes. B, D. PhenoGraph cluster frequencies (%) of adoptive (B) and endogenous (D) T cells across treatments in specified tissues. Each dot represents a mouse (n=4 Empty, n=5 IFN, n=5 oIL2, n=5 IFN+oIL2). E. IFN-γ spot forming unit (SFU) per million of CD3+PBMCs (from n=5 Empty, n=7 IFN, n=5 oIL2, n=4 IFN+oIL2 mice) cultured on either wt or B7-H3- mGB2 cells as feeders. DETAILED DESCRIPTION OF THE INVENTION The terms “comprising”, “comprises” and “comprised of” as used herein are synonymous with “including” or “includes”; or “containing” or “contains”, and are inclusive or open-ended and do not exclude additional, non-recited members, elements or steps. The terms “comprising”, “comprises” and “comprised of” also include the term “consisting of”. CELLS A stem cell is able to differentiate into many cell types. A cell that is able to differentiate into all cell types is known as totipotent. In mammals, only the zygote and early embryonic cells are totipotent. Stem cells are found in most, if not all, multicellular organisms. They are characterised by the ability to renew themselves through mitotic cell division and differentiate into a diverse range of specialised cell types. The two broad types of mammalian stem cells are embryonic stem cells that are isolated from the inner cell mass of blastocysts, and adult stem cells that are found in adult tissues. In a developing embryo, stem cells can differentiate into all of the specialised embryonic tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing specialised cells, but also maintaining the normal turnover of regenerative organs, such as blood, skin or intestinal tissues. Haematopoietic stem cells (HSCs) are multipotent stem cells that may be found, for example, in peripheral blood, bone marrow and umbilical cord blood. HSCs are capable of self-renewal and differentiation into any blood cell lineage. They are capable of recolonising the entire immune system, and the erythroid and myeloid lineages in all the haematopoietic tissues (such as bone marrow, spleen and thymus). They provide for life-long production of all lineages of haematopoietic cells. Haematopoietic progenitor cells (HPCs) have the capacity to differentiate into a specific type of cell. In contrast to stem cells however, they are already far more specific: they are pushed to differentiate into their “target” cell. A difference between HSCs and HPCs is that HSCs can replicate indefinitely, whereas HPCs can only divide a limited number of times. In one embodiment, the present invention may use a mixed population of cells comprising HSCs and HPCs (e.g. a HSPC population). A differentiated cell is a cell which has become more specialised in comparison to a stem cell or progenitor cell. Differentiation occurs during the development of a multicellular organism as the organism changes from a single zygote to a complex system of tissues and cell types. Differentiation is also a common process in adults: adult stem cells divide and create fully- differentiated daughter cells during tissue repair and normal cell turnover. Differentiation dramatically changes a cell’s size, shape, membrane potential, metabolic activity and responsiveness to signals. These changes are largely due to highly-controlled modifications in gene expression. In other words a differentiated cell is a cell which has specific structures and performs certain functions due to a developmental process which involves the activation and deactivation of specific genes. Here, a differentiated cell includes differentiated cells of the haematopoietic lineage such as monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes / platelets, dendritic cells, T-cells, B-cells and NK- cells. For example, differentiated cells of the haematopoietic lineage can be distinguished from HSCs and HPCs by detection of cell surface molecules which are not expressed or are expressed to a lesser degree on undifferentiated cells (HSCs and HPCs). Examples of suitable human lineage markers include CD33, CD13, CD14, CD15 (myeloid), CD19, CD20, CD22, CD79a (B), CD36, CD71, CD235a (erythroid), CD2, CD3, CD4, CD8 (T), CD56 (NK). Cell source In one embodiment, the HSC, the HPC, the myeloid / monocyte-committed progenitor cell, the macrophage or the monocyte used in the present invention is obtained from a tissue sample. For example, the HSC, the HPC, the myeloid / monocyte-committed progenitor cell, the macrophage or the monocyte can be obtained from adult and foetal peripheral blood, umbilical cord blood, bone marrow, liver or spleen. Preferably, these cells are obtained from peripheral blood or bone marrow. They may be obtained after mobilisation of the cells in vivo by means of growth factor treatment. Mobilisation of HSC or HPC may be carried out using, for example, G-CSF, plerixaphor or combinations thereof. Other agents, such as NSAIDs, CXCR2 ligands (Grobeta) and dipeptidyl peptidase inhibitors may also be useful as mobilising agents. With the availability of the stem cell growth factors GM-CSF and G-CSF, most haematopoietic stem cell transplantation procedures are now performed using stem cells collected from the peripheral blood, rather than from the bone marrow. Collecting peripheral blood stem cells provides a bigger graft, does not require that the donor be subjected to general anaesthesia to collect the graft, results in a shorter time to engraftment and may provide for a lower long- term relapse rate. Bone marrow may be collected by standard aspiration methods (either steady-state or after mobilisation), or by using next-generation harvesting tools. In addition, HSCs may also be derived from induced pluripotent stem cells. HSC characteristics HSCs are typically of low forward scatter and side scatter profile by flow cytometric procedures. Some are metabolically quiescent, as demonstrated by Rhodamine labelling which allows determination of mitochondrial activity. HSCs may comprise certain cell surface markers such as CD34, CD45, CD133, CD90 and CD49f. They may also be defined as cells lacking the expression of the CD38 and CD45RA cell surface markers. However, expression of some of these markers is dependent upon the developmental stage and tissue-specific context of the HSC. Some HSCs called “side population cells” exclude the Hoechst 33342 dye as detected by flow cytometry. Thus, HSCs have descriptive characteristics that allow for their identification and isolation. Negative markers CD38 is the most established and useful single negative marker for human HSCs. Human HSCs may also be negative for lineage markers such as CD2, CD3, CD14, CD16, CD19, CD20, CD24, CD36, CD56, CD66b, CD271 and CD45RA. However, these markers may need to be used in combination for HSC enrichment. By negative marker it is to be understood that human HSCs lack the expression of these markers. Positive markers CD34 and CD133 are the most useful positive markers for HSCs. Some HSCs are also positive for lineage markers such as CD90, CD49f and CD93. However, these markers may need to be used in combination for HSC enrichment. By positive marker it is to be understood that human HSCs express these markers. Accordingly, the therapeutic population of cells may be CD34+CD38-. Further separations may be carried out to obtain, for example, CD34+CD38-CD45RA-CD90+CD49f+cells. miRNA expression The expression of miRNAs miR-126 and miR-130a in a cell may indicate that the cell is a HSC or a HPC. More specifically, miR-126 expression may indicate that the cell is a primitive HPC. miR-130a expression may indicate that the cell is a more primitive HPC. CYTOKINES Cytokines are a category of small proteins, typically approximately 5–20 kDa in size, that play an important role in cell signalling. Cytokines may include interferons, chemokines, interleukins, lymphokines and tumour necrosis factors, and are produced by a broad range of cells, including macrophages, B lymphocytes, T lymphocytes, mast cells, endothelial cells and fibroblasts. Cytokines act through receptors, and have a particularly important role in the immune system, modulating the balance between humoral and cell-based immune responses. In some embodiments, the cytokine activates an immune response, for example activates an anti-tumour response. Exemplary cytokines include IL-2, IL-15 and IL-9. Further exemplary cytokines include IL-1β, IL-7, IL-12, IFNα, IFNβ, IFNγ, TNFα and CXCL9. Interleukins Interleukins are a group of cytokines that regulate the immune and inflammatory responses, and the majority are produced by helper CD4 T cells and other body cells such as monocytes, macrophages and endothelial cells. They have a function in the promotion of the development and differentiation of T and B lymphocytes, and hematopoietic cells. Interleukins mediate their activity through the binding of interleukin receptors. Interleukins utilise a common receptor signaling system that results in T cell activation and expansion. Exemplary interleukins include IL-2, IL-15, and IL-9, further exemplary interleukins include IL- 7, and IL-12. Interleukin-2 (IL-2) Interleukin-2 (IL-2) plays a role in the regulation of the activities of white blood cells that are responsible for immunity. IL-2 has activity in promoting T cell proliferation, activation and function. IL-2 mediates its effects by binding to IL-2 receptors (IL-2R), which are expressed on the surface of cells, for example lymphocytes. IL-2 binding to IL-2R induces Janus family kinase (JAK) activity and the phosphorylation and activation of STAT5 which can influence gene expression in cells. An example human wild type IL-2 amino acid sequence is: APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEE VLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 1) An example human wild type IL-2Rβ amino acid sequence is: AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQASWACNLILGAPD SQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLRLMAPISLQVVHVETHRCNISWEISQASHYFE RHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPLAFR TKPAALGKDTIPWLGHLLVGLSGAFGFIILVYLLINCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGG DVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFF FHLPDALEIEACQVYFTYDPYSEEDPDEGVAGAPTGSSPQPLQPLSGEDDAYCTFPSRDDLLLFSPSL LGGPSPPSTAPGGSGAGEERMPPSLQERVPRDWDPQPLGPPTPGVPDLVDFQPPPELVLREAGEEVPD AGPREGVSFPWSRPPGQGEFRALNARLPLNTDAYLSLQELQGQDPTHLV (SEQ ID NO: 2) An example mouse wild type IL-2 amino acid sequence is: APTSSSTSSSTAEAQQQQQQQQQQQQHLEQLLMDLQELLSRMENYRNLKLPRMLTFKFYLPKQATELK DLQCLEDELGPLRHVLDLTQSKSFQLEDAENFISNIRVTVVKLKGSDNTFECQFDDESATVVDFLRRW IAFCQSIISTSPQ (SEQ ID NO: 3) An example mouse wild type IL-2Rβ amino acid sequence is: AVKNCSHLECFYNSRANVSCMWSHEEALNVTTCHVHAKSNLRHWNKTCELTLVRQASWACNLILGSFP ESQSLTSVDLLDINVVCWEEKGWRRVKTCDFHPFDNLRLVAPHSLQVLHIDTQRCNISWKVSQVSHYI EPYLEFEARRRLLGHSWEDASVLSLKQRQQWLFLEMLIPSTSYEVQVRVKAQRNNTGTWSPWSQPLTF RTRPADPMKEILPMSWLRYLLLVLGCFSGFFSCVYILVKCRYLGPWLKTVLKCHIPDPSEFFSQLSSQ HGGDLQKWLSSPVPLSFFSPSGPAPEISPLEVLDGDSKAVQLLLLQKDSAPLPSPSGHSQASCFTNQG YFFFHLPNALEIESCQVYFTYDPCVEEEVEEDGSRLPEGSPHPPLLPLAGEQDDYCAFPPRDDLLLFS PSLSTPNTAYGGSRAPEERSPLSLHEGLPSLASRDLMGLQRPLERMPEGDGEGLSANSSGEQASVPEG NLHGQDQDRGQGPILTLNTDAYLSLQELQAQDSVHLI (SEQ ID NO: 4) Interleukin-15 (IL-15) Interleukin-15 (IL-15) has structural similarity to IL-2. IL-15 induces proliferation of natural killer cells. Interleukin-15 (IL-15) may bind to the IL-15 receptor (IL-15R) which comprises the IL-15β subunit which is common to the IL-15 receptor and the IL-2 receptor. Interleukin-9 (IL-9) Interleukin-9 (IL-9) has a role in various inflammatory processes and is associated with multiple inflammatory diseases. IL-9 may bind to the IL-9 receptor (IL-9R) to mediate its activity. Orthogonal cytokines / receptors As used herein, the terms “orthogonal cytokine” and “orthogonal receptor” refer to proteins that are modified by amino acid changes to exhibit (a) reduced binding (e.g. substantially lack or lack binding) to the native cognate receptor or cytokine, respectively; and (b) bind to the counterpart (orthogonal) ligand or receptor. Upon binding of the orthogonal cytokine, the orthogonal receptor activates signalling that is transduced through native cellular elements to provide for a biological activity that mimics its native response, but which is specific to the cell expressing the orthogonal receptor. The orthogonal receptor has reduced binding to (e.g. substantially lacks or lacks binding to) the endogenous counterpart cytokine, including the native counterpart of the orthogonal cytokine, while the orthogonal cytokine has reduced binding to (e.g. substantially lacks or lacks binding to) any endogenous receptors, including the native counterpart of the orthogonal receptor. The orthogonal cytokine may, for example, not activate signalling of any endogenous receptor. In some embodiments, the orthogonal cytokine has reduced binding to its native receptor compared to the wild type cytokine. In some embodiments, the orthogonal cytokine binds to and activates the orthogonal receptor. In some embodiments, the orthogonal receptor has reduced binding to its native ligand, compared to the wild type receptor. In some embodiments, the orthogonal cytokine has reduced binding to its native receptor compared to the wild type cytokine; the orthogonal cytokine binds to and activates the orthogonal receptor; and the orthogonal receptor has reduced binding to its native ligand, compared to the wild type receptor. Reduced binding may refer to binding affinity that is reduced by at least 50%, for example at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% compared to the biding affinity of the wild type cytokine and receptor. Methods for assessing binding affinity are well known to the skilled person. Preferably, binding is reduced to an extent that results in no detectable activation of the receptor. In some embodiments, the orthogonal cytokine substantially does not bind to its native receptor. In some embodiments, the orthogonal cytokine binds to and activates the orthogonal receptor. In some embodiments, the orthogonal receptor substantially does not bind to its native ligand. “Substantially does not bind” may refer to a level of binding between agents (e.g. proteins) that is insufficient to cause a biological effect, for example insufficient to activate one of the agents (e.g. a receptor). In some embodiments, the orthogonal cytokine does not bind to its native receptor. In some embodiments, the orthogonal cytokine binds to and activates the orthogonal receptor. In some embodiments, the orthogonal receptor does not bind to its native ligand. In some embodiments, the orthogonal cytokine substantially does not bind to its native receptor; the orthogonal cytokine binds to and activates the orthogonal receptor; and the orthogonal receptor substantially does not bind to its native ligand. In some embodiments, the orthogonal cytokine does not bind to its native receptor; the orthogonal cytokine binds to and activates the orthogonal receptor; and the orthogonal receptor does not bind to its native ligand. In some embodiments, the affinity of the orthogonal cytokine for the orthogonal receptor is comparable to the affinity of the native cytokine for the native receptor. In some embodiments, the affinity of the orthogonal cytokine for the orthogonal receptor is at least about 1% of the native cytokine receptor pair affinity, at least about 5%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 100%, and may be higher, for example 1.1x, 1.5x, 2x, 3x, 4x, 5x or 10x or more of the affinity of the native cytokine for the native receptor. In some embodiments, the orthogonal cytokine is orthogonal interleukin-2 (ortho-IL-2), orthogonal interleukin-15 (ortho-IL-15) or orthogonal interleukin-9 (ortho-IL-9). In some embodiments, the orthogonal cytokine is orthogonal interleukin-2 (IL-2). In some embodiments, the orthogonal receptor is orthogonal interleukin-2-receptor-beta (ortho-IL2Rβ). An example human orthogonal IL-2Rβ amino acid sequence is: AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQASWACNLILGAPD SQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLRLMAPISLQVVHVETHRCNISWEISQASDFFE RHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPLAFR TKPAALGKDTIPWLGHLLVGLSGAFGFIILVYLLINCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGG DVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFF FHLPDALEIEACQVYFTYDPYSEEDPDEGVAGAPTGSSPQPLQPLSGEDDAYCTFPSRDDLLLFSPSL LGGPSPPSTAPGGSGAGEERMPPSLQERVPRDWDPQPLGPPTPGVPDLVDFQPPPELVLREAGEEVPD AGPREGVSFPWSRPPGQGEFRALNARLPLNTDAYLSLQELQGQDPTHLV (SEQ ID NO: 5) An example human orthogonal IL-2 amino acid sequence is: APTSSSTKKTQLQLENLLVLLTHILNKINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEE VLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 6) A further example human orthogonal IL-2 amino acid sequence is: APTSSSTKKTQLQLDNLLVLLKAILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEE VLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 7) An example mouse orthogonal IL-2Rβ amino acid sequence is: AVKNCSHLECFYNSRANVSCMWSHEEALNVTTCHVHAKSNLRHWNKTCELTLVRQASWACNLILGSFP ESQSLTSVDLLDINVVCWEEKGWRRVKTCDFHPFDNLRLVAPHSLQVLHIDTQRCNISWKVSQVSDFI EPYLEFEARRRLLGHSWEDASVLSLKQRQQWLFLEMLIPSTSYEVQVRVKAQRNNTGTWSPWSQPLTF RTRPADPMKEILPMSWLRYLLLVLGCFSGFFSCVYILVKCRYLGPWLKTVLKCHIPDPSEFFSQLSSQ HGGDLQKWLSSPVPLSFFSPSGPAPEISPLEVLDGDSKAVQLLLLQKDSAPLPSPSGHSQASCFTNQG YFFFHLPNALEIESCQVYFTYDPCVEEEVEEDGSRLPEGSPHPPLLPLAGEQDDYCAFPPRDDLLLFS PSLSTPNTAYGGSRAPEERSPLSLHEGLPSLASRDLMGLQRPLERMPEGDGEGLSANSSGEQASVPEG NLHGQDQDRGQGPILTLNTDAYLSLQELQAQDSVHLI (SEQ ID NO: 8) An example mouse orthogonal IL-2 amino acid sequence is: APTSSSTSSSTAEAQQQQQQQQQQQQHLENLLVLLTHLLSKMENYRNLKLPRMLTFKFYLPKQATELK DLQCLEDELGPLRHVLDLTQSKSFQLEDAENFISNIRVTVVKLKGSDNTFECQFDDESATVVDFLRRW IAFCQSIISTSPQ (SEQ ID NO: 9) A further example mouse orthogonal IL-2 amino acid sequence is: APTSSSTSSSTAEAQQQQQQQQQQQQHLDNLLVLLKALLSRMENYRNLKLPRMLTFKFYLPKQATELK DLQCLEDELGPLRHVLDLTQSKSFQLEDAENFISNIRVTVVKLKGSDNTFECQFDDESATVVDFLRRW IAFCQSIISTSPQ (SEQ ID NO: 10) An example nucleotide sequence encoding a human orthogonal IL-2Rβ is: ATGGCGGCGCCGGCGCTGAGCTGGCGCCTGCCGCTGCTGATTCTGCTGCTGCCGCTGGCGACCAGCTG GGCGAGCGCGGCGGTGAACGGCACCAGCCAGTTTACCTGCTTTTATAACAGCCGCGCGAACATTAGCT GCGTGTGGAGCCAGGATGGCGCGCTGCAGGATACCAGCTGCCAGGTGCATGCGTGGCCGGATCGCCGC CGCTGGAACCAGACCTGCGAACTGCTGCCGGTGAGCCAGGCGAGCTGGGCGTGCAACCTGATTCTGGG CGCGCCGGATAGCCAGAAACTGACCACCGTGGATATTGTGACCCTGCGCGTGCTGTGCCGCGAAGGCG TGCGCTGGCGCGTGATGGCGATTCAGGATTTTAAACCGTTTGAAAACCTGCGCCTGATGGCGCCGATT AGCCTGCAGGTGGTGCATGTGGAAACCCATCGCTGCAACATTAGCTGGGAAATTAGCCAGGCGAGCGA TTTTTTTGAACGCCATCTGGAATTTGAAGCGCGCACCCTGAGCCCGGGCCATACCTGGGAAGAAGCGC CGCTGCTGACCCTGAAACAGAAACAGGAATGGATTTGCCTGGAAACCCTGACCCCGGATACCCAGTAT GAATTTCAGGTGCGCGTGAAACCGCTGCAGGGCGAATTTACCACCTGGAGCCCGTGGAGCCAGCCGCT GGCGTTTCGCACCAAACCGGCGGCGCTGGGCAAAGATACCATTCCGTGGCTGGGCCATCTGCTGGTGG GCCTGAGCGGCGCGTTTGGCTTTATTATTCTGGTGTATCTGCTGATTAACTGCCGCAACACCGGCCCG TGGCTGAAAAAAGTGCTGAAATGCAACACCCCGGATCCGAGCAAATTTTTTAGCCAGCTGAGCAGCGA ACATGGCGGCGATGTGCAGAAATGGCTGAGCAGCCCGTTTCCGAGCAGCAGCTTTAGCCCGGGCGGCC TGGCGCCGGAAATTAGCCCGCTGGAAGTGCTGGAACGCGATAAAGTGACCCAGCTGCTGCTGCAGCAG GATAAAGTGCCGGAACCGGCGAGCCTGAGCAGCAACCATAGCCTGACCAGCTGCTTTACCAACCAGGG CTATTTTTTTTTTCATCTGCCGGATGCGCTGGAAATTGAAGCGTGCCAGGTGTATTTTACCTATGATC CGTATAGCGAAGAAGATCCGGATGAAGGCGTGGCGGGCGCGCCGACCGGCAGCAGCCCGCAGCCGCTG CAGCCGCTGAGCGGCGAAGATGATGCGTATTGCACCTTTCCGAGCCGCGATGATCTGCTGCTGTTTAG CCCGAGCCTGCTGGGCGGCCCGAGCCCGCCGAGCACCGCGCCGGGCGGCAGCGGCGCGGGCGAAGAAC GCATGCCGCCGAGCCTGCAGGAACGCGTGCCGCGCGATTGGGATCCGCAGCCGCTGGGCCCGCCGACC CCGGGCGTGCCGGATCTGGTGGATTTTCAGCCGCCGCCGGAACTGGTGCTGCGCGAAGCGGGCGAAGA AGTGCCGGATGCGGGCCCGCGCGAAGGCGTGAGCTTTCCGTGGAGCCGCCCGCCGGGCCAGGGCGAAT TTCGCGCGCTGAACGCGCGCCTGCCGCTGAACACCGATGCGTATCTGAGCCTGCAGGAACTGCAGGGC CAGGATCCGACCCATCTGGTGTAA (SEQ ID NO: 28) An example nucleotide sequence encoding a human orthogonal IL-2 is: ATGTATCGCATGCAGCTGCTGAGCTGCATTGCGCTGAGCCTGGCGCTGGTGACCAACAGCGCGCCGAC CAGCAGCAGCACCAAAAAAACCCAGCTGCAGCTGGAAAACCTGCTGGTGCTGCTGACCCATATTCTGA ACAAAATTAACAACTATAAAAACCCGAAACTGACCCGCATGCTGACCTTTAAATTTTATATGCCGAAA AAAGCGACCGAACTGAAACATCTGCAGTGCCTGGAAGAAGAACTGAAACCGCTGGAAGAAGTGCTGAA CCTGGCGCAGAGCAAAAACTTTCATCTGCGCCCGCGCGATCTGATTAGCAACATTAACGTGATTGTGC TGGAACTGAAAGGCAGCGAAACCACCTTTATGTGCGAATATGCGGATGAAACCGCGACCATTGTGGAA TTTCTGAACCGCTGGATTACCTTTTGCCAGAGCATTATTAGCACCCTGACCTAA (SEQ ID NO: 29) An example nucleotide sequence encoding a mouse orthogonal IL-2 is: ATGTATAGCATGCAGCTGGCGAGCTGCGTGACCCTGACCCTGGTGCTGCTGGTGAACAGCGCGCCGAC CAGCAGCAGCACCAGCAGCAGCACCGCGGAAGCGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGC AGCATCTGGAAAACCTGCTGGTGCTGCTGACCCATCTGCTGAGCAAAATGGAAAACTATCGCAACCTG AAACTGCCGCGCATGCTGACCTTTAAATTTTATCTGCCGAAACAGGCGACCGAACTGAAAGATCTGCA GTGCCTGGAAGATGAACTGGGCCCGCTGCGCCATGTGCTGGATCTGACCCAGAGCAAAAGCTTTCAGC TGGAAGATGCGGAAAACTTTATTAGCAACATTCGCGTGACCGTGGTGAAACTGAAAGGCAGCGATAAC ACCTTTGAATGCCAGTTTGATGATGAAAGCGCGACCGTGGTGGATTTTCTGCGCCGCTGGATTGCGTT TTGCCAGAGCATTATTAGCACCAGCCCGCAGTAA (SEQ ID NO: 30) In some embodiments, the orthogonal receptor is human IL2Rβ modified at H133 and / or Y134, wherein the amino acids are numbered with reference to SEQ ID NO: 2. In some embodiments, the orthogonal receptor is human IL2Rβ modified at H133 and Y134, wherein the amino acids are numbered with reference to SEQ ID NO: 2. The terms “corresponding to”, “reference to” and “relative to” when used in the context of the numbering of a given amino acid or polynucleotide sequence may refer to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. In other words, the residue number or residue position of a given polymer is designated with respect to the reference sequence rather than by the actual numerical position of the residue within the given amino acid or polynucleotide sequence. For example, a given amino acid sequence, such as that of an orthogonal cytokine or receptor, can be aligned to a reference sequence by introducing gaps to optimise residue matches between the two sequences. In these cases, although the gaps are present, the numbering of the residue in the given amino acid or polynucleotide sequence is made with respect to the reference sequence to which it has been aligned. In some embodiments, the orthogonal receptor is human IL2Rβ comprising: (a) a D at the position corresponding to amino acid 133; and / or (b) an F at the position corresponding to amino acid 134, wherein the amino acids are numbered with reference to SEQ ID NO: 2. In some embodiments, the orthogonal receptor is human IL2Rβ comprising: (a) a D at the position corresponding to amino acid 133; and (b) an F at the position corresponding to amino acid 134, wherein the amino acids are numbered with reference to SEQ ID NO: 2. In some embodiments, the orthogonal receptor comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5, and comprises: (a) a D at the position corresponding to amino acid 133; and / or (b) an F at the position corresponding to amino acid 134, wherein the amino acids are numbered with reference to SEQ ID NO: 5. In some embodiments, the orthogonal receptor comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 5, and comprises: (a) a D at the position corresponding to amino acid 133; and (b) an F at the position corresponding to amino acid 134, wherein the amino acids are numbered with reference to SEQ ID NO: 5. Mutations are indicated using the single-letter amino acid abbreviations, for example “D” is aspartic acid. In some embodiments, the orthogonal receptor is encoded by a nucleotide sequence that comprises or consists of a sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 28. In some embodiments, the orthogonal cytokine is human IL-2 modified at H16, L19, D20, Q22, M23 and / or G27, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 modified at H16, L19, D20, Q22, M23 and G27, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 comprising: (a) a N at the position corresponding to amino acid 16; (b) a V at the position corresponding to amino acid 19; (c) an L at the position corresponding to amino acid 20; (d) a T at the position corresponding to amino acid 22; (e) an H at the position corresponding to amino acid 23; and / or (f) a K at the position corresponding to amino acid 27, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 comprising: (a) a N at the position corresponding to amino acid 16; (b) a V at the position corresponding to amino acid 19; (c) an L at the position corresponding to amino acid 20; (d) a T at the position corresponding to amino acid 22; (e) an H at the position corresponding to amino acid 23; and (f) a K at the position corresponding to amino acid 27, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6, and comprises: (a) a N at the position corresponding to amino acid 16; (b) a V at the position corresponding to amino acid 19; (c) an L at the position corresponding to amino acid 20; (d) a T at the position corresponding to amino acid 22; (e) an H at the position corresponding to amino acid 23; and / or (f) a K at the position corresponding to amino acid 27, wherein the amino acids are numbered with reference to SEQ ID NO: 6. