Method for providing antigen-reactive lymphocytes

Abstract

Disclosed is a method for providing antigen-reactive lymphocytes, comprising: (a) obtaining lymphocytes of an individual, wherein the individual harbours at least one antigen; (b) establishing a primary culture of the lymphocytes; (c) introducing a transient reporter system into lymphocytes of the primary culture, wherein the reporter system produces a signal upon nuclear translocation of Nuclear Factor of Activated T cells (NFAT); (d) challenging said lymphocytes with at least one antigen; and (e) selecting from said lymphocytes at least one antigen-reactive lymphocyte by detecting the signal. Also disclosed is a pharmaceutical composition comprising expanded antigen-reactive lymphocytes obtained by this method and a kit for performing this method.

Description

[0001]Method for providing antigen-reactive lymphocytes The field of the present invention relates to methods for providing antigen-reactive lymphocytes, in particular for autologous cell therapy. In recent years, immunotherapeutic strategies have gained prominence as a powerful approach to treat various medical conditions, most notably cancer. One such immunotherapeutic strategy is autologous cell therapy. This therapy involves harvesting cells from a patient, manipulating or enriching them in a controlled environment to enhance their therapeutic potential, and then reintroducing these modified or enriched cells back into the same patient. This avoids the complications associated with immune rejection, which is often a concern in allogeneic therapies that use cells from a donor. Lymphocytes (such as B cells or T cells) may be used for cell therapy. The field of immunotherapy with T lymphocytes, especially chimeric antigen receptor (CAR) T cell therapy (see e.g., Sterner & Sterner, 2021), is already quite advanced. Cell therapy based on T lymphocytes with engineered T cell receptors (TCRs) represent a promising therapeutic alternative (Baulu et al, 2023). Immunotherapy based on regulatory T cells may be used to achieve antigen-specific immune suppression and stable tolerance inductions in autoimmune diseases or for immune suppression after organ transplantation (Sakaguchi et al, 2023). T-cell-based immunotherapy is also being developed as a strategy against infectious diseases, see for instance Zhou et al, 2021. WO 2022 / 200456 A1 concerns antigen-reactive TCRs. Disclosed is a method of identifying a T-cell reactive to cells of a subject presenting a T-cell activating antigen (reactive T-cell), comprising (a) determining expression of at least one of CCL4, CCL4L2, CCL3, CCL3L1, and CXCL13 in T-cells from a sample of said subject; and (b) identifying a reactive T-cell based on the determination of step (a). The document also discloses a pharmaceutical composition comprising reactive T-cells identified by the method. Remarkable progress has also been made in the field of B cell therapy, as reviewed in Gupta et al, 2022. Further, autologous cell therapy involving tumour-infiltrating lymphocytes (TILs) has shown significant promise in the treatment of cancer (Zhao et al, 2022). TILs are specialized lymphocytes that have been isolated from a patient's tumour tissue and possess the intrinsic capability to target and eliminate cancerous cells. WO 2022 / 087380 A1 relates to compositions and methods for TCR identification. More specifically, the document discloses a method for identifying an antigen-reactive cell that recognizes an endogenous antigen of a cancer cell line in complex with an MHC molecule expressed by a subject, comprising: (a) providing a cell that is a cancer cell line expressing an endogenous antigen in complex with an exogenous MHC molecule, wherein the exogenous MHC molecule is the MHC molecule expressed by the subject or derived from the subject; (b) contacting the cancer cell line with a first plurality of TCR-expressing cells, wherein the first plurality of TCR-expressing cells or a subset of the first plurality of TCR-expressing cells is activated by the endogenous antigen in complex with the exogenous MHC of the cancer cell line; and (c) subsequent to contacting in (b), identifying the subset of the first plurality of TCR-expressing cells, thereby identifying the antigen-reactive cell that recognizes the endogenous antigen of the cancer cell line. The TCR-expressing cell may be TILs. Rosenberg et al, 2023, discusses TIL therapy for patients with solid epithelial cancers. According to this publication, the natural lymphocyte reactivity targeting non-shared unique antigens in each patient emphasizes the highly personalized nature of this immunotherapy. In general, patients are treated with their own cells that target antigens unique to their own cancer. Rohaan et al, 2022, discloses a seminal clinical trial of TIL therapy in advanced melanoma. It was found that, in patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received checkpoint therapy with the anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab. While these are impressive results, still more than half of the patients in the TIL treatment group did not show a response to the treatment. One reason for this is probably that in this subgroup of patients, the yield of effective TILs obtained from the resected tumours of the patients was insufficient. More generally, providing effective antigen-reactive lymphocytes based on biopsies obtained from the patient is challenging, also for diseases other than cancer, such as inflammatory diseases, infections or autoimmune disorders. It is thus an object of the present invention to provide improved methods for obtaining antigen-reactive lymphocytes. The present invention relates to a method for providing antigen- reactive