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 6, and comprises: (a) a N at the position corresponding to amino acid 16; (b) a V at the position corresponding to amino acid 19; (c) an L at the position corresponding to amino acid 20; (d) a T at the position corresponding to amino acid 22; (e) an H at the position corresponding to amino acid 23; and (f) a K at the position corresponding to amino acid 27, wherein the amino acids are numbered with reference to SEQ ID NO: 6. In some embodiments, the orthogonal cytokine is human IL-2 modified at E15, H16, L19, D20, Q22 and / or M23, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 modified at E15, H16, L19, D20, Q22 and M23, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 comprising: (a) a D at the position corresponding to amino acid 15; (b) a N at the position corresponding to amino acid 16; (c) an V at the position corresponding to amino acid 19; (d) a L at the position corresponding to amino acid 20; (e) a K at the position corresponding to amino acid 22; and / or (f) an A at the position corresponding to amino acid 23, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL- 2 comprising: (a) a D at the position corresponding to amino acid 15; (b) a N at the position corresponding to amino acid 16; (c) an V at the position corresponding to amino acid 19; (d) a L at the position corresponding to amino acid 20; (e) a K at the position corresponding to amino acid 22; and (f) an A at the position corresponding to amino acid 23, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7, and comprises: (a) a D at the position corresponding to amino acid 15; (b) a N at the position corresponding to amino acid 16; (c) an V at the position corresponding to amino acid 19; (d) a L at the position corresponding to amino acid 20; (e) a K at the position corresponding to amino acid 22; and / or (f) an A at the position corresponding to amino acid 23, wherein the amino acids are numbered with reference to SEQ ID NO: 7. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 7, and comprises: (a) a D at the position corresponding to amino acid 15; (b) a N at the position corresponding to amino acid 16; (c) an V at the position corresponding to amino acid 19; (d) a L at the position corresponding to amino acid 20; (e) a K at the position corresponding to amino acid 22; and (f) an A at the position corresponding to amino acid 23, wherein the amino acids are numbered with reference to SEQ ID NO: 7. In some embodiments, the orthogonal cytokine is human IL-2 modified at Q13, L14, E15, H16, L19, D20, Q22, M23, G27, R81 and / or N88, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 modified at H16, L19, D20, Q22, M23 and / or G27, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 modified at H16, L19, D20, Q22, M23 and G27, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 with one or more of the following amino acid substitutions: E15S, E15T, E15Q, or E15H; H16Q; L19V, or L19I; D20T, D20S, D20M, or D20L; Q22K, or Q22N; and / or M23L, M23S, M23V, or M23T, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations E15S, H16Q, L19V, D20T, Q22K, and M23L wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations E15S, H16Q, L19V, D20S, Q22K, and M23L wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations E15S, H16Q, L19V, D20M, Q22K, and M23L wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations E15S, H16Q, L19V, D20T, Q22K, and M23S wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations E15S, H16Q, L19V, D20S, Q22K, and M23S wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations E15S, H16Q, L19V, D20M, Q22K, and M23S wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1 and comprises one or more of the following amino acid substitutions: E15S, E15T, E15Q, or E15H; H16Q; L19V, or L19I; D20T, D20S, D20M, or D20L; Q22K, or Q22N; and / or M23L, M23S, M23V, or M23T, relative to SEQ ID NO: 1. In some embodiments the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1 and comprises the following mutations: E15S, H16Q, L19V, D20T, Q22K, and M23L relative to SEQ ID NO: 1. In some embodiments the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1 and comprises the following mutations: E15S, H16Q, L19V, D20S, Q22K, and M23L relative to SEQ ID NO: 1. In some embodiments the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1 and comprises the following mutations: E15S, H16Q, L19V, D20M, Q22K, and M23L relative to SEQ ID NO: 1. In some embodiments the orthogonal comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1 and comprises the following mutations: E15S, H16Q, L19V, D20T, Q22K, and M23S relative to SEQ ID NO: 1. In some embodiments the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1 and comprises the following mutations: E15S, H16Q, L19V, D20S, Q22K, and M23S relative to SEQ ID NO: 1. In some embodiments the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1 and comprises the following mutations: E15S, H16Q, L19V, D20M, Q22K, and M23S relative to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations: E15S, H16Q, L19V, D20L, and M23Q, and optionally Q22K, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine is human IL-2 with the following mutations: E15S, H16Q, L19V, D20L, and M23A, and optionally Q22K, wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1 and comprises the following mutations: E15S, H16Q, L19V, D20L, and M23Q, and optionally Q22K, relative to SEQ ID NO: 1. In some embodiments the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1 and comprises the following mutations: E15S, H16Q, L19V, D20L, and M23A, and optionally Q22K, relative to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is human IL-2 with one or more of the following sets of amino acid substitutions: [E15S; H16Q; L19V, D20T; Q22K, M23L]; [E15S; H16Q; L19V, D20T; Q22K, M23S]; [E15S; H16Q; L19V, D20S; Q22K, M23L]; [E15S; H16Q; L19V, D20S; Q22K, M23S]; [E15S; H16Q; L19I; D20S; Q22K; M23L]; [E15S; L19V; D20M; Q22K; M23S]; [E15T; H16Q; L19V; D20S; M23S]; [E15Q; L19V; D20M; Q22K; M23S]; [E15Q; H16Q; L19V; D20T; Q22K; M23V]; [E15H; H16Q; L19I; D20S; Q22K; M23L]; [E15H; H16Q; L19I; D20L; Q22K; M23T]; [L19V; D20M; Q22N; M23S]; [E15S, H16Q, L19V, D20L, M23Q, R81D, T51I], [E15S, H16Q, L19V, D20L, M23Q, R81Y], [E15S, H16Q, L19V, D20L, Q22K, M23A], [E15S, H16Q, L19V, D20L, M23A], wherein the amino acids are numbered with reference to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 1 and comprises one or more of the following sets of substitutions: [E15S; H16Q; L19V, D20T; Q22K, M23L]; [E15S; H16Q; L19V, D20T; Q22K, M23S]; [E15S; H16Q; L19V, D20S; Q22K, M23L]; [E15S; H16Q; L19V, D20S; Q22K, M23S]; [E15S; H16Q; L19I; D20S; Q22K; M23L]; [E15S; L19V; D20M; Q22K; M23S]; [E15T; H16Q; L19V; D20S; M23S]; [E15Q; L19V; D20M; Q22K; M23S]; [E15Q; H16Q; L19V; D20T; Q22K; M23V]; [E15H; H16Q; L19I; D20S; Q22K; M23L]; [E15H; H16Q; L19I; D20L; Q22K; M23T]; [L19V; D20M; Q22N; M23S]; [E15S, H16Q, L19V, D20L, M23Q, R81D, T51I], [E15S, H16Q, L19V, D20L, M23Q, R81Y], [E15S, H16Q, L19V, D20L, Q22K, M23A], [E15S, H16Q, L19V, D20L, M23A], relative to SEQ ID NO: 1. In some embodiments, the orthogonal cytokine is encoded by a nucleotide sequence that comprises or consists of a sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 29. In some embodiments, the orthogonal receptor is mouse IL2Rβ modified at H134 and / or Y135, wherein the amino acids are numbered with reference to SEQ ID NO: 4. In some embodiments, the orthogonal receptor is mouse IL2Rβ modified at H134 and Y135, wherein the amino acids are numbered with reference to SEQ ID NO: 4. In some embodiments, the orthogonal receptor is mouse IL2Rβ comprising: (a) a D at the position corresponding to amino acid 134; and / or (b) an F at the position corresponding to amino acid 135, wherein the amino acids are numbered with reference to SEQ ID NO: 4. In some embodiments, the orthogonal receptor is mouse IL2Rβ comprising: (a) a D at the position corresponding to amino acid 134; and (b) an F at the position corresponding to amino acid 135, wherein the amino acids are numbered with reference to SEQ ID NO: 4. In some embodiments, the orthogonal receptor comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 8, and comprises: (a) a D at the position corresponding to amino acid 134; and / or (b) an F at the position corresponding to amino acid 135, wherein the amino acids are numbered with reference to SEQ ID NO: 8. In some embodiments, the orthogonal receptor comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 8, and comprises: (a) a D at the position corresponding to amino acid 134; and (b) an F at the position corresponding to amino acid 135, wherein the amino acids are numbered with reference to SEQ ID NO: 8. In some embodiments, the orthogonal cytokine is mouse IL-2 modified at Q30, M33, D34, Q36, E37 and / or R41, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine is mouse IL-2 modified at Q30, M33, D34, Q36, E37 and R41, wherein the amino acids are numbered with reference to SEQ ID NO: 3 In some embodiments, the orthogonal cytokine is mouse IL-2 comprising: (a) a N at the position corresponding to amino acid 30; (b) a V at the position corresponding to amino acid 33; (c) an L at the position corresponding to amino acid 34; (d) a T at the position corresponding to amino acid 36; (e) an H at the position corresponding to amino acid 37; and / or (f) a K at the position corresponding to amino acid 41, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine is mouse IL-2 comprising: (a) a N at the position corresponding to amino acid 30; (b) a V at the position corresponding to amino acid 33; (c) an L at the position corresponding to amino acid 34; (d) a T at the position corresponding to amino acid 36; (e) an H at the position corresponding to amino acid 37; and (f) a K at the position corresponding to amino acid 41, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 9, and comprises: (a) a N at the position corresponding to amino acid 30; (b) a V at the position corresponding to amino acid 33; (c) an L at the position corresponding to amino acid 34; (d) a T at the position corresponding to amino acid 36; (e) an H at the position corresponding to amino acid 37; and / or (f) a K at the position corresponding to amino acid 41, wherein the amino acids are numbered with reference to SEQ ID NO: 9. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 9, and comprises: (a) a N at the position corresponding to amino acid 30; (b) a V at the position corresponding to amino acid 33; (c) an L at the position corresponding to amino acid 34; (d) a T at the position corresponding to amino acid 36; (e) an H at the position corresponding to amino acid 37; and (f) a K at the position corresponding to amino acid 41, wherein the amino acids are numbered with reference to SEQ ID NO: 9. In some embodiments, the orthogonal cytokine is mouse IL-2 modified at E29, Q30, M33, D34, Q36 and / or E37, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine is mouse IL-2 modified at E29, Q30, M33, D34, Q36 and E37, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine is mouse IL-2 comprising: (a) a D at the position corresponding to amino acid 29; (b) a N at the position corresponding to amino acid 30; (c) an V at the position corresponding to amino acid 33; (d) a L at the position corresponding to amino acid 34; (e) a K at the position corresponding to amino acid 36; and / or (f) an A at the position corresponding to amino acid 37, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine is mouse IL- 2 comprising: (a) a D at the position corresponding to amino acid 29; (b) a N at the position corresponding to amino acid 30; (c) an V at the position corresponding to amino acid 33; (d) a L at the position corresponding to amino acid 34; (e) a K at the position corresponding to amino acid 36; and (f) an A at the position corresponding to amino acid 37, wherein the amino acids are numbered with reference to SEQ ID NO: 3. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 10, and comprises: (a) a D at the position corresponding to amino acid 29; (b) a N at the position corresponding to amino acid 30; (c) an V at the position corresponding to amino acid 33; (d) a L at the position corresponding to amino acid 34; (e) a K at the position corresponding to amino acid 36; and / or (f) an A at the position corresponding to amino acid 37, wherein the amino acids are numbered with reference to SEQ ID NO: 10. In some embodiments, the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 10, and comprises: (a) a D at the position corresponding to amino acid 29; (b) a N at the position corresponding to amino acid 30; (c) an V at the position corresponding to amino acid 33; (d) a L at the position corresponding to amino acid 34; (e) a K at the position corresponding to amino acid 36; and (f) an A at the position corresponding to amino acid 37, wherein the amino acids are numbered with reference to SEQ ID NO: 10. In some embodiments, the orthogonal cytokine is encoded by a nucleotide sequence that comprises or consists of a sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 30. Preferably, the orthogonal cytokine and orthogonal receptor encoded by the nucleotide sequences have the particular amino acids described herein at the positions described. The orthogonal cytokine may bind the orthogonal receptor and induce activation of downstream signalling in a comparable manner to the wild type cytokine / receptor pair. The binding of the orthogonal cytokine to the orthogonal receptor may induce the same effects as the binding of wild type cytokine to wild type receptor does. For example, orthogonal interleukin-2 (ortho-IL-2) binding to orthogonal interleukin-2-receptor-beta (ortho-IL2R-β) may induce Janus kinase activation and STAT5 activation in a comparable manner to the binding of wild type IL-2 to the wild type IL-2R. Signal sequence In some embodiments, the orthogonal cytokine further comprises a signal sequence. Example cytokine signal sequences include: MYRMQLLSCIALSLALVTNS (SEQ ID NO: 11; human IL-2) MYSMQLASCVTLTLVLLVNS (SEQ ID NO: 12; mouse IL-2) In some embodiments, the orthogonal cytokine further comprises a signal sequence having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 11 or 12. In some embodiments, the orthogonal receptor further comprises a signal sequence. Example receptor signal sequences include: MAAPALSWRLPLLILLLPLATSWASA (SEQ ID NO: 13; human IL-2Rβ) MATIALPWSLSLYVFLLLLATPWASA (SEQ ID NO: 14; mouse IL-2Rβ) In some embodiments, the orthogonal receptor further comprises a signal sequence having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 13 or 14. Second cytokine In some embodiments, the transgene further encodes a second cytokine. In some embodiments, the second cytokine is selected from the group consisting of IFNα, IL- 15, IL-9, IL-1β, IL-7, IL-12, IFNβ, IFNγ, TNFα, CXCL10 and CXCL9. In preferred embodiments, the second cytokine is IFNα. An example nucleotide sequence encoding human IFNα is: ATGGCCTTGACCTTTGCTTTACTGGTGGCCCTCCTGGTGCTCAGCTGCAAGTCAAGCTGCTCTGTGGG CTGTGATCTGCCTCAAACCCACAGCCTGGGTAGCAGGAGGACCTTGATGCTCCTGGCACAGATGAGGA GAATCTCTCTTTTCTCCTGCTTGAAGGACAGACATGACTTTGGATTTCCCCAGGAGGAGTTTGGCAAC CAGTTCCAAAAGGCTGAAACCATCCCTGTCCTCCATGAGATGATCCAGCAGATCTTCAATCTCTTCAG CACAAAGGACTCATCTGCTGCTTGGGATGAGACCCTCCTAGACAAATTCTACACTGAACTCTACCAGC AGCTGAATGACCTGGAAGCCTGTGTGATACAGGGGGTGGGGGTGACAGAGACTCCCCTGATGAAGGAG GACTCCATTCTGGCTGTGAGGAAATACTTCCAAAGAATCACTCTCTATCTGAAAGAGAAGAAATACAG CCCTTGTGCCTGGGAGGTTGTCAGAGCAGAAATCATGAGATCTTTTTCTTTGTCAACAAACTTGCAAG AAAGTTTAAGAAGTAAGGAA (SEQ ID NO: 22) An example human IFNα amino acid sequence is: MALTFALLVALLVLSCKSSCSVGCDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGN QFQKAETIPVLHEMIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKE DSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESLRSKE (SEQ ID NO: 23) An example nucleotide sequence encoding mouse IFNα is: ATGGCTAGGCTCTGTGCTTTCCTGATGGTCCTGGCGGTGCTGAGCTACTGGCCAACCTGCTCTCTAGG ATGTGACCTTCCTCAGACTCATAACCTCAGGAACAAGAGAGCCTTGACACTCCTGGTACAAATGAGGA GACTCTCCCCTCTCTCCTGCCTGAAGGACAGGAAGGACTTTGGATTCCCGCAGGAGAAGGTGGATGCC CAGCAGATCAAGAAGGCTCAAGCCATCCCTGTCCTGAGTGAGCTGACCCAGCAGATCCTGAACATCTT CACATCAAAGGACTCATCTGCTGCATGGAATACAACCCTCCTAGACTCATTCTGCAATGACCTCCACC AGCAGCTCAATGACCTGCAAGGCTGTCTGATGCAGCAGGTGGGGGTGCAGGAATTTCCCCTGACCCAG GAAGATGCCCTGCTGGCTGTGAGGAAATACTTCCACAGGATCACTGTGTACCTGAGAGAGAAGAAACA CAGCCCCTGTGCCTGGGAGGTGGTCAGAGCAGAAGTCTGGAGAGCCCTGTCTTCCTCTGCCAATGTGC TGGGAAGACTGAGAGAAGAGAAA (SEQ ID NO: 24) An example mouse IFNα amino acid sequence is: MARLCAFLMVLAVLSYWPTCSLGCDLPQTHNLRNKRALTLLVQMRRLSPLSCLKDRKDFGFPQEKVDA QQIKKAQAIPVLSELTQQILNIFTSKDSSAAWNTTLLDSFCNDLHQQLNDLQGCLMQQVGVQEFPLTQ EDALLAVRKYFHRITVYLREKKHSPCAWEVVRAEVWRALSSSANVLGRLREEK* (SEQ ID NO: 25) In some embodiments, the second cytokine is encoded by a nucleotide sequence that comprises or consists of a sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 22 or 24, preferably SEQ ID NO: 22. In some embodiments, the second cytokine comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 23 or 25, preferably SEQ ID NO: 23. Preferably, the second cytokine substantially retains the IFNα activity of the protein represented by SEQ ID NO: 23. In some embodiments, the transgene encodes a cleavable linker between the orthogonal cytokine and the second cytokine. The cleavable linker may be a self cleaving sequence. Suitably, the self-cleaving sequence is a 2A self-cleaving peptide. In some embodiments, the 2A self-cleaving peptide is selected from the group consisting of P2A peptide, T2A peptide, E2A peptide and F2A peptide. In preferred embodiments, the cleavable linker is a P2A peptide. An example nucleotide sequence encoding P2A is: GGCAGCGGCGCGACCAACTTTAGCCTGCTGAAACAGGCGGGCGATGTGGAAGAAAACCCGGGCCCG (SEQ ID NO: 26) An example P2A amino acid sequence is: GSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 27) In some embodiments, the cleavable linker is encoded by a nucleotide sequence that comprises or consists of a sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 26. In some embodiments, the cleavable linker comprises or consists of an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 27. Preferably, the cleavable linker substantially retains the activity of the protein represented by SEQ ID NO: 27. VECTOR A vector is a tool that allows or facilitates the transfer of an entity from one environment to another. In accordance with the present invention, and by way of example, some vectors used in recombinant nucleic acid techniques allow entities, such as a segment of nucleic acid (e.g. a heterologous DNA segment, such as a heterologous cDNA segment), to be transferred into a target cell. The vector may serve the purpose of maintaining the heterologous nucleic acid (DNA or RNA) within the cell, facilitating the replication of the vector comprising a segment of nucleic acid, or facilitating the expression of the protein encoded by a segment of nucleic acid. Vectors may be non-viral or viral. Examples of vectors used in recombinant nucleic acid techniques include, but are not limited to, plasmids, chromosomes, artificial chromosomes and viruses. The vector may also be, for example, a naked nucleic acid (e.g. DNA). In its simplest form, the vector may itself be a nucleotide of interest. The vectors used in the invention may be, for example, plasmid or virus vectors and may include a promoter for the expression of a polynucleotide and optionally a regulator of the promoter. In a preferred embodiment the vector is a viral vector. Vectors comprising polynucleotides used in the invention may be introduced into cells using a variety of techniques known in the art, such as transformation, transfection and transduction. Several techniques are known in the art, for example transduction with recombinant viral vectors, such as retroviral, lentiviral, adenoviral, adeno-associated viral, baculoviral and herpes simplex viral vectors, Sleeping Beauty vectors; direct injection of nucleic acids and biolistic transformation. Non-viral delivery systems include but are not limited to DNA transfection methods. Here, transfection includes a process using a non-viral vector to deliver a gene to a target cell. Typical transfection methods include electroporation, DNA biolistics, lipid-mediated transfection, compacted DNA-mediated transfection, liposomes, immunoliposomes, lipofectin, cationic agent-mediated transfection, cationic facial amphiphiles (CFAs) (Nature Biotechnology 199614; 556) and combinations thereof. The term “transfection” is to be understood as encompassing the delivery of polynucleotides to cells by both viral and non-viral delivery. In addition, the invention may employ gene targeting protocols, for example the delivery of DNA-modifying agents. Viral delivery systems include but are not limited to an adenoviral vector, an adeno-associated viral (AAV) vector, a herpes viral vector, a retroviral vector, a lentiviral vector, and a baculoviral vector. Retroviruses are RNA viruses with a life cycle different to that of lytic viruses. In this regard, a retrovirus is an infectious entity that replicates through a DNA intermediate. When a retrovirus infects a cell, its genome is converted to a DNA form by a reverse transcriptase enzyme. The DNA copy serves as a template for the production of new RNA genomes and virally encoded proteins necessary for the assembly of infectious viral particles. There are many retroviruses, for example murine leukemia virus (MLV), human immunodeficiency virus (HIV), equine infectious anaemia virus (EIAV), mouse mammary tumour virus (MMTV), Rous sarcoma virus (RSV), Fujinami sarcoma virus (FuSV), Moloney murine leukemia virus (Mo-MLV), FBR murine osteosarcoma virus (FBR MSV), Moloney murine sarcoma virus (Mo-MSV), Abelson murine leukemia virus (A-MLV), Avian myelocytomatosis virus-29 (MC29), and Avian erythroblastosis virus (AEV) and all other retroviridiae including lentiviruses. A detailed list of retroviruses may be found in Coffin et al (“Retroviruses” 1997 Cold Spring Harbour Laboratory Press Eds: JM Coffin, SM Hughes, HE Varmus pp 758-763). Lentiviruses also belong to the retrovirus family, but they can infect both dividing and non- dividing cells (Lewis et al (1992) EMBO J.3053-3058). In some embodiments, the vector is a lentiviral vector. MICRORNA TARGET SEQUENCE MicroRNA genes are scattered across all human chromosomes, except for the Y chromosome. They can be either located in non-coding regions of the genome or within introns of protein-coding genes. Around 50% of miRNAs appear in clusters which are transcribed as polycistronic primary transcripts. Similar to protein-coding genes, miRNAs are usually transcribed from polymerase-II promoters, generating a so-called primary miRNA transcript (pri-miRNA). This pri-miRNA is then processed through a series of endonucleolytic cleavage steps, performed by two enzymes belonging to the RNAse Type III family, Drosha and Dicer. From the pri-miRNA, a stem loop of about 60 nucleotides in length, called mirna precursor (pre-mirna), is excised by a specific nuclear complex, composed of Drosha and DiGeorge syndrome critical region gene (DGCR8), which crops both strands near the base of the primary stem loop and leaves a 5’ phosphate and a 2 bp long, 3’ overhang. The pre-miRNA is then actively transported from the nucleus to the cytoplasm by RAN-GTP and Exportin. Then, Dicer performs a double strand cut at the end of the stem loop not defined by the Drosha cut, generating a 19-24 bp duplex, which is composed of the mature miRNA and the opposite strand of the duplex, called miRNA*. In agreement with the thermodynamic asymmetry rule, only one strand of the duplex is selectively loaded into the RNA-induced silencing complex (RISC), and accumulates as the mature microRNA. This strand is usually the one whose 5’ end is less tightly paired to its complement, as was demonstrated by single-nucleotide mismatches introduced into the 5’ end of each strand of siRNA duplexes. However, there are some miRNAs that support accumulation of both duplex strands to similar extent. MicroRNAs trigger RNAi, very much like small interfering RNAs (siRNA) which are extensively being used for experimental gene knockdown. The main difference between miRNA and siRNA is their biogenesis. Once loaded into RISC, the guide strand of the small RNA molecule interacts with mRNA target sequences preferentially found in the 3' untranslated region (3'UTR) of protein-coding genes. It has been shown that nucleotides 2-8 counted from the 5' end of the miRNA, the so-called seed sequence, are essential for triggering RNAi. If the whole guide strand sequence is perfectly complementary to the mRNA target, as is usually the case for siRNAs and plant miRNAs, the mRNA is endonucleolytically cleaved by involvement of the Argonaute (Ago) protein, also called "slicer" of the small RNA duplex into the RNA-induced silencing complex (RISC). DGRC (DiGeorge syndrome critical region gene 8) and TRBP (TAR (HIV) RNA binding protein 2) are double-stranded RNA-binding proteins that facilitate mature miRNA biogenesis by Drosha and Dicer RNase III enzymes, respectively. The guide strand of the miRNA duplex gets incorporated into the effector complex RISC, which recognises specific targets through imperfect base-pairing and induces post-transcriptional gene silencing. Several mechanisms have been proposed for this mode of regulation: miRNAs can induce the repression of translation initiation, mark target mRNAs for degradation by deadenylation, or sequester targets into the cytoplasmic P-body. On the other hand, if only the seed is perfectly complementary to the target mRNA but the remaining bases show incomplete pairing, RNAi acts through multiple mechanisms leading to translational repression. Eukaryotic mRNA degradation mainly occurs through the shortening of the polyA tail at the 3’ end of the mRNA, and de-capping at the 5’ end, followed by 5’-3’ exonuclease digestion and accumulation of the miRNA in discrete cytoplasmic areas, the so called P-bodies, enriched in components of the mRNA decay pathway. According to the present invention, expression of the transgene, such as the orthogonal cytokine, is regulated by endogenous miRNAs using corresponding miRNA target sequences. Using this method, a miRNA endogenously expressed in a cell prevents or reduces transgene expression in that cell by binding to its corresponding miRNA target sequence positioned in the vector or polynucleotide. This has a number of advantages over relying on tissue specific promoters, not least the fact that tissue specific promoters are often associated with leaky expression in a fraction of non-target cells. miRNA target sequences that are useful in the present invention are miRNA target sequences which are expressed in HSCs but which are not expressed extensively in differentiated cells, e.g. myeloid cells (including tumor-infiltrating macrophages). Preferred examples of miRNA target sequences for use in the invention are miR-130a and miR-126. Binding of miR-126 miRNA to the miR-126 target sequence blocks expression most effectively in HSC and in cells of the erythroid lineage. Thus, the miR-126 target sequence is particularly suitable for gene therapy applications relying on robust transgene expression in the myeloid and lymphoid lineage. The miR-126 miRNA may have the nucleotide sequence: UCGUACCGUGAGUAAUAAUGCG (SEQ ID NO: 15). In one embodiment, the miR-126 target sequence comprises the nucleotide sequence of: GCATTATTACTCACGGTACGA (SEQ ID NO: 16). In one embodiment, the vector or polynucleotide used in the present invention comprises at least one, at least two, or at least three, copies of the nucleotide sequence of SEQ ID NO:16. In a preferred embodiment, the miR-126 target sequence comprises two copies of the nucleotide sequence of SEQ ID NO: 16. The copies miR-126 target sequences may be separated by a spacer sequence. The spacer sequence may comprise at least one, at least two, at least three, at least four or at least five nucleotide bases. Binding of miR-130a miRNA to the miR-130a target sequence blocks expression most effectively in HSC and in cells of the erythroid lineage (similar to miR-126). Thus, the miR- 130a target sequence is particularly suitable for gene therapy applications relying on robust transgene expression in the myeloid and lymphoid lineage. The miR-130a miRNA may have the nucleotide sequence of: CAGUGCAAUGUUAAAAGGGCAU (SEQ ID NO: 17) In one embodiment, the miR-130a target sequence comprises the nucleotide sequence of: ATGCCCTTTTAACATTGCACTG (SEQ ID NO: 18) In one embodiment, the miR-130a target sequence comprises at least one, at least two or at least three copies of the nucleotide sequence of SEQ ID NO: 18. In a preferred embodiment, the miR-130a target sequence comprises two copies of the nucleotide sequence of SEQ ID NO: 18. The copies miR-130a target sequences may be separated by a spacer sequence. The spacer sequence may comprise at least one, at least two, at least three, at least four or at least five nucleotide bases. In one embodiment, the vector comprises two copies of a miR-126 target sequence and two copies of a miR-130a target sequence. In one embodiment, two copies of the miR-126 target sequence and two copies of the miR- 130a target sequence are comprised in the nucleotide sequence of: GCATTATTACTCACGGTACGACGATGCATTATTACTCACGGTACGAACGCGTATGCCCTTTTAACATT GCACTGATGCATATGCCCTTTTAACATTGCACTG (SEQ ID NO: 19) Combination target sequences, e.g. a target sequence comprising two copies of the miR-126 target sequence and two copies of the miR-130a target sequence are a particular preferred for use in the present invention since use of this combination maximises repression of the vector in HSCs and expression in the myeloid progeny. Furthermore, when using the combination target, transgene downregulation in HSCs is assured by two independent miRNAs, and the risk of interfering with endogenous miRNA regulation is reduced, thus increasing safety and efficacy of the target sequence. PROMOTER In some embodiments the vector comprises a tissue specific promoter. Preferably, the tissue specific promoter drives specific expression to a subset of tumor infiltrating myeloid cells, such as Tie2 expressing monocytes (TEM) or M2-polarised macrophages. In a preferred embodiment, the tissue specific promoter is the TEK (Tie2) promoter. An example TEK promoter nucleotide sequence is: gatcacgagactagcctcgagtcacacctgcaaactggaaacattaattggttcttaagatcatcatc gacgtgataaaacctgggacagaaattagtcaagactagctgcatctgccttttcctctggtgggtag gaaaaggaggagtataatgatttcctcaggcatgaaggtcgatgatgagcaaagtgtatactctctaa tctaatgtcataattcatattgtggagtaattatctggataagtgtagggtctctgacctcattctag atattgtacattccatggctattttcattttggtccatgaactctctttgctctcatgagcaccattt ttatcccaatctaatcctgtatgtttgtgtttttacacagattagtttttaaatgttatatataattt gcttctgaaacaccattgctcaatgactaccaaatctttctcattaccaaaatccttctatgccaact tcttcaagaaatttgatcacctttagatgaattgttaatgaaaattaaagctatagccggcaacatgg gtatctttgggctaatggccaaccaacaggccatctgtgtgaaagaaaacaggctaacaattttggac tctggtctcttggggctacattgagcattgacctcaccggtgctcactgaaattaattgcttttcagg ttgtattttctcatcacggaaaccttcttctcccaattcaaaccatgtgggttaaaatgagaaaacaa aagccaaaacggcttcccacacccaaaagctccttctgtcagagatcccagtagccccgggagagctg ttagaagtctgagaaggattggtcatcatcgcataccatacataggtggagggcttgttattctcagt ttcccgcctatgagaggatacccctattgtttctgaaaatgctgaccgggacccacacttccaacaaa aattcctctgcccctacagcagcagcaaaagcagcagcagaagcaacagcaacagataagtgttttga tgaattgcgagatggatagggcttgagtgcccccagccctgctgataccaaatgcctttaagatacag cctttcccatcctaatctacaaaggaaacaggaaaaaggaacttaaaactccctgtgctcagacagaa atgagactgttacagcctgcttctgtgctgttccttcttgcctctaacttgtaaacaagacgtagtag gacgatgctaatggaaagtcacaaaccgctgggtttttgaaaggatcctagactcgagcggccgcca (SEQ ID NO: 20) In one embodiment, the TEK promoter comprises the nucleotide sequence of SEQ ID NO: 20. In one embodiment, the TEK promoter comprises a nucleotide sequence having at least 70%, 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%, at least 99%, at least 99.5% identity to SEQ ID NO:20. The TEK (Tie2) promoter may be combined with the miR-126 target sequence and / or the miR- 130a target sequence. This enables specific transgene expression in a subset of tumor- infiltrating myeloid cells, e.g. tumor infiltrating macrophages. In one embodiment, the vector may further comprise a TEK (Tie2) enhancer sequence. An example TEK (Tie2) enhancer sequence is: cttcagacctggaggaggagatatgagggaccaattgtggccagacgattccttaactcgtgttacac ctgcagaatgagttttagatctagctgtgacctcttcccccagccccacccccattgtccccttgtgt gccttcaggaatctgatcattcttctctcctgctccttcccaaaggctgcaggagcaggtgtgaagac gtggatgtgccagatgcagagtcctgacacttttcaacacatctgcatattagaggaagtacataccc attgcttggtggtttcatgtctaatgtggtatgagtgtgacaaagagagggagaaaatttggactagc caaagaagccagtcaggcgtggggtttgaagggcatcgtgggcggctgtcatttgctctctgcttgtc acagccccttgcccagggcttgaccagtgaggtgtatgtgctggtcacacccatctcagcagatctgt cagctttcccgcttttgttaaagggtgatatcatgcttcctggggggagcactggaagacaatgctcg gccactttcctccagatacaataggcggagtcaggaaggcagtattgacattgctggggctggggagg cactcactgctctgcggccgtcagatggtgaaccagcttaaccttggcacacagggcctgggttgtgc aaggcgtctggctgcagagccaaaggggactccaccctggggacaggagtgctttagacatctgggaa tctgggatgggcttcaaattctgatccctgtgtcagaaacaaccacaaaacaataagagtaccagtaa taacaaaaatgactaccctaggttgaatgcctttatgtgccaagtgtcaattg (SEQ ID NO: 21) In one embodiment, the TEK enhancer sequence comprises the nucleotide sequence of SEQ ID NO: 21. In one embodiment, the TEK enhancer comprises a nucleotide sequence having at least 70%, 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%, at least 99%, at least 99.5% identity to SEQ ID NO: 21. An example mouse Tie2 promoter / enhancer sequence is gatctaatgaaaatcaagatgctaggcacagtgccagatactttaacatagtaatatgactctttaga gttttgagacagggcctcatatagtttatgatgaattcactgttttggcaaagatgaccttgaactct taatccattcccaaagtgttgttgtcatatgtttggaccactcctggcttcatagtgttttttaaaac acccatggagagtcggtgtgaagatccacacgtctaaccctcagcatctgtgaatcaagccaggaggc gggtggttcagctgcctataatatctaagtttcagttagtaaggcctgcataatgaaacactgtctta aacacaaaaccaaaacccatgaaggagatactattgccatttaaaagtctctggaatggaaatagcta tcataatcttacctctgagccagtgtctgccctcaggtgtgcctgaggactgaacagggctatgcact cctcaggttggaaacattactagtcctcagtgtctgctcttgacctgttaacagctgagtcagggtct gccctcagctgtgcctgaggacagagctgagctatctacccctgcagattggaagcattacaggcact caagatcagccctgaagtgataaaacctaaggcagaaatccaccaagactagcagtgcctccgtgtct cttcctgtggctggtgggaaagagaggggcagtccttccttgatgcaaggtcgtgtgtctagtggcac gcttccttcattcccagtgagagcaagtgatcacctgggtaaggaaggttcaggtgcctgagctcgct ggagaattcatcactcatccatcactctgctcctgtagacataatcacttcttgttgggtctttatag agatgatttataactttgttgtttatagttttatgaatgtgtgtattcatttaggtcacatgggaggt acacattttcaggtgtctgtctttccatcacacgggctttgaattaaactcagtcttggttttaccgg ctggccatctcacctgcctgattatttaaaaatctccggagtaatccaggagtgtggtttatgattgt agtatcaacactcgggaggctgagggagcatcgttatcatgagctccaggctagttccaggcttgcct aagctgtagagcaagtcactctcgttaaaaagtgcctctcccatatttttgtatataatttgcatctg aaattctgtttgccaataactatgaaattattcacattactaaaatcttcctgtgccaagttctccaa cgaattagatcacactcagatgaaatgctaataaaaattaaagctgtagccagtagcatgcgtatatt tgggctcagggccaacaggcaggcgatctgggtgtaagaaaataggctaatggctgtggaatctggtc tctagtggctccgctgagagctgacctcaaccacgctccctcaaattgattgccttccaggttatgat ttctcatcacaggaaactttgttgtccaattcaaaccctgtgagtgaaaacaaaaacaggagagcaag tgctgctccccgtgccccaaagccccttctgtcagggatcccaaatgcaccccagagaacagcttagc ctgcaagggctggtcctcatcgcataccatacataggtggagggcttgttattcaattcctggcctat gagaggatacccctattgttcctgaaaatgctgaccaggaccttacttgtaacaaagatccctctgcc ccacaatccagttaaggcaggagcaggagccggagcaggagcagaagataagccttggatgaagggca agatggatagggctcgctctgccccaagccctgctgataccaagtgcctttaagatacagcctttccc atcctaatctggaaaggaaacaggaaaaaggaacttaaccctccctgtgctcagacagaaatgagact gttaccgcctgttctgtggtgtttctccttgccgccaacttgtaaacaagagcgagtggaccatgcga gcgggaagtcgcaaagttgtgagttgttgaaagct (SEQ ID NO: 34) In some embodiments, the vector comprises a nucleotide sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 34. POST-TRANSCRIPTIONAL REGULATORY ELEMENTS The vector of the invention may comprise one or more post-transcriptional regulatory elements. Suitably, the protein-coding sequence is operably linked to one or more post- transcriptional regulatory elements. The post-transcriptional regulatory element may improve gene expression. The vector of the present invention may comprise a Woodchuck Hepatitis Virus Post- transcriptional Regulatory Element (WPRE). Suitably, the protein-coding sequence is operably linked to a WPRE. Suitable WPRE sequences will be well known to those of skill in the art (see, for example, Zufferey et al. (1999) Journal of Virology 73: 2886-2892; Zanta-Boussif et al. (2009) Gene Therapy 16: 605-619). Suitably, the WPRE is a wild-type WPRE or is a mutant WPRE. For example, the WPRE may be mutated to abrogate translation of the woodchuck hepatitis virus X protein (WHX), for example by mutating the WHX ORF translation start codon. In some embodiments, the WPRE comprises or consists of a nucleotide sequence that has at least 70% sequence to SEQ ID NO: 35 or a fragment thereof. Suitably, the WPRE comprises or consists of a nucleotide sequence that has at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to SEQ ID NO: 35 or a fragment thereof. In some embodiments, the WPRE comprises or consists of the nucleotide sequence SEQ ID NO: 35 or a fragment thereof. AATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTAC GCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCT CCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGC GTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCT TTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCT GCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAATCATCGTCCTTT CCTTGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGC CCTCAATCCAGCGGACCTTCCTTCCCGC (SEQ ID NO: 35) An example WPRE-miRT126x2-miRT130x2 sequence is: TCGACAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCT TTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCAT TTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAAC GTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAG CTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGC CCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGT CCTTTCCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCT TCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTAGAGCATTATTACTCACG GTACGACGATGCATTATTACTCACGGTACGAACGCGTATGCCCTTTTAACATTGCACTGATGCATATG CCCTTTTAACATTGCACTG (SEQ ID NO: 36) In some embodiments, the vector comprises a nucleotide sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 36. EXEMPLARY TRANSGENES AND VECTORS An example nucleotide sequence encoding human IFNα-P2A-oIL-2 is: ATGGCGCTGACCTTTGCGCTGCTGGTGGCGCTGCTGGTGCTGAGCTGCAAAAGCAGCTGCAGCGTGGG CTGCGATCTGCCGCAGACCCATAGCCTGGGCAGCCGCCGCACCCTGATGCTGCTGGCGCAGATGCGCC GCATTAGCCTGTTTAGCTGCCTGAAAGATCGCCATGATTTTGGCTTTCCGCAGGAAGAATTTGGCAAC CAGTTTCAGAAAGCGGAAACCATTCCGGTGCTGCATGAAATGATTCAGCAGATTTTTAACCTGTTTAG CACCAAAGATAGCAGCGCGGCGTGGGATGAAACCCTGCTGGATAAATTTTATACCGAACTGTATCAGC AGCTGAACGATCTGGAAGCGTGCGTGATTCAGGGCGTGGGCGTGACCGAAACCCCGCTGATGAAAGAA GATAGCATTCTGGCGGTGCGCAAATATTTTCAGCGCATTACCCTGTATCTGAAAGAAAAAAAATATAG CCCGTGCGCGTGGGAAGTGGTGCGCGCGGAAATTATGCGCAGCTTTAGCCTGAGCACCAACCTGCAGG AAAGCCTGCGCAGCAAAGAAGGCAGCGGCGCGACCAACTTTAGCCTGCTGAAACAGGCGGGCGATGTG GAAGAAAACCCGGGCCCGATGTATCGCATGCAGCTGCTGAGCTGCATTGCGCTGAGCCTGGCGCTGGT GACCAACAGCGCGCCGACCAGCAGCAGCACCAAAAAAACCCAGCTGCAGCTGGAAAACCTGCTGGTGC TGCTGACCCATATTCTGAACAAAATTAACAACTATAAAAACCCGAAACTGACCCGCATGCTGACCTTT AAATTTTATATGCCGAAAAAAGCGACCGAACTGAAACATCTGCAGTGCCTGGAAGAAGAACTGAAACC GCTGGAAGAAGTGCTGAACCTGGCGCAGAGCAAAAACTTTCATCTGCGCCCGCGCGATCTGATTAGCA ACATTAACGTGATTGTGCTGGAACTGAAAGGCAGCGAAACCACCTTTATGTGCGAATATGCGGATGAA ACCGCGACCATTGTGGAATTTCTGAACCGCTGGATTACCTTTTGCCAGAGCATTATTAGCACCCTGAC CTAA (SEQ ID NO: 31) An example human IFNα-P2A-oIL-2 amino acid sequence is: MALTFALLVALLVLSCKSSCSVGCDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGN QFQKAETIPVLHEMIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKE DSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESLRSKEGSGATNFSLLKQAGDV EENPGPMYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLENLLVLLTHILNKINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADE TATIVEFLNRWITFCQSIISTLT (SEQ ID NO: 32) In some embodiments, the transgene comprises or consists of a nucleotide sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 31. In some embodiments, the transgene encodes an amino acid sequence that comprises or consists of a sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 32. An example nucleotide sequence encoding mouse IFNα-P2A-oIL-2 is: Atggctaggctctgtgctttcctgatggtcctggcggtgctgagctactggccaacctgctctctagg atgtgaccttcctcagactcataacctcaggaacaagagagccttgacactcctggtacaaatgagga gactctcccctctctcctgcctgaaggacaggaaggactttggattcccgcaggagaaggtggatgcc cagcagatcaagaaggctcaagccatccctgtcctgagtgagctgacccagcagatcctgaacatctt cacatcaaaggactcatctgctgcatggaatacaaccctcctagactcattctgcaatgacctccacc agcagctcaatgacctgcaaggctgtctgatgcagcaggtgggggtgcaggaatttcccctgacccag gaagatgccctgctggctgtgaggaaatacttccacaggatcactgtgtacctgagagagaagaaaca cagcccctgtgcctgggaggtggtcagagcagaagtctggagagccctgtcttcctctgccaatgtgc tgggaagactgagagaagagaaaggatccggcgccaccaacttctccctgctgaagcaggccggcgac gtggaggagaaccccgggcccATGTACTCCATGCAGCTGGCCTCTTGCGTGACCCTGACACTGGTGCT GCTGGTGAACAGCGCTCCTACCAGCTCCTCTACAAGCTCCTCTACCGCTGAGGCTCAGCAACAACAGC AACAACAGCAGCAGCAGCAGCAGCACCTGGAGAATCTGCTGGTGCTGCTGACACACCTGCTGTCCAAG ATGGAGAACTACCGGAATCTGAAGCTGCCTCGCATGCTGACATTCAAGTTTTATCTGCCCAAGCAGGC CACCGAGCTGAAGGACCTGCAGTGTCTGGAGGATGAGCTGGGaCCACTGAGGCACGTGCTGGACCTGA CCCAGAGCAAGTCCTTCCAGCTGGAGGATGCTGAGAACTTTATCAGCAATATCCGGGTGACAGTGGTG AAGCTGAAGGGcTCCGACAACACCTTCGAGTGCCAGTTTGACGATGAGTCTGCCACAGTGGTGGATTT CCTGAGGAGATGGATCGCTTTTTGTCAGTCTATCATCTCTACCAGCCCTCAGTGA (SEQ ID NO: 33) In some embodiments, the transgene comprises or consists of a nucleotide sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 33. An exemplary cassette (Tie2E / P-Ifna1-P2A-oIL2-miRT) that may be comprised in a vector of the invention is: gatctaatgaaaatcaagatgctaggcacagtgccagatactttaacatagtaatatgactctttaga gttttgagacagggcctcatatagtttatgatgaattcactgttttggcaaagatgaccttgaactct taatccattcccaaagtgttgttgtcatatgtttggaccactcctggcttcatagtgttttttaaaac acccatggagagtcggtgtgaagatccacacgtctaaccctcagcatctgtgaatcaagccaggaggc gggtggttcagctgcctataatatctaagtttcagttagtaaggcctgcataatgaaacactgtctta aacacaaaaccaaaacccatgaaggagatactattgccatttaaaagtctctggaatggaaatagcta tcataatcttacctctgagccagtgtctgccctcaggtgtgcctgaggactgaacagggctatgcact cctcaggttggaaacattactagtcctcagtgtctgctcttgacctgttaacagctgagtcagggtct gccctcagctgtgcctgaggacagagctgagctatctacccctgcagattggaagcattacaggcact caagatcagccctgaagtgataaaacctaaggcagaaatccaccaagactagcagtgcctccgtgtct cttcctgtggctggtgggaaagagaggggcagtccttccttgatgcaaggtcgtgtgtctagtggcac gcttccttcattcccagtgagagcaagtgatcacctgggtaaggaaggttcaggtgcctgagctcgct ggagaattcatcactcatccatcactctgctcctgtagacataatcacttcttgttgggtctttatag agatgatttataactttgttgtttatagttttatgaatgtgtgtattcatttaggtcacatgggaggt acacattttcaggtgtctgtctttccatcacacgggctttgaattaaactcagtcttggttttaccgg ctggccatctcacctgcctgattatttaaaaatctccggagtaatccaggagtgtggtttatgattgt agtatcaacactcgggaggctgagggagcatcgttatcatgagctccaggctagttccaggcttgcct aagctgtagagcaagtcactctcgttaaaaagtgcctctcccatatttttgtatataatttgcatctg aaattctgtttgccaataactatgaaattattcacattactaaaatcttcctgtgccaagttctccaa cgaattagatcacactcagatgaaatgctaataaaaattaaagctgtagccagtagcatgcgtatatt tgggctcagggccaacaggcaggcgatctgggtgtaagaaaataggctaatggctgtggaatctggtc tctagtggctccgctgagagctgacctcaaccacgctccctcaaattgattgccttccaggttatgat ttctcatcacaggaaactttgttgtccaattcaaaccctgtgagtgaaaacaaaaacaggagagcaag tgctgctccccgtgccccaaagccccttctgtcagggatcccaaatgcaccccagagaacagcttagc ctgcaagggctggtcctcatcgcataccatacataggtggagggcttgttattcaattcctggcctat gagaggatacccctattgttcctgaaaatgctgaccaggaccttacttgtaacaaagatccctctgcc ccacaatccagttaaggcaggagcaggagccggagcaggagcagaagataagccttggatgaagggca agatggatagggctcgctctgccccaagccctgctgataccaagtgcctttaagatacagcctttccc atcctaatctggaaaggaaacaggaaaaaggaacttaaccctccctgtgctcagacagaaatgagact gttaccgcctgttctgtggtgtttctccttgccgccaacttgtaaacaagagcgagtggaccatgcga gcgggaagtcgcaaagttgtgagttgttgaaagctAtggctaggctctgtgctttcctgatggtcctg gcggtgctgagctactggccaacctgctctctaggatgtgaccttcctcagactcataacctcaggaa caagagagccttgacactcctggtacaaatgaggagactctcccctctctcctgcctgaaggacagga aggactttggattcccgcaggagaaggtggatgcccagcagatcaagaaggctcaagccatccctgtc ctgagtgagctgacccagcagatcctgaacatcttcacatcaaaggactcatctgctgcatggaatac aaccctcctagactcattctgcaatgacctccaccagcagctcaatgacctgcaaggctgtctgatgc agcaggtgggggtgcaggaatttcccctgacccaggaagatgccctgctggctgtgaggaaatacttc cacaggatcactgtgtacctgagagagaagaaacacagcccctgtgcctgggaggtggtcagagcaga agtctggagagccctgtcttcctctgccaatgtgctgggaagactgagagaagagaaaggatccggcg ccaccaacttctccctgctgaagcaggccggcgacgtggaggagaaccccgggcccATGTACTCCATG CAGCTGGCCTCTTGCGTGACCCTGACACTGGTGCTGCTGGTGAACAGCGCTCCTACCAGCTCCTCTAC AAGCTCCTCTACCGCTGAGGCTCAGCAACAACAGCAACAACAGCAGCAGCAGCAGCAGCACCTGGAGA ATCTGCTGGTGCTGCTGACACACCTGCTGTCCAAGATGGAGAACTACCGGAATCTGAAGCTGCCTCGC ATGCTGACATTCAAGTTTTATCTGCCCAAGCAGGCCACCGAGCTGAAGGACCTGCAGTGTCTGGAGGA TGAGCTGGGaCCACTGAGGCACGTGCTGGACCTGACCCAGAGCAAGTCCTTCCAGCTGGAGGATGCTG AGAACTTTATCAGCAATATCCGGGTGACAGTGGTGAAGCTGAAGGGcTCCGACAACACCTTCGAGTGC CAGTTTGACGATGAGTCTGCCACAGTGGTGGATTTCCTGAGGAGATGGATCGCTTTTTGTCAGTCTAT CATCTCTACCAGCCCTCAGTGATcgacaatcaacctctggattacaaaatttgtgaaagattgactgg tattcttaactatgttgctccttttacgctatgtggatacgctgctttaatgcctttgtatcatgcta ttgcttcccgtatggctttcattttctcctccttgtataaatcctggttgctgtctctttatgaggag ttgtggcccgttgtcaggcaacgtggcgtggtgtgcactgtgtttgctgacgcaacccccactggttg gggcattgccaccacctgtcagctcctttccgggactttcgctttccccctccctattgccacggcgg aactcatcgccgcctgccttgcccgctgctggacaggggctcggctgttgggcactgacaattccgtg gtgttgtcggggaagctgacgtcctttccatggctgctcgcctgtgttgccacctggattctgcgcgg gacgtccttctgctacgtcccttcggccctcaatccagcggaccttccttcccgcggcctgctgccgg ctctagagcattattactcacggtacgacgatgcattattactcacggtacgaacgcgtatgcccttt taacattgcactgatgcatatgcccttttaacattgcactg (SEQ ID NO: 37) In some embodiments, the vector comprises a nucleotide sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 37. T CELLS T cells (or T lymphocytes) are a type of lymphocyte that play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells (NK cells), by the presence of a T cell receptor (TCR) on the cell surface. As used herein the term “T-cell” may refer to CD8+ T-cells, CD4+ T-cells, naive T-cells, memory stem T-cells, central memory T-cells, double negative T-cells, effector memory T- cells, effector T-cells, Th0 cells, Tc0 cells, Th1 cells, Tc1 cells, Th2 cells, Tc2 cells, Th17 cells, Th22 cells, gamma / delta T-cells. The T-cell used in the present invention may be used for adoptive T-cell transfer. The present invention also encompasses adoptive transfer of tumor-infiltrating lymphocytes (TIL) and / or marrow infiltrating lymphocytes (MIL). As used herein the term “adoptive T-cell transfer” refers to the administration of a T-cell population to a patient. A T-cell may be isolated from a subject and then genetically modified and cultured in vitro (ex vivo) in order to express a TCR or CAR (e.g. a tumor-associated- antigen (TAA)-specific TCR or CAR) before being administered to the patient. The T-cell may be genetically modified to also include a transgene. In some embodiments, the transgene may encode an orthogonal receptor. Adoptive cell transfer may be allogenic or autologous. By “autologous cell transfer” it is to be understood that the starting population of cells is obtained from the same subject as that to which the cell population is administered. Autologous transfer is advantageous as it avoids problems associated with immunological incompatibility and is available to subjects irrespective of the availability of a genetically matched donor. By “allogeneic cell transfer” it is to be understood that the starting population of cells is obtained from a different subject as that to which the cell population is administered. Preferably, the donor will be genetically matched to the subject to which the cells are administered to minimise the risk of immunological incompatibility. Alternatively, the donor may be mismatched and unrelated to the patient. Suitable doses of transduced cell populations are such as to be therapeutically and / or prophylactically effective. The dose to be administered may depend on the subject and condition to be treated, and may be readily determined by a skilled person. The T-cell may be derived from a T-cell isolated from a patient. The T-cell may be part of a mixed cell population isolated from the subject, such as a population of peripheral blood lymphocytes (PBL). T-cells within the PBL population may be activated by methods known in the art, such as using anti-CD3 and / or anti-CD28 antibodies or cell sized beads conjugated with anti-CD3 and / or anti-CD28 antibodies. The T-cell may be a CD4+helper T cell or a CD8+cytotoxic T cell. The T-cell may be in a mixed population of CD4+helper T cell / CD8+cytotoxic T-cells. Polyclonal activation, for example using anti-CD3 antibodies optionally in combination with anti-CD28 antibodies will trigger the proliferation of CD4+and CD8+T-cells. The T-cell may be isolated from the subject to which the genetically modified cell is to be adoptively transferred. In this respect, the cell may be made by isolating a T-cell from a subject, optionally activating the T-cell, transferring the TCR gene, CAR gene, and / or transgene encoding an orthogonal receptor to the cell ex vivo. Subsequent immunotherapy of the subject may then be carried out by adoptive transfer of the TCR-transduced cells. As used herein this process refers to autologous T-cell transfer - i.e. the TCR-transduced cells are administered to the same subject from which the T-cells were originally derived. Alternatively the T-cell may be isolated from a different subject, such that it is allogeneic. The T-cell may be isolated from a donor subject. For example, if the subject is undergoing allogeneic haematopoietic stem cell transplantation (Allo-HSCT) or solid organ transplantation or cell transplantation or stem cell therapy, the cell may be derived from the donor, from which the organs, tissues or cells are derived. The donor and the subject undergoing treatment may be siblings. Alternatively the T-cell may be derived from a stem cell, such as a haematopoietic stem cell (HSC). Gene transfer into HSCs does not lead to TCR expression at the cell surface as stem cells do not express CD3 molecules. However, when stem cells differentiate into lymphoid precursors that migrate to the thymus, the initiation of CD3 expression leads to the surface expression of the introduced TCR in thymocytes. An advantage of this approach is that the mature T-cells, once produced, express only the introduced TCR and little or no endogenous TCR chains, because the expression of the introduced TCR chains suppresses rearrangement of endogenous TCR gene segments to form functional TCR alpha and beta genes. A further benefit is that the gene-modified stem cells are a continuous source of mature T-cells with the desired antigen specificity. Accordingly, the HSC, the HPC, or the vector as defined herein may be used in combination with a gene-modified stem cell, preferably a gene-modified hematopoietic stem cell, which, upon differentiation, produces a T-cell expressing a TCR (e.g. a TAA-specific TCR). Other approaches known in the art may be used to reduce, limit, prevent, silence, or abrogate expression of endogenous genes in the cells of the present invention or cells prepared by the methods of the present invention. As used herein the term “disrupting” refers to reducing, limiting, preventing, silencing, or abrogating expression of a gene. The person skilled in the art is able to use any method known in the art to disrupt an endogenous gene, e.g., any suitable method for genome editing, gene silencing, gene knock-down or gene knock-out. For example, an endogenous gene may be disrupted with an artificial nuclease. An artificial nuclease is, e.g., an artificial restriction enzyme engineered to selectively target a specific polynucleotide sequence (e.g. encoding a gene of interest) and induce a double strand break in said polynucleotide sequence. Typically, the double strand break (DSB) will be repaired by error-prone non-homologous end joining (NHEJ) thereby resulting in the formation of a non- functional polynucleotide sequence, which may be unable to express an endogenous gene. In some embodiments, the artificial nuclease is selected from the group consisting of zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and CRISPR / Cas (e.g. CRISPR / Cas9). NK CELLS Natural killer (NK) cells are a type of cytolytic cell that form part of the innate immune system. NK cells provide rapid responses to innate signals from virally infected cells in an MHC independent manner. NK cells (belonging to the group of innate lymphoid cells) are defined as large granular lymphocytes (LGL) and constitute the third kind of cells differentiated from the common lymphoid progenitor generating B and T lymphocytes. NK cells are known to differentiate and mature in the bone marrow, lymph node, spleen, tonsils and thymus where they then enter into the circulation. TUMOR ASSOCIATED ANTIGEN (TAA) As used herein the term “tumor associated antigen” (TAA; also known as a tumor antigen) refers to an antigenic molecule expressed by a cancer cell, e.g. a tumor cell. A TAA may be recognised by an immune cell which expresses an immune receptor (e.g. a TCR, a transgenic TCR or a CAR) that is able to specifically bind to a portion (e.g. an epitope) of the TAA molecule. As used herein, the term TAA-specific T-cell refers to a T-cell which expresses a TCR or a CAR that is specific for a TAA. A T-cell expressing a TAA-specific TCR or TAA-specific CAR may be able to specifically target and kill tumor cells expressing the TAA. The TAA-specific TCR may be a transgenic TCR A particular TAA may be expressed at a high relative abundance on a particular type of tumor cell compared to a non-tumor cell (e.g. a healthy cell). Examples of TAAs include B7-H3, carcinoembryonic antigen (CEA), estrogen receptor, progesterone receptor, ephrinB2, ephrinA2, ROR1, mesothelin, c-Met, GD-2, and MAGE A3 TCR, 4-1BB, adenocarcinoma antigen, alpha-fetoprotein, BAFF, B-lymphoma cell, C242 antigen, carbonic anhydrase 9 (CA-IX), CCR4, CD152, CD200, CD22, CD19, CD22, CD123, CD133, CD221, CD23 (IgE receptor), CD28, CD4, CD40, CD44, CD44 v6, CD51, CD52, CD56, CD74, CD80, CS-1, CNT0888, CTLA-4, DR5, EpCAM, CD3, fibronectin extra domain- B, folate receptor 1, glycoprotein 75, GPNMB, HGF, human scatter factor receptor kinase, IGF-1 receptor, IGF-I, IgGl, L1-CAM, IL-13, IL-13 receptor α2, IL-6, insulin-like growth factor I receptor, integrin α5β1, integrin αvβ3, MORAb-009, MS4A1, mucin CanAg, N- glycolylneuraminic acid, NPC-1C, PDGF-Rα, PDL192, phosphatidylserine, prostatic carcinoma cells, RANKL, RON, SCH 900105, SDC1, SLAMF7, tenascin C, TGF beta 2, TGF- β, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, Vascular endothelial growth, factor (VEGF), VEGF-A, VEGFR-1, VEGFR2, vimentin, 5T4, CD5, CD19, CD20, CD21, CD25, CD37, CD30, CD33, CD45, CAMPATH-1 (CDw52), HLA-DR, Anti-idiotype, TAG-72, Ep-CAM, MUC1, Folate-binding protein, A33, G250, Prostate-specific membrane antigen, (PSMA), Prostate specific antigen (PSA), Ferritin, Gangliosides (e.g. GD2, GD3, GM2), Ley, CA-125, CA19-9, Epidermal growth factor receptor (EGFR), p185HER2, IL-2 receptor, de2-7 EGFR, EGFR variant III, Fibroblast activation protein (FAP), Glypican 3 (GPC3), CSPG4, Tenascin, metalloproteinases, Endosialin, Carbonic anhydrase, Galectin 9, Aldolase A, eIFγ4, Tyrosinase, Galectin 4, HERKV-K10, p53, NY-LU-12, Restin, NY-CO-38, MAGE-1, MAGE- 4a, SSX2, NY-ESO-1, SCP-1, 707-AP, AFP, ART-4, BAGE, b-catenin / m, Bcr-abl, CAMEL, CAP-1, CASP-8, CDC27m, CDK4 / m, CT, Cyp-B, DAM-6 (MAGE-B2) and DAM-10 (MAGE- B1), ELF2M, ETV6-AML1, G250, GAGE, GnT-V, Gp100, HAGE, HER-2 / neu, HLA-A*0201- R170I, HPV-E7, HSP70-2M, HST-2, hTERT (hTRT), iCE, KIAA0205, LAGE, LDLR / FUT, MAGE, MART-1 / Melan-A, MC1R, Myosin / m, MUC1, MUM-1, MUM-2, MUM-3, NA88-A, NY- ESO-1, P15, p190 minor bcr-abl, Pml / RARa, PRAME, RAGE, RU1, RU2, SAGE, SART-1, SART-3, TEL / AML1, TPI / m, TRP-1, protein 1, gp75, TRP-2, TRP-2 / INT2 or WT1. Additional TAAs may be identified using methods known in the art - see, e.g. the review article by Zilberberg et al.2015 (Biology of Blood and Marrow Transplantation, Volume 21, Issue 6, June 2015, Pages 1000–1007) the content of which is incorporated herein by reference. T-CELL RECEPTOR (TCR) During antigen processing, antigens are degraded inside cells and then carried to the cell surface by major histocompatibility complex (MHC) molecules. T-cells are able to recognise this peptide:MHC complex at the surface of the antigen presenting cell. There are two different classes of MHC molecules: MHC I and MHC II, each class delivers peptides from different cellular compartments to the cell surface. A T cell receptor (TCR) is a molecule found on the surface of T-cells that is responsible for recognising antigens bound to MHC molecules. The TCR heterodimer consists of an alpha (α) and beta (β) chain in around 95% of T-cells, whereas around 5% of T-cells have TCRs consisting of gamma (γ) and delta (δ) chains. Engagement of the TCR with antigen and MHC results in activation of the T lymphocyte on which the TCR is expressed through a series of biochemical events mediated by associated enzymes, co-receptors, and specialised accessory molecules. Each chain of the TCR is a member of the immunoglobulin superfamily and possesses one N-terminal immunoglobulin (Ig)-variable (V) domain, one Ig-constant (C) domain, a transmembrane / cell membrane-spanning region, and a short cytoplasmic tail at the C-terminal end. The variable domain of both the TCR α chain and β chain have three hypervariable or complementarity determining regions (CDRs). CDR3 is the main CDR responsible for recognising processed antigen, although CDR1 of the alpha chain has also been shown to interact with the N-terminal part of the antigenic peptide, whereas CDR1 of the beta chain interacts with the C-terminal part of the peptide. CDR2 is thought to recognize the MHC molecule. The constant domain of the TCR domain consists of short connecting sequences in which a cysteine residue forms a disulfide bond, making a link between the two chains. The TCR used in the present invention may have one or more additional cysteine residues in each of the α and β chains such that the TCR may comprise two or more disulfide bonds in the constant domains. The structure allows the TCR to associate with other molecules like CD3 which possess three distinct chains (γ, δ, and ε) in mammals and the ζ-chain. These accessory molecules have negatively charged transmembrane regions and are vital to propagating the signal from the TCR into the cell. The CD3- and ζ-chains, together with the TCR, form what is known as the T cell receptor complex. The signal from the T cell complex is enhanced by simultaneous binding of the MHC molecules by a specific co-receptor. For helper T-cells, this co-receptor is CD4 (specific for class II MHC); whereas for cytotoxic T-cells, this co-receptor is CD8 (specific for class I MHC). The co- receptor allows prolonged engagement between the antigen presenting cell and the T cell and recruits essential molecules (e.g., LCK) inside the cell involved in the signalling of the activated T lymphocyte. Accordingly, as used herein the term "T-cell receptor” (TCR) refers to a molecule capable of recognising a peptide when presented by an MHC molecule. The molecule may be a heterodimer of two chains α and β (or optionally γ and δ) or it may be a single chain TCR construct. The TCR used in the present invention may be a hybrid TCR comprising sequences derived from more than one species. For example, it has surprisingly been found that murine TCRs are more efficiently expressed in human T-cells than human TCRs. The TCR may therefore comprise human variable regions and murine constant regions. A disadvantage of this approach is that the murine constant sequences may trigger an immune response, leading to rejection of the transferred T-cells. However, the conditioning regimens used to prepare patients for adoptive T-cell therapy may result in sufficient immunosuppression to allow the engraftment of T-cells expressing murine sequences. The portion of the TCR that establishes the majority of the contacts with the antigenic peptide bound to the major histocompatibility complex (MHC) is the complementarity determining region 3 (CDR3), which is unique for each T cell clone. The CDR3 region is generated upon somatic rearrangement events occurring in the thymus and involving non-contiguous genes belonging to the variable (V), diversity (D, for β and δ chains) and joining (J) genes. Furthermore, random nucleotides inserted / deleted at the rearranging loci of each TCR chain gene greatly increase diversity of the highly variable CDR3 sequence. Thus, the frequency of a specific CDR3 sequence in a biological sample indicates the abundance of a specific T cell population. The great diversity of the TCR repertoire in healthy human beings provides a wide range protection towards a variety of foreign antigens presented by MHC molecules on the surface of antigen presenting cells. In this regard, it is of note that theoretically up to 1015different TCRs can be generated in the thymus. T-cell receptor diversity is focused on CDR3 and this region is primarily responsible for antigen recognition. The CDRs may, for example, comprise one, two, or three substitutions, additions or deletions from the given sequence, provided that the TCR retains the capacity to bind TAA derived peptide when presented by an MHC molecule. TCRs specific for a TAA may be generated easily by the person skilled in the art using any method known in the art. For example, TAA-specific TCRs may be identified by the TCR gene capture method of Linnemann et al (Nature Medicine 19, 1534–1541 (2013)). Briefly, this method uses a high- throughput DNA-based strategy to identify TCR sequences by the capture and sequencing of genomic DNA fragments encoding the TCR genes and may be used to identify TAA-specific TCRs. IMPROVED TCR EXPRESSION AND REDUCED TCR MISPAIRING Increasing the supply of CD3 molecules may increase TCR expression, for example, in a cell that has been modified to express the TCRs of the present invention. Accordingly, the T cell may be modified (e.g. using a vector) to comprise one or more genes encoding CD3-gamma, CD3-delta, CD3-epsilon and / or CD3-zeta. In one embodiment, the T cell comprises a gene encoding CD3-zeta. The T cell may comprise a gene encoding CD8. The vector encoding such genes may encode a selectable marker or a suicide gene, to increase the safety profile of the genetically engineered cell. The genes may be linked by self-cleaving sequences, such as the 2A self-cleaving sequence. Alternatively one or more separate vectors encoding a CD3 gene may be provided for co- transfer to a T cell simultaneously, sequentially or separately with one or more vectors encoding TCRs. The transgenic TCR may be expressed in a T-cell used in the present invention to alter the antigen specificity of the T-cell. TCR-transduced T-cells express at least two TCR alpha and two TCR beta chains. While the endogenous TCR alpha / beta chains form a receptor that is self-tolerant, the introduced TCR alpha / beta chains form a receptor with defined specificity for the given target antigen. However, TCR gene therapy requires sufficient expression of transferred (i.e. transgenic) TCRs as the transferred TCR might be diluted by the presence of the endogenous TCR, resulting in suboptimal expression of the transferred (e.g. tumor specific) TCR. Furthermore, mispairing between endogenous and introduced chains may occur to form novel receptors, which might display unexpected specificities for self-antigens and cause autoimmune damage when transferred into patients. Hence, several strategies have been explored to reduce the risk of mispairing between endogenous and introduced TCR chains. Mutations of the TCR alpha / beta interface is one strategy currently employed to reduce unwanted mispairing. For example, the introduction of a cysteine in the constant domains of the alpha and beta chain allows the formation of a disulfide bond and enhances the pairing of the introduced chains while reducing mispairing with wild type chains. Accordingly, the TCRs used in the present invention may comprise one or more mutations at the α chain / β chain interface, such that when the α chain and the β chain are expressed in a T-cell, the frequency of mispairing between said chains and endogenous TCR α and β chains is reduced. In one embodiment, the one or more mutations introduce a cysteine residue into the constant region domain of each of the α chain and the β chain, wherein the cysteine residues are capable of forming a disulfide bond between the α chain and the β chain. Another strategy to reduce mispairing relies on the introduction of polynucleotide sequences encoding siRNA, added to the genes encoding for the TCR α and or β chains, and designed to limit the expression of the endogenous TCR genes (Okamoto S. Cancer research 69, 9003- 9011, 2009). Accordingly, the vector or polynucleotide encoding the TCRs used in the present invention may comprise one or more siRNA or other agents aimed at limiting or abrogating the expression of the endogenous TCR genes. It is also possible to combine artificial nucleases, such as zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) or CRISPR / Cas systems, designed to target the constant regions of the endogenous TCR genes (TRAC and, or TRBC), to obtain the permanent disruption of the endogenous TCR alpha and / or beta chain genes, thus allowing full expression of the desired (e.g. tumor specific) TCR and thus reducing or abrogating the risk of TCR mispairing. This process, known as the TCR gene editing proved superior to TCR gene transfer in vitro and in vivo (Provasi E., Genovese P., Nature Medicine May; 18(5):807-15; 2012). In addition, the genome editing technology allows targeted integration of an expression cassette, comprising a polynucleotide encoding a TCR used in the present invention, and optionally one or more promoter regions and / or other expression control sequences, into an endogenous gene disrupted by the artificial nucleases (Lombardo A., Nature biotechnology 25, 1298-1306; 2007). Another strategy developed to increase expression of transgenic TCRs and to reduce TCR mispairing consists in “murinisation,” which replaces the human TCR α and TCR β constant regions (e.g. the TRAC, TRBC1 and TRBC2 regions) by their murine counterparts. Murizination of TCR constant regions is described in, for example, Sommermeyer and Uckert J Immunol; 2010 (184:6223-6231). Accordingly, the TCR used in the present invention may be murinised. CHIMERIC ANTIGEN RECEPTOR (CAR) “Chimeric antigen receptor" or "CAR" or "CARs" as used herein refers to engineered receptors which can confer an antigen specificity onto cells (for example, T cells, such as naive T cells, central memory T cells, effector memory T cells or combinations thereof). CARs are also known as artificial T-cell receptors, chimeric T-cell receptors or chimeric immunoreceptors. Preferably the CARs of the invention comprise an antigen-specific targeting region, an extracellular domain, a transmembrane domain, optionally one or more co-stimulatory domains, and an intracellular signaling domain. Antigen-specific targeting domain The antigen-specific targeting domain provides the CAR with the ability to bind to the target antigen of interest. The antigen-specific targeting domain preferably targets an antigen of clinical interest against which it would be desirable to trigger an effector immune response that results in tumor killing. The antigen-specific targeting domain may be any protein or peptide that possesses the ability to specifically recognise and bind to a biological molecule (e.g. a cell surface receptor or tumor protein, or a component thereof). The antigen-specific targeting domain includes any naturally occurring, synthetic, semi-synthetic, or recombinantly produced binding partner for a biological molecule of interest. Illustrative antigen-specific targeting domains include antibodies or antibody fragments or derivatives, extracellular domains of receptors, ligands for cell surface molecules / receptors, or receptor binding domains thereof, and tumor binding proteins. In a preferred embodiment, the antigen-specific targeting domain is, or is derived from, an antibody. An antibody-derived targeting domain can be a fragment of an antibody or a genetically engineered product of one or more fragments of the antibody, which fragment is involved in binding with the antigen. Examples include a variable region (Fv), a complementarity determining region (CDR), a Fab, a single chain antibody (scFv), a heavy chain variable region (VH), a light chain variable region (VL) and a camelid antibody (VHH). In a preferred embodiment, the binding domain is a single chain antibody (scFv). The scFv may be murine, human or humanised scFv. "Complementarity determining region" or "CDR" with regard to an antibody or antigen- binding fragment thereof refers to a highly variable loop in the variable region of the heavy chain or the light chain of an antibody. CDRs can interact with the antigen conformation and largely determine binding to the antigen (although some framework regions are known to be involved in binding). The heavy chain variable region and the light chain variable region each contain 3 CDRs. "Heavy chain variable region" or "VH" refers to the fragment of the heavy chain of an antibody that contains three CDRs interposed between flanking stretches known as framework regions, which are more highly conserved than the CDRs and form a scaffold to support the CDRs. "Light chain variable region" or "VL" refers to the fragment of the light chain of an antibody that contains three CDRs interposed between framework regions. "Fv" refers to the smallest fragment of an antibody to bear the complete antigen binding site. An Fv fragment consists of the variable region of a single light chain bound to the variable region of a single heavy chain. "Single-chain Fv antibody" or "scFv" refers to an engineered antibody consisting of a light chain variable region and a heavy chain variable region connected to one another directly or via a peptide linker sequence. Antibodies that specifically bind a tumor cell surface molecule can be prepared using methods well known in the art. Such methods include phage display, methods to generate human or humanised antibodies, or methods using a transgenic animal or plant engineered to produce human antibodies. Phage display libraries of partially or fully synthetic antibodies are available and can be screened for an antibody or fragment thereof that can bind to the target molecule. Phage display libraries of human antibodies are also available. Once identified, the amino acid sequence or polynucleotide sequence coding for the antibody can be isolated and / or determined. With respect to targeting domains that target cancer antigens, the selection of the targeting domain will depend on the type of cancer to be treated, and may target tumor antigens. A tumor sample from a subject may be characterised for the presence of certain biomarkers or cell surface markers. For example, breast cancer cells from a subject may be positive or negative for each of Her2Neu, Estrogen receptor, and / or the Progesterone receptor. A tumor antigen or cell surface molecule is selected that is found on the individual subject's tumor cells. Preferably the antigen-specific targeting domain targets a cell surface molecule that is found on tumor cells and is not substantially found on normal tissues, or restricted in its expression to non-vital normal tissues. TAAs which may be targeted by the CAR used in the present invention include but are not limited to any one or more of B7-H3, carcinoembryonic antigen (CEA), estrogen receptor, progesterone receptor, ephrinB2, ephrinA2, ROR1, mesothelin, c-Met, GD-2, MAGE A3 TCR, 4-1BB, adenocarcinoma antigen, alpha-fetoprotein, BAFF, B-lymphoma cell, C242 antigen, carbonic anhydrase 9 (CA-IX), CCR4, CD152, CD200, CD22, CD19, CD22, CD123, CD133, CD221, CD23 (IgE receptor), CD28, CD4, CD40, CD44, CD44 v6, CD51, CD52, CD56, CD74, CD80, CS-1, CNT0888, CTLA-4, DR5, EpCAM, CD3, fibronectin extra domain-B, folate receptor 1, glycoprotein 75, GPNMB, HGF, human scatter factor receptor kinase, IGF-1 receptor, IGF-I, IgGl, L1-CAM, IL-13, IL-13 receptor α2, IL-6, insulin-like growth factor I receptor, integrin α5β1, integrin αvβ3, MORAb-009, MS4A1, mucin CanAg, N- glycolylneuraminic acid, NPC-1C, PDGF-Rα, PDL192, phosphatidylserine, prostatic carcinoma cells, RANKL, RON, SCH 900105, SDC1, SLAMF7, tenascin C, TGF beta 2, TGF- β, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, Vascular endothelial growth, factor (VEGF), VEGF-A, VEGFR-1, VEGFR2, vimentin, 5T4, CD5, CD19, CD20, CD21, CD25, CD37, CD30, CD33, CD45, CAMPATH-1 (CDw52), HLA-DR, Anti-idiotype, TAG-72, Ep-CAM, MUC1, Folate-binding protein, A33, G250, Prostate-specific membrane antigen, (PSMA), Prostate specific antigen (PSA), Ferritin, Gangliosides (e.g. GD2, GD3, GM2), Ley, CA-125, CA19-9, Epidermal growth factor receptor (EGFR), p185HER2, IL-2 receptor, de2-7 EGFR, EGFR variant III, Fibroblast activation protein (FAP), Glypican 3 (GPC3), CSPG4, Tenascin, metalloproteinases, Endosialin, Carbonic anhydrase, Galectin 9, Aldolase A, eIFγ4, Tyrosinase, Galectin 4, HERKV-K10, p53, NY-LU-12, Restin, NY-CO-38, MAGE-1, MAGE- 4a, SSX2, NY-ESO-1, SCP-1, 707-AP, AFP, ART-4, BAGE, b-catenin / m, Bcr-abl, CAMEL, CAP-1, CASP-8, CDC27m, CDK4 / m, CT, Cyp-B, DAM-6 (MAGE-B2) and DAM-10 (MAGE- B1), ELF2M, ETV6-AML1, G250, GAGE, GnT-V, Gp100, HAGE, HER-2 / neu, HLA-A*0201- R170I, HPV-E7, HSP70-2M, HST-2, hTERT (hTRT), iCE, KIAA0205, LAGE, LDLR / FUT, MAGE, MART-1 / Melan-A, MC1R, Myosin / m, MUC1, MUM-1, MUM-2, MUM-3, NA88-A, NY- ESO-1, P15, p190 minor bcr-abl, Pml / RARa, PRAME, RAGE, RU1, RU2, SAGE, SART-1, SART-3, TEL / AML1, TPI / m, TRP-1, protein 1, gp75, TRP-2, TRP-2 / INT2 and WT1. Co-stimulatory domain The CAR used in the present invention may also comprise one or more co-stimulatory domain. This domain may enhance cell proliferation, cell survival and development of memory cells. Each co-stimulatory domain comprises the co-stimulatory domain of any one or more of, for example, members of the TNFR super family, CD28, CD137 (4-1BB), CD134 (OX40), DaplO, CD27, CD2, CD5, ICAM-1, LFA-1, Lck, TNFR-1, TNFR-II, Fas, CD30, CD40 or combinations thereof. Co-stimulatory domains from other proteins may also be used with the CAR used in the present invention. Additional co-stimulatory domains will be apparent to those of skill in the art. Intracellular signaling domain The CAR used in the present invention may also comprise an intracellular signaling domain. This domain may be cytoplasmic and may transduce the effector function signal and direct the cell to perform its specialised function. Examples of intracellular signaling domains include, but are not limited to, ζ chain of the T-cell receptor or any of its homologs (e.g., η chain, FcεR1γ and β chains, MB1 (Igα) chain, B29 (Igβ) chain, etc.), CD3 polypeptides (∆, δ and ε), syk family tyrosine kinases (Syk, ZAP 70, etc.), src family tyrosine kinases (Lck, Fyn, Lyn, etc.) and other molecules involved in T-cell transduction, such as CD2, CD5 and CD28. The intracellular signaling domain may be human CD3 zeta chain, FcyRIII, FcsRI, cytoplasmic tails of Fc receptors, immunoreceptor tyrosine-based activation motif (ITAM) bearing cytoplasmic receptors or combinations thereof. Transmembrane domain The CAR used in the present invention may also comprise a transmembrane domain. The transmembrane domain may comprise the transmembrane sequence from any protein which has a transmembrane domain, including any of the type I, type II or type III transmembrane proteins. The transmembrane domain of the CAR used in the present invention may also comprise an artificial hydrophobic sequence. The transmembrane domains of the CARs used in the present invention may be selected so as not to dimerise. Additional transmembrane domains will be apparent to those of skill in the art. Examples of transmembrane (TM) regions used in CAR constructs are: 1) The CD28 TM region (Pule et al, Mol Ther, 2005, Nov;12(5):933-41; Brentjens et al, CCR, 2007, Sep 15;13(18 Pt 1):5426-35; Casucci et al, Blood, 2013, Nov 14;122(20):3461-72.); 2) The OX40 TM region (Pule et al, Mol Ther, 2005, Nov;12(5):933-41); 3) The 41BB TM region (Brentjens et al, CCR, 2007, Sep 15;13(18 Pt 1):5426-35); 4) The CD3 zeta TM region (Pule et al, Mol Ther, 2005, Nov;12(5):933-41; Savoldo B, Blood, 2009, Jun 18;113(25):6392-402.); 5) The CD8a TM region (Maher et al, Nat Biotechnol, 2002, Jan;20(1):70-5.; Imai C, Leukemia, 2004, Apr;18(4):676-84; Brentjens et al, CCR, 2007, Sep 15;13(18 Pt 1):5426-35; Milone et al, Mol Ther, 2009, Aug;17(8):1453-64.). VARIANTS, DERIVATIVES, ANALOGUES, HOMOLOGUES AND FRAGMENTS In addition to the specific proteins and polynucleotides mentioned herein, the present invention also encompasses the use of variants, derivatives, analogues, homologues and fragments thereof. In the context of the present invention, a variant of any given sequence is a sequence in which the specific sequence of residues (whether amino acid or nucleic acid residues) has been modified in such a manner that the polypeptide or polynucleotide in question substantially retains at least one of its desired functions. A variant sequence can be obtained by addition, deletion, substitution, modification, replacement and / or variation of at least one residue present in the protein sequences disclosed herein. The term “derivative” as used herein, in relation to proteins or polypeptides of the present invention includes any substitution of, variation of, modification of, replacement of, deletion of and / or addition of one (or more) amino acid residues from or to the sequence providing that the resultant protein or polypeptide substantially retains at least one of its desired functions. The term “analogue” as used herein, in relation to polypeptides or polynucleotides includes any mimetic, that is, a chemical compound that possesses at least one of the desired functions of the polypeptides or polynucleotides which it mimics. Proteins used in the present invention may also have deletions, insertions or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent protein. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and / or the amphipathic nature of the residues as long as the endogenous function is retained. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include asparagine, glutamine, serine, threonine and tyrosine. A substitution may involve replacement of an amino acid for a similar amino acid (a conservative substitution). A similar amino acid is one which has a side chain moiety with related properties as grouped together, for example as shown below: (i) basic side chains: lysine (K), arginine (R), histidine (H); (ii) acidic side chains: aspartic acid (D) and glutamic acid (E); (iii) uncharged polar side chains: asparagine (N), glutamine (Q), serine (S), threonine (T) and tyrosine (Y); or (iv) non-polar side chains: glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), methionine (M), tryptophan (W) and cysteine (C). Variant sequences may comprise amino acid substitutions, additions, deletions and / or insertions. Conservative substitutions, additions or deletions may be made, for example according to the Table below. Amino acids in the same block in the second column and preferably in the same line in the third column may be substituted for each other: ALIPHATIC Non-polar G A P I L V Polar – uncharged C S T M N Q Polar - charged D E K R AROMATIC H F W Y The present invention also encompasses homologous substitution (substitution and replacement are both used herein to mean the interchange of an existing amino acid residue, with an alternative residue), e.g. like-for-like substitution such as basic for basic, acidic for acidic, polar for polar etc. Non-homologous substitution may also occur e.g. from one class of residue to another or alternatively involving the inclusion of unnatural amino acids, such as ornithine. The term “variant” as used herein may mean an entity having a certain homology with an amino acid sequence or a nucleotide sequence. The term “homology” can be equated with “identity”. A variant sequence may include an amino acid sequence which may be at least 50%, 55%, 65%, 75%, 85% or 90% identical, preferably at least 95%, at least 97%, at least 98% or at least 99% identical to the subject sequence. Typically, the variants will comprise the same active sites etc. as the subject amino acid sequence. Although homology can also be considered in terms of similarity (i.e. amino acid residues having similar chemical properties / functions), in the context of the present invention it is preferred to express homology in terms of sequence identity. A variant sequence may include a nucleotide sequence which may be at least 40%, 45%, 50%, 55%, 65%, 75%, 85% or 90% identical, preferably at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% identical to the subject sequence. Although homology can also be considered in terms of similarity, in the context of the present invention it is preferred to express homology in terms of sequence identity. Preferably, reference to a sequence which has a percent identity to any one of the SEQ ID NOs detailed herein refers to a sequence which has the stated percent identity over the entire length of the SEQ ID NO referred to. Identity comparisons can be conducted by eye or, more usually, with the aid of readily available sequence comparison programs. These commercially available computer programs can calculate percentage homology or identity between two or more sequences. Percentage homology may be calculated over contiguous sequences, i.e. one sequence is aligned with the other sequence and each amino acid in one sequence is directly compared with the corresponding amino acid in the other sequence, one residue at a time. This is called an “ungapped” alignment. Typically, such ungapped alignments are performed only over a relatively short number of residues. Although this is a very simple and consistent method, it fails to take into consideration that, for example, in an otherwise identical pair of sequences, one insertion or deletion in the nucleotide sequence may cause the following codons to be put out of alignment, thus potentially resulting in a large reduction in percent homology when a global alignment is performed. Consequently, most sequence comparison methods are designed to produce optimal alignments that take into consideration possible insertions and deletions without penalising unduly the overall homology score. This is achieved by inserting “gaps” in the sequence alignment to try to maximise local homology. However, these more complex methods assign “gap penalties” to each gap that occurs in the alignment so that, for the same number of identical amino acids, a sequence alignment with as few gaps as possible, reflecting higher relatedness between the two compared sequences, will achieve a higher score than one with many gaps. “Affine gap costs” are typically used that charge a relatively high cost for the existence of a gap and a smaller penalty for each subsequent residue in the gap. This is the most commonly used gap scoring system. High gap penalties will of course produce optimised alignments with fewer gaps. Most alignment programs allow the gap penalties to be modified. However, it is preferred to use the default values when using such software for sequence comparisons. For example when using the GCG Wisconsin Bestfit package the default gap penalty for amino acid sequences is -12 for a gap and -4 for each extension. Calculation of maximum percentage homology therefore firstly requires the production of an optimal alignment, taking into consideration gap penalties. A suitable computer program for carrying out such an alignment is the GCG Wisconsin Bestfit package (University of Wisconsin, U.S.A.; Devereux et al. (1984) Nucleic Acids Res. 12: 387). Examples of other software that can perform sequence comparisons include, but are not limited to, the BLAST package (see Ausubel et al. (1999) ibid – Ch.18), FASTA (Atschul et al. (1990) J. Mol. Biol. 403-410) and the GENEWORKS suite of comparison tools. Both BLAST and FASTA are available for offline and online searching (see Ausubel et al. (1999) ibid, pages 7-58 to 7-60). However, for some applications, it is preferred to use the GCG Bestfit program. Another tool, called BLAST 2 Sequences is also available for comparing protein and nucleotide sequences (see FEMS Microbiol. Lett. (1999) 174: 247-50; FEMS Microbiol. Lett. (1999) 177: 187-8). Although the final percentage homology can be measured in terms of identity, the alignment process itself is typically not based on an all-or-nothing pair comparison. Instead, a scaled similarity score matrix is generally used that assigns scores to each pairwise comparison based on chemical similarity or evolutionary distance. An example of such a matrix commonly used is the BLOSUM62 matrix – the default matrix for the BLAST suite of programs. GCG Wisconsin programs generally use either the public default values or a custom symbol comparison table if supplied (see the user manual for further details). For some applications, it is preferred to use the public default values for the GCG package, or in the case of other software, the default matrix, such as BLOSUM62. Once the software has produced an optimal alignment, it is possible to calculate percentage homology, preferably percentage sequence identity. The software typically does this as part of the sequence comparison and generates a numerical result. “Fragments” are also variants and the term typically refers to a selected region of the polypeptide or polynucleotide that is of interest either functionally or, for example, in an assay. “Fragment” thus refers to an amino acid or nucleic acid sequence that is a portion of a full- length polypeptide or polynucleotide. Such variants may be prepared using standard recombinant DNA techniques such as site- directed mutagenesis. Where insertions are to be made, synthetic DNA encoding the insertion together with 5' and 3' flanking regions corresponding to the naturally-occurring sequence either side of the insertion site may be made. The flanking regions will contain convenient restriction sites corresponding to sites in the naturally-occurring sequence so that the sequence may be cut with the appropriate enzyme(s) and the synthetic DNA ligated into the cut. The DNA is then expressed in accordance with the invention to make the encoded protein. These methods are only illustrative of the numerous standard techniques known in the art for manipulation of DNA sequences and other known techniques may also be used. Codon optimisation The polynucleotides used in the present invention may be codon-optimised. Codon optimisation has previously been described in WO 1999 / 41397 and WO 2001 / 79518. Different cells differ in their usage of particular codons. This codon bias corresponds to a bias in the relative abundance of particular tRNAs in the cell type. By altering the codons in the sequence so that they are tailored to match with the relative abundance of corresponding tRNAs, it is possible to increase expression. By the same token, it is possible to decrease expression by deliberately choosing codons for which the corresponding tRNAs are known to be rare in the particular cell type. Thus, an additional degree of translational control is available. Many viruses, including HIV and other lentiviruses, use a large number of rare codons and by changing these to correspond to commonly used mammalian codons, increased expression of the packaging components in mammalian producer cells can be achieved. Codon usage tables are known in the art for mammalian cells, as well as for a variety of other organisms. Codon optimisation may also involve the removal of mRNA instability motifs and cryptic splice sites. PHARMACEUTICAL COMPOSITION The HSCs, HPCs, myeloid / monocyte-committed progenitor cells, macrophages, monocytes, and T-cells or NK cells (e.g. TAA-specific T cells) for use according to the present invention may be formulated with a pharmaceutically acceptable carrier, diluent or excipient. By “pharmaceutically acceptable” is included that the formulation is sterile and pyrogen free. The carrier, diluent, and / or excipient must be “acceptable” in the sense of being compatible with the vector and not deleterious to the recipients thereof. Typically, the carriers, diluents, and excipients will be saline or infusion media which will be sterile and pyrogen free, however, other acceptable carriers, diluents, and excipients may be used. Acceptable carriers, diluents, and excipients for therapeutic use are well known in the pharmaceutical art. The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s) or solubilising agent(s). Examples of pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohol, silicone, waxes, petroleum jelly, vegetable oils, polyethylene glycols, propylene glycol, liposomes, sugars, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and the like. The product, cells, composition, kit or pharmaceutical composition according to the present invention may be administered in a manner appropriate for treating and / or preventing the diseases described herein. The quantity and frequency of administration will be determined by such factors as the condition of the subject, and the type and severity of the subject's disease, although appropriate dosages may be determined by clinical trials. The pharmaceutical composition may be formulated accordingly. The product, cells, composition, kit or pharmaceutical composition according to the present invention may be administered parenterally, for example, intravenously, or by infusion techniques. The vector, cell or pharmaceutical composition may be administered in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solution may be suitably buffered (preferably to a pH of from 3 to 9). The pharmaceutical composition may be formulated accordingly. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. The product, cells, composition, kit or pharmaceutical composition according to the present invention may be administered systemically, for example by intravenous injection. The pharmaceutical compositions may comprise cells of the invention in infusion media, for example sterile isotonic solution. The pharmaceutical composition may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The product, cells, composition, kit or pharmaceutical composition may be administered in a single or in multiple doses. Particularly, the vector, cell or pharmaceutical composition may be administered in a single, one off dose. The pharmaceutical composition may be formulated accordingly. The product, cells, composition, kit or pharmaceutical composition may be administered at varying doses (e.g. measured in vector genomes (vg) per kg). The physician in any event will determine the actual dosage which will be most suitable for any individual subject and it will vary with the age, weight and response of the particular subject. The pharmaceutical composition may further comprise one or more other therapeutic agents. The product, cells, composition, kit or pharmaceutical composition may be administered in combination with one or more other therapeutic agents. The term “combination”, or terms “in combination”, “used in combination with” or “combined preparation” as used herein may refer to the combined administration of two or more agents simultaneously, sequentially or separately. The term “simultaneous” as used herein means that the agents are administered concurrently, i.e. at the same time. The term “sequential” as used herein means that the agents are administered one after the other. The term “separate” as used herein means that the agents are administered independently of each other but within a time interval that allows the agents to show a combined, preferably synergistic, effect. Thus, administration “separately” may permit one agent to be administered, for example, within 1 minute, 5 minutes or 10 minutes after the other. In preferred embodiments, the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte comprising the vector is administered before the T cell or NK cell (e.g. TAA-specific T cell). PATIENT The patient may be a human patient. The patient may be a non-human animal. The patient may be afflicted with a cancer. Alternatively, the patient may be at risk of developing a cancer. The patient may have been previously determined to be at risk of developing a cancer. The increased risk may have been determined by genetic screening and / or by reviewing the patient’s family history. The patient may have been determined to express one or more genetic markers indicative of an increased risk of developing a cancer. Suitably, a person skilled in the art will be aware of genetic risk factors (e.g. genetic markers) associated with increased risk of developing a cancer. The skilled person may use any suitable method or technique known in the art to determine whether the subject has an increased risk of developing a cancer. The subject may have previously received treatment for the cancer. The subject may be in remission from the cancer. The subject may be resistant to chemotherapy. In some embodiments, the patient has been previously administered a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte of the invention prior to administration of the T cell or NK cell (e.g. TAA-specific T-cell). In some embodiments, the HSC, the HPC, the myeloid / monocyte-committed progenitor cell, the macrophage or the monocyte of the present invention is administered to the patient at least 6 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours prior to administration of the T cell or NK cell (e.g. TAA-specific T-cell). In some embodiments, the HSC, the HPC, the myeloid / monocyte-committed progenitor cell, the macrophage or the monocyte of the present invention is administered to the patient at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least seven days, or at least 14 days prior to administration of the T cell or NK cell (e.g. TAA-specific T-cell). In some embodiments, the HSC, the HPC, the myeloid / monocyte-committed progenitor cell, the macrophage or the monocyte of the present invention is administered to the patient at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks prior to administration of the T cell or NK cell (e.g. TAA-specific T-cell). In some embodiments, the HSC, the HPC, the myeloid / monocyte-committed progenitor cell, the macrophage or the monocyte of the present invention is administered to the patient at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least 10 months, at least 11 months, or at least 12 months prior to administration of the T cell or NK cell (e.g. TAA-specific T-cell). Both human and veterinary treatments are within the scope of the present invention. The terms “comprising”, “comprises” and “comprised of” as used herein are synonymous with “including” or “includes”; or “containing” or “contains”, and are inclusive or open-ended and do not exclude additional, non-recited members, elements or steps. The terms “comprising”, “comprises” and “comprised of” also include the term “consisting of”. The skilled person will understand that they can combine all features of the invention disclosed herein without departing from the scope of the invention as disclosed. Preferred features and embodiments of the invention will now be described by way of non- limiting examples. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of chemistry, biochemistry, molecular biology, microbiology and immunology, which are within the capabilities of a person of ordinary skill in the art. Such techniques are explained in the literature. See, for example, Sambrook, J., Fritsch, E.F. and Maniatis, T. (1989) Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory Press; Ausubel, F.M. et al. (1995 and periodic supplements) Current Protocols in Molecular Biology, Ch.9, 13 and 16, John Wiley & Sons; Roe, B., Crabtree, J. and Kahn, A. (1996) DNA Isolation and Sequencing: Essential Techniques, John Wiley & Sons; Polak, J.M. and McGee, J.O’D. (1990) In Situ Hybridization: Principles and Practice, Oxford University Press; Gait, M.J. (1984) Oligonucleotide Synthesis: A Practical Approach, IRL Press; and Lilley, D.M. and Dahlberg, J.E. (1992) Methods in Enzymology: DNA Structures Part A: Synthesis and Physical Analysis of DNA, Academic Press. Each of these general texts is herein incorporated by reference. EXAMPLES EXAMPLE 1 RESULTS Intratumour release of ortho-IL-2 ameliorates orthogonal CAR T cell functionality without overt toxicities We generated bidirectional lentiviral vectors (BdLV) encoding for either murine CARhCD19(as control) or CARB7H3and murine ortho-IL2Rβ (SEQ ID NO: 8) (Fig.1A). At first, we demonstrated the therapeutic benefit of local release of ortho-IL-2 in the tumour in an in vivo setting. Firefly luciferase-expressing GL261 murine GBM cells (GL261-Luc), also known to express the B7-H3 antigen (Fig.1B) were modified to constitutively express one of the two described ortho-IL-2 forms, i.e. 1G12 (SEQ ID NO: 9), the most potent and less specific, and 3A10, the most specific and less potent (Fig. 1C). The cells were then orthotopically injected in immunocompetent congenic B6 albino mice (Fig. 1C). Sequential bioluminescence imaging showed that tumour cells expressing ortho-IL-23A10 (SEQ ID NO: 10) grew as unmodified GL261-Luc cells, while ortho-IL-2 1G12 showed delayed tumour growth (day 20, P=0.0140 vs wt; P=0.0301 vs 3A10) (Fig.1D). These data suggest that ortho- IL-2 can activate some endogenous tumour-reactive T cells, especially when reaching high concentrations. Indeed, since in this setting the cytokine expression correlated with tumour burden, spill-over on the wild-type (wt) IL2Rβ occurs more evidently at late stages of tumour growth. Nevertheless, since our goal was to apply the orthogonal strategy to the TEM platform, which is known to allow mild and stable expression of the payload preferentially at the tumour site, we decided to leverage on the 1G12 form, also described as the form with more toxic potential when administered systemically, to potentiate orthogonal CAR T cells safely. Another cohort of B6 albino mice was challenged with ortho-IL-21G12-expressing GL261-Luc cells followed by intra-tumour injection of CARhCD19 or CARB7H3 T cells, with or without ortho- IL2Rβ (Fig.1E). CARB7H3 T cells promptly reduced tumour burden, but only with co-expression of the ortho-IL2Rβ tumour clearance was achieved in 100% of mice by day 18 (Fig.1F). In this artificial setting, tumours treated with control CARhCD19 T cells, regardless the co- expression of ortho-IL2Rβ, also started to shrink from day 14 on, with some of them clearing the tumour by day 18. We hypothesise that such behavior is due to an increased tumour growth that mirrored an increase in cytokine release, which is accompanied by loss of specificity due to spill-over on endogenous receptors, thus boosting also B7-H3 unrelated tumour-reactive T cell clones. Nonetheless, we gathered solid indications about the therapeutic potential and safety of tumour-directed ortho-IL-2 signalling in CAR T cells for the treatment of GBM, and in principle other tumours. Orthogonal IL-2 can be safely delivered by TEM-based gene therapy with no hemopoietic toxicity We aimed at implementing the ortho-pair strategy into the TEM-based gene and cell therapy platform for tumour-targeted release of ortho-IL-2 1G12 to establish a private crosstalk between TEMs and CAR T cells. Thus, we generated Tie2E / P-miRT constructs for the LV delivery of orthogonal 1G12 IL-2 (Fig. 2A). Lethally irradiated mice were transplanted with HSCs transduced with Empty or ortho-IL-2 LVs. After hemopoietic reconstitution (8 weeks later), ortho-IL-2 mice showed similar, and almost full engraftment as Empty mice, excluding any engraftment delay of Tie2-ortho-IL2-miRT transduced HSCs (Fig.2B). Furthermore, since ortho-IL-2 toxicity during systemic treatment was primarily detected as body weight loss, we demonstrated that mice transplanted with Tie2-ortho-IL2-miRT transduced HSCs did not experience any weight loss compared to Empty ones at full hemopoietic reconstitution (Fig. 2C). Measurement of vector copy number (VCN) on cultured HSCs at the time of transplant (Empty 4.13 copies / genome; ortho-IL-2 2.42 copies / genome) and on blood nucleated cells after hemopoietic reconstitution (Empty mice, median 4.36 copies / genome; ortho-IL-2 median, 1.90 copies / genome; Fig.2D) excluded any counter selection and highlighted overlapping fitness of Tie2-ortho-IL2-miRT transduced HSCs compared to Empty-transduced ones, since the level of transduction remained stable in the circulating progeny of both groups of mice. As expected, since TEMs are preferentially, but not exclusively, recruited at tumour sites, we detected circulating levels of IL-2 in the plasma of ortho-IL-2 mice, and not in Empty ones, even though at low levels (median 248 pg / mL; Fig.2E). Discrimination between orthogonal and wt IL-2 detected in the plasma was not technically feasible. The low levels of circulating IL-2 did not impact on any hemopoietic lineage, since reconstitution was completely overlapping to that of Empty mice in all lineages, further supporting the safety of our delivery platform also for highly toxic cytokines, as IL2. Red blood cell lineage was assessed by hemoglobin concentration (HGB, Fig.2F), platelets as absolute count (PLT, Fig.2G), and white blood cells both as total counts (WBC, Fig.2H) and counts of specific subpopulations, i.e. B cells (Fig.2I), myeloid CD11b+ cells (Fig.2J) and T cells (Fig. 2K) in both CD4 (Fig.2L) and CD8 (Fig.2M) subsets, with no difference between Empty and ortho-IL-2 mice in any comparison. TEM-based orthoIL-2 delivery safely improves orthoCAR T-cell function After hemopoietic reconstitution, syngeneic GBM cells (mGB2) were orthotopically injected in experimental mice. Twenty days after tumour challenge, intratumour injection of CAR T cells was performed. Empty and ortho-IL-2 (oIL2) mice received either CARhCD19or CARB7H3T cells also expressing the ortho-IL2Rβ (oCARhCD19and oCARB7H3, respectively; Fig. 3A). As hypothesized, mice from the oIL2+oCARB7H3group had the lowest tumour burden compared to other groups (vs Empty+oCARhCD19, P=0.0093) 14 days after administration of T cells (Fig. 3B). Importantly, no weight loss was observed from baseline in any experimental group (Fig. 3C), supporting the better tolerability profile of our delivery platform over the systemic administration of orthogonal cytokines. A mild increase in absolute counts of adoptive T cells per mg of tumour was observed in oIL- 2 mice receiving oCAR, both control and B7-H3 redirected (Fig. 3D), suggesting specific proliferation and / or improved survival of adoptive T cells. Analysis of tumour immune infiltrate showed that adoptively transferred T cells were more abundant in the CD8+ subset, while being around 20% in the CD4+ subset in all groups, highlighting that this oIL-2 gene therapy does not enrich for CD4+ cells (Fig.3E). Furthermore, both CD4+ and CD8+ oCAR T cells expressed higher levels of Granzyme-B in mice receiving oIL-2 gene therapy compared to Empty mice (Fig.3F-G), suggesting an improved activation status. oIL-2 increased the fraction of PD-1+LAG-3+ double positive CD8 T cells (Fig.3H). No differences were observed neither in terms of abundance nor in composition with oIL-2 gene therapy on the endogenous T cell compartment, which was composed prevalently by CD4+ over CD8+ T cells in all groups (Fig.4B), highlighting the specificity of the orthogonal receptor. Endogenous CD4+ T cells of Empty and oIL-2 mice, regardless the adoptive T cell received, expressed similar levels of CD25 and FoxP3, excluding the possibility of detrimental expansion of T regulatory cells that would be expected with wt IL-2 (Fig.4C-D). Considering tumour cells, the CAR target antigen B7-H3 was not down-regulated in any experimental group, suggesting that antigen escape is not the main resistance mechanism occurring in this setting (Fig.4E). We then evaluated the orthogonal IL-2 strategy in another cohort of mice. Empty and oIL-2 mice were challenged with mGB2 cells and then all of them received CARB7H3 T cells, with or without ortho-IL2Rβ, via intra-tumour delivery (Fig 5A). Two sequential MRI scans were performed, at 29 and 44 days after tumour injection. While at the first time-point there was no difference in tumour burden among groups, in the second one oIL-2 mice that received oCARB7H3 T cells had almost stable lesions, showing complete inhibition of tumour growth compared to other groups (Fig 5B; P=0.0476 vs Empty+CARB7H3; P=0.0293 vs Empty+oCARB7H3). In particular, tumour burden of oIL2+CARB7H3mice did not significantly increase from the previous time-point, whereas all the other groups experienced a significant outgrowth (P=0.039 Empty+CARB7H3; P=0.033 Empty+oCARB7H3; P=0.003 oIL2+CARB7H3) (Fig. 5D). This accounted also for a prolonged survival of oIL2+CARB7H3 mice (P=0.020 vs Empty+CARB7H3; P=0.011 vs Empty+oCARB7H3; P=0.055 vs oIL2+CARB7H3), while other groups were almost overlapping (Fig. 5C). A slight reduction in tumour burden and improvement in survival, although not significant, were observed in oIL2+CARB7H3mice, indicating at least a partial activity of ortho-IL-21G12 on the endogenous receptor, but the requirement of ortho-IL2Rβ to strongly potentiate CAR T-cell function. Double-route CAR T-cell delivery coupled with TEM-mediated delivery of ortho-IL-2 achieve robust anti-tumour activity against GBM We then applied repeated CAR T-cell injections both systemically and locally using the intra- tumour route for local delivery. We injected CARhCD19 or CARB7H3 T cells in tumour-bearing Empty mice first systemically and, 12 days after, locally (Fig.6A). We observed a significant reduction of tumour burden at two MRI evaluations (Fig.6B) and prolonged survival (Fig.6C) of Empty mice treated with CARB7H3T cells compared to CARhCD19T cells. These effects were not achieved with intra-tumour single administration in previous experiments. By leveraging on such strategy, we then wanted to apply this clinically relevant and highly effective ACT regimen to ortho-IL-2 gene delivery by TEMs. To do so, recipient mice were transplanted with HSCs transduced with Empty (Empty) or Tie2-oIl2-miRT (oIL2) LVs. After mGB2 orthotopic injection, all mice received orthoCARB7H3 with two different administrations, first intravenously and then intra-tumour (Fig.7A). All mice well tolerated the double-route ACT, with no significant weight loss (Fig. 7B), further supporting the safety of oIL-2 gene therapy in combination with oCAR T cells. A strong improvement of oCARB7H3 T- cell anti-tumour activity was reached by coupling them to oIL-2 gene delivery, significantly decreasing the tumour burden (Fig.7C) and prolonging survival (Fig.7D), with a fraction of long-term (>100days) surviving mice. Altogether, we demonstrated that superior anti-tumour activity of CAR T cells against GBM is achievable through oIL-2 TEM-mediated gene therapy leveraging on an immunocompetent mouse model and a clinically compliant delivery regimen. This approach is well tolerated and in principle extremely versatile for other tumours, CAR specificities, orthogonal pairs and combinations thereof. METHODS Plasmid construction and lentiviral vector production Empty vector LV was previously described (Escobar et al. (2018) Nat. Commun.9: 2896). The mouse CARB7H3and control CARhCD19sequence were generated by replacing the 1D3 scFv sequence of the ITAM-inactivated mouse CAR19 with the 376.96 and FMC63 ones, respectively, by DNA synthesis (Genscript). The two CAR sequences were cloned in place of the CAR19 cDNA (AgeI–SalI) in the ^NGFR-CAR19 transfer BdLV plasmid (Escobar et al. (2018) Nat. Commun.9: 2896). DNA sequence encoding for IL-2 receptor beta (IL2Rβ, reference protein sequence: Uniprot P16297) mutated as previously described (H134D+Y135F, ortho IL2Rβ; Sockolosky et al. (2018) Science 359: 1037-1042) was synthesised (Genscript) and cloned in place of ^NGFR in the ^NGFR-CARhCD19 and DNGFR-CARB7H3 transfer BdLV plasmids (RsrII-NheI). DNA sequences encoding for interleukin-2 (IL-2, reference protein sequence: Uniprot P04351) mutated as previously described (orthoIL-21G12: Q30N, M33V, D34L, Q36T, E37H, R41K; orthoIL-23A10: E29D, Q30N, M33V, D34L, Q36K, E37A; Sockolosky et al. (2018) Science 359: 1037-1042) were synthesised (Genscript) and cloned in place of CARhCD19in the ^NGFR- CARhCD19 transfer BdLV plasmid (AgeI-SalI) and in place of Ifna1 in the previously described Tie2-Ifna1-miRT126 / 130 (Escobar et al. (2018) Nat. Commun.9: 2896) (AgeI-SalI). Third generation VSV-G-pseudotyped LVs were produced by transient 4-plasmid co- transfection in HEK 293T cell line, concentrated by ultracentrifugation and titered as previously described (De Palma, M. et al. (2002) Transduction of a gene expression cassette using advanced generation lentiviral vectors. Methods Enzymol). Cell culture The human embryonic kidney 293T cells (HEK293T) were cultured in Iscove's modified Dulbecco’s medium (IMDM; Sigma-Aldrich) supplemented with 10% fetal bovine serum (FBS; Gibco), 100 IU / mL penicillin (Invitrogen), 100 μg / mL streptomycin (Invitrogen) and 2% glutamine (Gibco). Luciferase-transduced GL261 cells (GL261-luc2) were cultured in DMEM supplemented with 10% FBS and 100 μg / mL G418. mGB2 murine cells were cultured using DMEM-F12 (Invitrogen) supplemented with EGF 20 ng / mL (Peprotech), FGF2 20 ng / mL (Peprotech), 2% glutamine (Gibco), N2 supplement (Gibco), 100 IU / mL penicillin (Invitrogen) and 100 μg / mL streptomycin (Invitrogen). Splenocytes were obtained from the spleens of wild-type female CD45.1+ / CD45.2+ C57Bl / 6 mice (8-12 weeks-old). Spleens were mechanically smashed in PBS containing 0,5% BSA (Sigma-Aldrich) and 2mM EDTA (Sigma-Aldrich) with gentleMACS Octo Dissociator (Miltenyi) and passed through a 40- ^m-pore nylon filter. T cells were then purified by negative immune- magnetic selection (Pan T cell isolation kit, Miltenyi, # 130-095-130) and subsequently activated by culturing into coated plates: 24-well plates were previously coated with 660 μL / well of 1μg / mL anti-CD3 (BioXCell BE0002) and anti-CD28 (BioXCell BE0248) each in PBS for >2 hours at 37°C. After PBS removal, T cells were cultured in Roswell Park Memorial Institute (RPMI) medium (Lonza) supplemented with 10% FBS, 100 U / mL penicillin (Invitrogen), 100 μg / mL streptomycin (Invitrogen), 2% glutamine (Gibco), 1 mM Sodium Pyruvate (Gibco), 20mM HEPES (Gibco), 1 mM MEM NEAA (Gibco), 0.05mM Beta- Mercaptoethanol (Gibco), 30 U / mL IL-2 (Proleukin), 5 ng / mL IL-7 (Peprotech) and 5 ng / mL IL- 15 (Peprotech). CD3 / CD28 stimulation was maintained for 96 hours. LV transduction was performed after 24 hours from stimulation with 20 TU / cell in the presence of 8 ^M Cyclosporin H and 2 mg / mL Lentiboost. A washing step was performed 24 hours after transduction, and T cells expanded by splitting every other day. Transduction and phenotype checks were performed by flow cytometry on day 7 of culture. All cells were maintained in a 5% CO2humidified atmosphere at 37°C. ELISA assay for IL-2 IL-2 concentration in culture supernatants and mouse plasma was assessed using ELISA MAX™ Deluxe Set Mouse IL-2 (BioLegend) according to the manufacturer's instructions. Mice C57Bl / 6 mice, both wild-type (CD45.2+) and Ly5.1 (CD45.1+), and B6 albino mice were purchased from Charles River Laboratory and maintained in a specific pathogen-free animal facility. All experiments and procedures were performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC) at San Raffaele Hospital animal facilities (IACUC number: 979 and 1136) and authorised by the Italian Ministry of Health and local authorities according to the Italian law. HSC transplantation Eight- to 12-week-old wild-type C57Bl / 6 (CD45.2+) mice were euthanised with CO2, and bone marrow (BM) harvested by flushing of the femurs and tibias. Lineage-negative (Lin-) cells enriched in HSCs were isolated from total BM using an immunomagnetic column-based cell purification system (QuadroMACS Separator with LS columns or MultiMACS Cell 24 Separator Plus with Multi-24 Column Blocks, Miltenyi Biotec) and Lineage Cell Depletion Kit (Miltenyi Biotec). HSCs transduction, culture and transplantation in recipient female 6-8 week-old C57Bl / 6 Ly5.1 mice (CD45.1+) were performed as previously described (De Palma et al. (2003) Nat. Med.9: 789–795). Transduction conditions were set to reach a vector copy number (VCN) ranging between 1.5- 2.5 per cell genome in the culture outgrowth of ortho-IL-2 treated cells. Because the CTRL vector routinely had higher infectivity than the ortho-IL-2 LV we always obtained higher VCN for the former vector. A fraction of transduced cells was cultured in IMDM supplemented with 10% FBS, 2% glutamine, 100 ng / mL mouse stem cell factor (SCF, Peprotech) and 100 ng / mL mouse fms- like tyrosine kinase 3 ligand (FLT3L, Peprotech), 100 U / mL penicillin and 100 μg / mL streptomycin. After 12 / 14 days of culture, VCN was measured. Hematopoietic reconstitution analyses Blood samples (~200 ^L) were collected into Microvette 500 Capillary Blood Collection Tubes containing tri-potassium EDTA (K3 EDTA, Sarstedt) by tail ventral artery wound. Hemocytometer analysis was performed with ProCyte Dx Hematology Analyzer (IDEXX).50 μL of blood were used for flow cytometric analyses; 100 μL were centrifuged at 3400 RCF for 10 minutes at room temperature (RT) to collect plasma. The remaining pellet was resuspended in PBS and DNA extracted for VCN analysis as described below. For flow-cytometric analysis, PB was first incubated with anti-mouse FcγIII / II receptor (CD16 / CD32) blocking antibody (1:100 dilution) for 10 minutes at RT and then incubated for 20 minutes at RT in the dark in the presence of the following antibodies: CD19, APC; CD3, PE; CD11b, FITC; CD4, Pe-Cy7; CD8, V500; CD45.1, APC-Cy7 and CD45.2, Pacific Blue (see Table below). Erythrocytes were lysed with the TQ-Prep workstation (Beckman-Coulter) in the presence of an equal volume of FBS and washed with PBS supplemented with 2% FBS. 7-aminoactinomycin D (7-AAD) (Sigma-Aldrich) was added to each tube to stain dead cells before acquisition on BD FACSCanto II (BD Biosciences) equipped with FACSDiva software (BD Biosciences). Analyses were performed using FlowJo software (version 10.6.1). Genomic DNA extraction, ddPCR and VCN calculation gDNA was extracted using either Maxwell 16 Cell DNA Purification Kit or Maxwell 16 Blood DNA Purification Kit according to sample nature, cultured cells or PB respectively, in the Maxwell 16 Instrument (Promega). For VCN measurement, 5-20 ng of gDNA were analysed through QX200 Droplet Digital PCR System (Bio-Rad) according to the manufacturer's instructions. Briefly, a primers / probe set for LV quantification was designed on the primer binding site region of the LV (FAM probe): - Fw primer: 5’-TACTGACGCTCTCGACC -3’ - Rv primer: 5’-TCTCGACGCAGGACTCG -3’ - FAM probe: 5’-(FAM)-ATCTCTCTCCTTCTAGCCTC -3’ and one for diploid gene quantification was designed on the murine Sema3a gene (HEX probe): -Fw primer: 5’-ACCGATTCCAGATGATTGGC -3’ - Rv primer: 5’-TCCATATTAATGCAGTGCTTG -3’ - HEX probe: 5’-(HEX)-AGAGGCCTGTCCTGCAGCTCATGG - 3’ The PCR reaction was performed with each primer (900 nM) and the probe (250 nM) following the manufacturer’s instructions (Bio-Rad). Reading of the droplets was performed with Bio- Rad QX200 Droplet Reader and analysed with QuantaSoft software (Bio-Rad). GBM cells orthotopic intracranial injection After deep anesthetisation with 2,2,2-tribromoethanol (250 mg / Kg, Sigma-Aldrich), or ketamine and xylazine (100 mg / Kg and 10 mg / Kg) mice were placed on a digital stereotaxic frame (Stoelting). A total of 2.5x105mGB2 cells or 5x103GL261-Luc2 cells in 2 μL PBS were injected at the following coordinates from the bregma: 2 mm right; 1 mm anterior; 3.5 mm deep at a flow of 0.2 μL / min using a 5-μl micro-syringe (Hamilton) with a 30G needle with an infusion pump (KD Scientific). After the surgical procedure, the skull hole was sealed with bone wax (Ethicon) and dental cement (Harvard). The skin was sutured and the wound disinfected. Pain was mitigated with subcutaneous injection of 5mg / Kg carprofen (Rymadil, Pfizer). CAR T cell injections T cells were transduced and processed as above described. For systemic adoptive transfer of T cells, 107CAR+ T cells (or equivalent amount of UT T cells, as control) were administered by tail vein injection. Mice were conditioned with 50 μg / g of cyclophosphamide one day prior to T cell injection. For local delivery of CAR T cells, 3x106CAR T cells were injected using the same procedure of GBM cells orthotopic intracranial injection, but injecting 5μL (0.5 μL / min), without prior conditioning. In vivo Magnetic resonance imaging (MRI) All experiments were performed on a 7-Tesla MRI scanner (BioSpec, Bruker BioSpin Gmbh) fully equipped for in vivo imaging in mice. Mice were anesthetised with a mixture of oxygen / isoflurane (97 / 3% for induction and 98-99 / 2-1% for maintenance) and placed on a warmed bed to keep the body temperature at 37°C. The breath rate was constantly monitored to adjust the anesthesia during the entire MRI exam. A mouse brain surface array coil used as receiver was placed over the animal head. To quantify tumour brain volume, coronal T2 weighted images were acquired along the entire brain using a 2D-TurboRARE sequence with the following parameters: FOV 1.9 × 1.4 cm, matrix 170 × 170, 18 slices 0.75 mm thick, spatial resolution of 82 × 112 μm2, repetition time TR 3000 ms, echo time TE = 48 ms, RARE factor of 10 and 5 averages. Tumour volume was calculated from the sum of tumour areas manually delineated with ImageJ tools (https: / / imagej.nih.gov / ij / index.htmL) on each acquired image. Tumour volumes were calculated by two independent operators. Plotted data represent mean values of the two calculations for each mouse. In vivo bioluminescence imaging In vivo bioluminescence imaging (BLI) was performed by using the IVIS SpectrumCT System (Perkin Elmer). This system is equipped with a back-thinned, back-illuminated CCD camera cooled at −90°C with a quantum efficiency in the visible range above 85%. Each animal received an intra-peritoneal injection of 150 mg luciferin / Kg body weight 10 minutes before performing BLI. During BLI acquisition, the animals were kept at 37°C and under gaseous anesthesia (2–3% isoflurane and 1 l / min oxygen). A set of images was acquired every 2 minutes from 10 to 20 minutes after luciferin injection to detect the highest BLI signal. The images were obtained using the following settings: exposure time=auto, binning=8, f=1 and a field of view equal to 13 cm (field C). Dark images were acquired before and then subtracted to bioluminescence images; no emission filters were used during BLI acquisitions. BLI image analysis BLI image analysis was performed by placing region of interests (ROI) over the head of the mice. The total flux (photons / seconds) was measured to quantify light emission in each ROI. Images were acquired and analysed using the Living Image 4.5 software (Perkin Elmer). Tumour isolation, dissociation and flow cytometric analysis Mice showing severe neurological and / or systemic symptoms or at predetermined experimental times were i.p. injected with lethal dose of 2,2,2-tribromoethanol (500 mg / Kg, Sigma-Aldrich) and perfused with saline solution plus EDTA 1 mM (Sigma-Aldrich) by intracardiac puncture and peristaltic pump (Watson-Marlow) and brains collected after perfusion. Tumours (GFP+, isolated under fluorescence stereo-microscope, Nikon SMZ1500) were dissociated using mouse Tumour Dissociation Kit (Miltenyi Biotec) and gentleMACSTM Octo Dissociator (Miltenyi Biotec), according to the manufacturer’s instructions. Debris removal was performed with Debris Removal Solution (Miltenyi Biotec) according to the manufacturer’s instructions. Single-cell suspensions were immunostained with a combination of antibodies described in the following table, and acquired on BD FACSymphony (BD Biosciences) equipped with FACSDiva software (BD Biosciences). Analyses were performed using FlowJo software (version 10.6.1). Statistical analysis Since normality assumptions were not met, nonparametric statistical tests were performed. Mann-Whitney or Kruskal-Wallis tests with Dunn’s correction were performed when comparing two or more experimental groups, respectively, with at least n=3 replicates. For survival experiments, the log-rank (Mantel–Cox) test was run. All statistical analyses were performed using Prism8 software. Mouse antibodies for flow cytometry Antibody target Fluorochrome Clone Company Code B7-H3 - EPNCIR122 Abcam ab134161 (CD276) B7-H3 AlexaFluor594 EPNCIR122 Abcam ab218282 (CD276) c-Kit Pe-Cy7 2B8 Biolegend 47-1171-8 CD11b FITC M1 / 70 Biolegend 101206 CD11b BUV737 M1 / 70 BD 564443 CD19 APC 1D3 BD 550992 CD25 APC PC-61 BioLegend 102012 CD3 PE 145-2C11 BD 553063 CD3 APC-Cy7 145-2C11 BD 557596 CD3 FITC 145-2C11 BD 553061 CD4 Pe-Cy7 GK1.5 eBioscience 25-0041-82 CD4 BUV737 GK1.5 BD 564298 CD4 FITC GK1.5 BioLegend 100406 CD44 BV421 RM4-5 BD 558107 CD45.1 APC-Cy7 A20 Biolegend 110716 CD45.1 FITC A20 BD 553775 CD45.1 BV650 A20 Biolegend 110735 CD45.2 PB 104 Biolegend 109820 CD45.2 APC-Cy7 104 eBioscience 47-0454-82 CD45.2 Percp-Cy5.5 104 BD 552950 CD62L BV786 MEL-14 BD 564109 CD62L APC MEL-14 BioLegend 104412 CD8 V500 53-6.7 BD 560778 LAG-3 PE C9B7W BD 552380 LAG-3 BV421 C9B7W BioLegend 125221 Lineage PE 17A2 BD 555275 cocktail NGFR APC ME20.4- Miltenyi 130-113-418 1.H4 NGFR PE ME20.4- Miltenyi 130-113-421 1.H4 PD-1 PE-Cy7 RMP1-30 BioLegend 109110 Sca-1 PB D7 Biolegend 108120 TCR β BV711 H57-597 BD 563135 LIVE / DEAD™ Fixable Yellow Dead Cell Stain Invitrogen L34959 Kit EXAMPLE 2 IFN-α and oIL-2 co-delivery potentiate CAR-T rescue by promoting effector function and recruiting endogenous T cells against GBM antigens Coupling the tumor-target delivery of an immune stimulating pleiotropic cytokine, e.g. IFN-α, along with private orthogonal stimulation of CAR T cells may achieve even superior therapeutic efficacy acting on complimentary anti-tumor mechanisms. Thus, we generated a Tie2-Ifna1-P2A-oIL2-miRT LV by inserting a self-cleaving P2A peptide coding sequence between the IFN-α and oIL2 coding sequences (Fig.8A). This construct enabled secretion of both cytokines by TIE2-expressing cells as observed in in vitro experiments and upon transplantation of engineered HSCs (Fig.8B-C). Engraftment of HSCs transduced with Empty, Tie2-Ifna1-miRT, Tie2-oIL2-miRT and Tie2- Ifna1-P2A-oIL2-miRT LV and hematopoietic reconstitution in peripheral blood (PB) were similar among the different groups (Empty, IFN, oIL2, IFN+oIL2 mice, respectively), except for VCN measurements in nucleated PB cells that were lower in IFN and IFN+oIL2 mice (Fig.8D- K). When combined with double-route administered oCARB7H3T cells, both oIL2 and IFN-α, either alone or in combination, reduced tumor burden at MRI evaluation as compared to Empty mice (Fig. 9A-B). Co-delivery of IFN-α and oIL2 by TEMs achieved prolonged overall survival compared to Empty mice at a greater extent than single-cytokine treatments (hazard ratios - HR- for death: oIL2 vs Empty HR 0.47; IFN vs Empty HR 0.22; IFN+oIL2 vs Empty HR 0.09; p=0.0019 Log-rank Mantel-Cox test) (Fig.9C). To investigate T-cell dynamics across the organism, tumor lesions, tumor-draining deep cervical lymph nodes (tdLNs), superficial cervical lymph nodes (non-tumor draining LN: ntdLNs), spleen, bone marrow (BM) and PB samples were profiled by high dimensional flow cytometry panel encompassing markers of T-cell memory and effector differentiation, activation, exhaustion, as well as Treg markers. CD45-mismatched adoptively transferred and endogenous CD3+cells were separately analyzed by PhenoGraph (Levine et al. (2015) Cell 162: 184–197), an algorithm capable of clustering single cells according to their relative expression of antigens. We identified 11 adoptive and 14 endogenous T-cell PhenoGraph clusters, which showed a clear tissue-specific distribution (Fig.10A). Tumor-infiltrating adoptive T cells were mainly composed by CD8+clusters, among which cluster 4 was highly enriched by IFN-α, oIL2 and further by their co-delivery (Fig.10A-B). These enriched cells expressed EOMES and T-bet, known transcription factors required by T cells to differentiate into effector phenotype, the activation marker CD25 and high levels of PD-1, likely representing CAR-Ts robustly activated within the TME (Fig.10A). Consistently, a CAR-T subset characterized by high PD-1 expression, was shown in previous studies to display superior cytotoxic function and persistence in the tumor site. Conversely, cluster 6, which was also found in tdLNs, was depleted upon cytokine delivery, especially in the combination group (Fig. 10A-B). These cells expressed low levels of activation markers (CD39, PD-1, KI-67) and high levels of TCF-7, representing a more stem-like population, possibly of non-transduced adoptive T cells. Altogether, these changes in cluster composition suggest a tumor-specific enrichment of activated CAR-Ts by both cytokines without detectable off-target activation throughout the other tissues analyzed. Endogenous tumor-infiltrating T cells were instead composed of a majority of CD4+cells (Fig. 10C). Intriguingly, cluster 5, the only CD4+GBM cluster expressing high levels of CD39, a marker associated with tumor reactivity, and effector markers (T-bet, CD44), was significantly increased in IFN and IFN+oIL2 mice (Fig.10C-D). Cluster 12, which was the only CD8+cluster identified in the tumor tissue, was similarly enriched in IFN and IFN+oIL2 mice and showed expression markers of effector T cells (Fig.10C-D). On the contrary, the more stem-like cluster 4, characterized by the absence of CD39 and higher expression of TCF-7, was under- represented in tumors of IFN and IFN+oIL2 mice and likely represented bystander cells (Fig. 10C-D). Interestingly, CD39+putative tumor-reactive endogenous CD8+cells could be identified also in PB, BM and spleen (cluster 10 of more naïve and 14 of short-lived effector KLRG-1+cells) and were significantly increased by IFN and IFN+oIL2 (Fig.10C-D). Finally, the central-memory cluster 7, co-expressing EOMES and TCF-7, was increased in PB and LNs of IFN and IFN+oIL2 mice. Altogether, these changes in endogenous T cell clusters suggest the engagement of a systemic anti-tumor response specifically triggered in the presence of IFN-α delivery. Conversely, the lack of major phenotypic changes in the endogenous compartment of oIL2 mice supports the private crosstalk established between TEMs and oCARB7H3 T cells selectively in the GBM TME. To functionally validate the findings of boosted effector function of oCARB7H3 and endogenous T cells by cytokine treatments, we performed IFN-γ ELISPOT with PB mononuclear cells (PBMCs) on B7-H3 positive or negative mGB2 cells (Fig.10E). Reactivity against mGB2 cells, mostly mediated by oCARB7H3 T cells targeting B7-H3, was similarly increased by oIL2 and IFN-α gene therapy and further by the co-delivery of the two cytokines. Co-delivery of IFN-α and oIL2, enhanced T-cell reactivity against B7-H3- mGB2 cells, suggesting a pivotal role of IFN-α in triggering antigenic spreading, which could be further promoted by concomitant orthogonal stimulation of oCAR-Ts by oIL2. All publications mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the disclosed products, cells, uses and methods of the invention will be apparent to the skilled person without departing from the scope and spirit of the invention. Although the invention has been disclosed in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the disclosed modes for carrying out the invention, which are obvious to the skilled person are intended to be within the scope of the following claims.

Claims

CLAIMS 1. A product comprising: (a) a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte comprising a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine; and (b) a T cell or NK cell, wherein the T cell or NK cell expresses an orthogonal receptor.

2. A hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte for use in therapy, wherein the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine, wherein the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte is used in combination with a T cell or NK cell, wherein the T cell or NK cell expresses an orthogonal receptor.

3. A T cell or NK cell for use in therapy, wherein the T cell or NK cell expresses an orthogonal receptor, wherein the T cell or NK cell is used in combination with a hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte, wherein the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte comprises a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine.

4. The product of claim 1, or the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to claim 2 or 3, wherein the orthogonal receptor is an IL-2 receptor or an IL-9 receptor.

5. The product of claim 1 or 4, or the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-4, wherein the orthogonal receptor is an IL2Rβ.

6. The product of any one of claims 1 or 4-5, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-5, wherein the orthogonal cytokine is an IL-2, IL-15 or IL-9.

7. The product of any one of claims 1 or 4-6, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-6, wherein the orthogonal cytokine is an IL-2.

8. The product of any one of claims 1 or 4-7, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-7, wherein: (i) the orthogonal receptor is human IL2Rβ modified at H133 and / or Y134, wherein the amino acids are numbered with reference to SEQ ID NO: 2; (ii) the orthogonal receptor is human IL2Rβ comprising: (a) a D at the position corresponding to amino acid 133; and / or (b) an F at the position corresponding to amino acid 134, wherein the amino acids are numbered with reference to SEQ ID NO: 2; or (iii) the orthogonal receptor comprises or consists of an amino acid sequence having at least 70% sequence identity to SEQ ID NO: 5, and comprises: (a) a D at the position corresponding to amino acid 133; and / or (b) an F at the position corresponding to amino acid 134, wherein the amino acids are numbered with reference to SEQ ID NO:

5.

9. The product of any one of claims 1 or 4-8, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-8, wherein: (i) the orthogonal cytokine is human IL-2 modified at H16, L19, D20, Q22, M23 and / or G27, wherein the amino acids are numbered with reference to SEQ ID NO: 1; (ii) the orthogonal cytokine is human IL-2 comprising: (a) a N at the position corresponding to amino acid 16; (b) a V at the position corresponding to amino acid 19; (c) an L at the position corresponding to amino acid 20; (d) a T at the position corresponding to amino acid 22; (e) an H at the position corresponding to amino acid 23; and / or (f) a K at the position corresponding to amino acid 27, wherein the amino acids are numbered with reference to SEQ ID NO: 1; or(iii) the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70% sequence identity to SEQ ID NO: 6, and comprises: (a) a N at the position corresponding to amino acid 16; (b) a V at the position corresponding to amino acid 19; (c) an L at the position corresponding to amino acid 20; (d) a T at the position corresponding to amino acid 22; (e) an H at the position corresponding to amino acid 23; and / or (f) a K at the position corresponding to amino acid 27, wherein the amino acids are numbered with reference to SEQ ID NO:

6.

10. The product of any one of claims 1 or 4-8, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-8, wherein: (i) the orthogonal cytokine is human IL-2 modified at E15, H16, L19, D20, Q22 and / or M23, wherein the amino acids are numbered with reference to SEQ ID NO: 1; (ii) the orthogonal cytokine is human IL-2 comprising: (a) a D at the position corresponding to amino acid 15; (b) a N at the position corresponding to amino acid 16; (c) an V at the position corresponding to amino acid 19; (d) a L at the position corresponding to amino acid 20; (e) a K at the position corresponding to amino acid 22; and / or (f) an A at the position corresponding to amino acid 23, wherein the amino acids are numbered with reference to SEQ ID NO: 1; or (iii) the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70% sequence identity to SEQ ID NO: 7, and comprises: (a) a D at the position corresponding to amino acid 15; (b) a N at the position corresponding to amino acid 16; (c) an V at the position corresponding to amino acid 19; (d) a L at the position corresponding to amino acid 20; (e) a K at the position corresponding to amino acid 22; and / or (f) an A at the position corresponding to amino acid 23, wherein the amino acids are numbered with reference to SEQ ID NO:

7.

11. The product of any one of claims 1 or 4-7, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-7, wherein: (i) the orthogonal receptor is mouse IL2Rβ modified at H134 and / or Y135, wherein the amino acids are numbered with reference to SEQ ID NO: 4; (ii) the orthogonal receptor is mouse IL2Rβ comprising: (a) a D at the position corresponding to amino acid 134; and / or (b) an F at the position corresponding toamino acid 135, wherein the amino acids are numbered with reference to SEQ ID NO: 4; or (iii) the orthogonal receptor comprises or consists of an amino acid sequence having at least 70% sequence identity to SEQ ID NO: 8, and comprises: (a) a D at the position corresponding to amino acid 134; and / or (b) an F at the position corresponding to amino acid 135, wherein the amino acids are numbered with reference to SEQ ID NO:

8.

12. The product of any one of claims 1, 4-7 or 11, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-7 or 11, wherein: (i) the orthogonal cytokine is mouse IL-2 modified at Q30, M33, D34, Q36, E37 and / or R41, wherein the amino acids are numbered with reference to SEQ ID NO: 3; (ii) the orthogonal cytokine is mouse IL-2 comprising: (a) a N at the position corresponding to amino acid 30; (b) a V at the position corresponding to amino acid 33; (c) an L at the position corresponding to amino acid 34; (d) a T at the position corresponding to amino acid 36; (e) an H at the position corresponding to amino acid 37; and / or (f) a K at the position corresponding to amino acid 41, wherein the amino acids are numbered with reference to SEQ ID NO: 3; or (iii) the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70% sequence identity to SEQ ID NO: 9, and comprises: (a) a N at the position corresponding to amino acid 30; (b) a V at the position corresponding to amino acid 33; (c) an L at the position corresponding to amino acid 34; (d) a T at the position corresponding to amino acid 36; (e) an H at the position corresponding to amino acid 37; and / or (f) a K at the position corresponding to amino acid 41, wherein the amino acids are numbered with reference to SEQ ID NO:

9.

13. The product of any one of claims 1, 4-7 or 11, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-7 or 11, wherein: (i) the orthogonal cytokine is mouse IL-2 modified at E29, Q30, M33, D34, Q36 and / or E37, wherein the amino acids are numbered with reference to SEQ ID NO: 3; (ii) the orthogonal cytokine is mouse IL-2 comprising: (a) a D at the position corresponding to amino acid 29; (b) a N at the position corresponding to amino acid30; (c) an V at the position corresponding to amino acid 33; (d) a L at the position corresponding to amino acid 34; (e) a K at the position corresponding to amino acid 36; and / or (f) an A at the position corresponding to amino acid 37, wherein the amino acids are numbered with reference to SEQ ID NO: 3; or (iii) the orthogonal cytokine comprises or consists of an amino acid sequence having at least 70% sequence identity to SEQ ID NO: 10, and comprises: (a) a D at the position corresponding to amino acid 29; (b) a N at the position corresponding to amino acid 30; (c) an V at the position corresponding to amino acid 33; (d) a L at the position corresponding to amino acid 34; (e) a K at the position corresponding to amino acid 36; and / or (f) an A at the position corresponding to amino acid 37, wherein the amino acids are numbered with reference to SEQ ID NO:

10.

14. The product of any one of claims 1 or 4-13, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-13, wherein the transgene further encodes a second cytokine.

15. The product of any one of claims 1 or 4-14, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-14, wherein the miRNA target sequence is a miR-130a and / or miR-126 target sequence.

16. The product of any one of claims 1 or 4-15, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-15, wherein the transgene is operably linked to a tissue-specific promoter.

17. The product of claim 16, or the HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to claim 16, wherein the tissue-specific promoter is a TEK (Tie2) promoter.

18. The product of any one of claims 1 or 4-17, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-17, wherein the vector is a lentiviral vector.

19. The product of any one of claims 1 or 4-18, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-18, wherein the T-cell or NK cell expresses a chimeric antigen receptor (CAR) and / or a transgenic T cell receptor (TCR).

20. The product of any one of claims 1 or 4-19, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-19, wherein the T cell or NK cell is a tumour-associated antigen (TAA) specific T cell or NK cell, wherein the TAA is selected from the group consisting of B7-H3, carcinoembryonic antigen (CEA), estrogen receptor, progesterone receptor, ephrinB2, ephrinA2, ROR1, mesothelin, c-Met, GD-2, MAGE A3 TCR, 4-1BB, adenocarcinoma antigen, alpha-fetoprotein, BAFF, B-lymphoma cell, C242 antigen, carbonic anhydrase 9 (CA-IX), CCR4, CD152, CD200, CD22, CD19, CD22, CD123, CD133, CD221, CD23 (IgE receptor), CD28, CD4, CD40, CD44, CD44 v6, CD51, CD52, CD56, CD74, CD80, CS-1, CNT0888, CTLA-4, DR5, EpCAM, CD3, fibronectin extra domain-B, folate receptor 1, glycoprotein 75, GPNMB, HGF, human scatter factor receptor kinase, IGF-1 receptor, IGF-I, IgGl, L1-CAM, IL- 13, IL-13 receptor α2, IL-6, insulin-like growth factor I receptor, integrin α5β1, integrin αvβ3, MORAb-009, MS4A1, mucin CanAg, N-glycolylneuraminic acid, NPC-1C, PDGF-Rα, PDL192, phosphatidylserine, prostatic carcinoma cells, RANKL, RON, SCH 900105, SDC1, SLAMF7, tenascin C, TGF beta 2, TGF-β, TRAIL-R1, TRAIL-R2, tumor antigen CTAA16.88, Vascular endothelial growth, factor (VEGF), VEGF-A, VEGFR-1, VEGFR2, vimentin, 5T4, CD5, CD19, CD20, CD21, CD25, CD37, CD30, CD33, CD45, CAMPATH-1 (CDw52), HLA-DR, Anti- idiotype, TAG-72, Ep-CAM, MUC1, Folate-binding protein, A33, G250, Prostate-specific membrane antigen, (PSMA), Prostate specific antigen (PSA), Ferritin, Gangliosides (e.g. GD2, GD3, GM2), Ley, CA-125, CA19-9, Epidermal growth factor receptor (EGFR), p185HER2, IL- 2 receptor, de2-7 EGFR, EGFR variant III, Fibroblast activation protein (FAP), Glypican 3 (GPC3), CSPG4, Tenascin, metalloproteinases, Endosialin, Carbonic anhydrase, Galectin 9, Aldolase A, eIFγ4, Tyrosinase, Galectin 4, HERKV-K10, p53, NY-LU-12, Restin, NY-CO-38, MAGE-1, MAGE-4a, SSX2, NY-ESO-1, SCP-1, 707-AP, AFP, ART-4, BAGE, b-catenin / m, Bcr-abl, CAMEL, CAP-1, CASP-8, CDC27m, CDK4 / m, CT, Cyp-B, DAM-6 (MAGE-B2) and DAM-10 (MAGE-B1), ELF2M, ETV6-AML1, G250, GAGE, GnT-V, Gp100, HAGE, HER-2 / neu, HLA-A*0201-R170I, HPV-E7, HSP70-2M, HST-2, hTERT (hTRT), iCE, KIAA0205, LAGE, LDLR / FUT, MAGE, MART-1 / Melan-A, MC1R, Myosin / m, MUC1, MUM-1, MUM-2, MUM-3, NA88-A, NY-ESO-1, P15, p190 minor bcr-abl, Pml / RARa, PRAME, RAGE, RU1, RU2, SAGE, SART-1, SART-3, TEL / AML1, TPI / m, TRP-1, protein 1, gp75, TRP-2, TRP-2 / INT2 and WT1.

21. The product of any one of claims 1 or 4-20, or the HSC, HPC, myeloid / monocyte- committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-20, wherein the T-cell or NK cell has been engineered to disrupt at least one endogenous gene, wherein the at least one endogenous gene is selected from an endogenous gene encoding a TCR α chain, a TCR β chain and a major histocompatibility complex (MHC).

22. The HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to any one of claims 2-21, wherein the therapy is treatment or prevention of cancer.

23. The HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to claim 22, wherein the cancer is a solid tumour, optionally wherein the solid tumour is selected from the group consisting of glioblastoma, malignant CNS tumor, lung cancer, breast cancer, oesophageal cancer, gastric cancer, colon cancer, cholangiocarcinoma, pancreatic cancer, ovarian cancer, head and neck cancers, synovial sarcoma, angiosarcoma, osteosarcoma, thyroid cancer, endometrial cancer, neuroblastoma, rabdomyosarcoma, liver cancer, melanoma, prostate cancer, renal cancer, soft tissue sarcoma, urothelial cancer, biliary cancer, cervical cancer, colorectal cancer, and non-melanoma skin cancer.

24. The HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte, or T cell or NK cell for use according to claim 22, wherein the cancer is a hematological malignancy, optionally wherein the hematological malignancy is selected from the group consisting of acute myeloid leukemia (AML), lymphoblastic leukemia, acute lymphoblastic leukemia (ALL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), primary myelofibrosis, essential thrombocythemia, polycythemia vera, atypical chronic myeloid leukemia, chronic myeloid leukemia (CML), chronic lymphoid leukemia (CLL), lymphoma, multiple myeloma, non Hodgkin lymphoma and Hodgkin lymphoma.

25. A hematopoietic stem cell (HSC), a hematopoietic progenitor cell (HPC), a myeloid / monocyte-committed progenitor cell, a macrophage or a monocyte comprising a vector, wherein the vector comprises at least one miRNA target sequence operably linked to a transgene, wherein the miRNA target sequence prevents or reduces expression of the transgene in the HSC, HPC and / or myeloid / monocyte-committed progenitor cell, wherein the transgene encodes an orthogonal cytokine.

26. The HSC, HPC, myeloid / monocyte-committed progenitor cell, macrophage or monocyte of claim 25, wherein the transgene further encodes a second cytokine.

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