lymphocytes, comprising: (a) obtaining lymphocytes of an individual, wherein the individual harbours at least one antigen (this is typically achieved by obtaining lymphocytes from a biopsy sample and / or blood sample obtained from the individual; (b) establishing a primary culture of the lymphocytes; (c) introducing a transient reporter system into lymphocytes of the primary culture, wherein the reporter system produces a signal upon nuclear translocation of Nuclear Factor of Activated T cells (NFAT); (d) challenging said lymphocytes with at least one antigen; and (e) selecting from said lymphocytes at least one antigen- reactive lymphocyte by detecting the signal. Preferably, the method further comprises the following steps: (f) expanding the at least one antigen-reactive lymphocyte; and (g) formulating a pharmaceutical composition comprising expanded antigen-reactive lymphocytes for administration to the individual. In an aspect, the present invention also relates to the pharmaceutical composition obtained by this method. In another aspect, the present invention relates to a method for providing and administering antigen-reactive lymphocytes to an individual in need thereof, as disclosed hereinbelow. In yet another aspect, the present invention provides a kit for selecting antigen-reactive lymphocytes, comprising: - a first container comprising a transient reporter system for producing a signal upon nuclear translocation of NFAT, wherein the reporter system is ready-for-use for transfection of lymphocytes, optionally upon reconstitution in a liquid such as a buffer; - a second container comprising a transfection buffer; and - a third container comprising at least one cytokine. In the course of the present invention, it turned out that lymphocyte screening methods based on transient reporter systems which are activated upon translocation of NFAT into the nucleus of the lymphocytes were particularly suitable for increasing the yield and / or quality (as measured e.g., by cytotoxicity assays) of antigen-reactive lymphocytes. This offers an opportunity to increase the efficacy of lymphocyte-based therapies, such as TIL therapy, especially in patients who would otherwise not be responsive to these therapies. The reporter system being transient offers an additional advantage, namely that the lymphocytes maintain their native characteristics (if expanded and re-introduced into patient), in contrast to stable genetic manipulation. This increases the safety of the inventive therapy. Furthermore, the inventive method has a reduced toxicity towards the lymphocytes to be transfected, thereby increasing their viability and allowing better use of the full lymphocyte repertoire used as input to the method. For obtaining the lymphocytes from the individual, the lymphocytes may be harvested from a biological sample of the individual. The sample may be peripheral blood, a sample from the biopsy of healthy tissue or a tumour. In embodiments, the lymphocytes are isolated from the collected sample using density-gradient centrifugation or alternative techniques known in the art. Primary culture of the lymphocytes may be established as known in the art. For instance, a suitable lymphocyte culture medium, containing essential nutrients and growth factors is prepared under sterile conditions. The isolated lymphocytes are introduced into the prepared culture medium at a density optimized for cell growth and viability. The culture is incubated at physiological conditions, typically at 37°C and 5% CO2, to facilitate lymphocyte survival and proliferation, typically for a period of at least 24 hours. In particular if the primary culture contains cells other than lymphocytes (e.g., if all cells of a tumour sample are cultured without prior selection, cf. Fig. 9), a subsequent lymphocyte selection step (e.g., selecting for mature T cells, for instance via FACS of CD3+cells) may be performed. This lymphocyte selection step is preferably prior to selecting step (e). The transient reporter system (which may consist of one or several mRNAs, e.g., coding for a first fluorescent component with a nuclear localization signal (NLS) and a second fluorescent component with NFAT or the fragment thereof) for the NFAT nuclear translocation event may be introduced into the lymphocytes by transfection (or transduction) as generally known in the art, e.g., by electroporation, viral vectors, or lipid- based methods. Also, peptide-based delivery methods (e.g., with cell penetrating peptides) may be used, in particular of the transient reporter system is mRNA-based. Such delivery systems are for instance disclosed in Yokoo et al, 2022 and Foss et al, 2023. The antigen for the inventive method may be obtained from e.g., cells, cell lysate, or antigen-presenting cells (APCs) such as dendritic cells loaded with cell lysate (all of which may be obtained from the individual to be treated). For the challenging step, the prepared antigen may be introduced into the lymphocyte primary culture at a concentration optimized for effective lymphocyte activation. The culture may then be incubated under physiological conditions to allow for antigen-lymphocyte interaction and subsequent lymphocyte activation for a period of, e.g., at least 12 hours or 24 hours. Consequently, for the selecting step, lymphocytes displaying the activation signal may be sorted by fluorescence-activated cell- sorting (FACS) or magnetic-activated cell-sorting (MACS). It is important that the selecting step takes place while the signal of the reporter is still active, e.g., within at most 96, preferably at most 72, more preferably at most 48, even more preferably at most 36 or even at most 24, especially at most 12 hours after the challenge. Establishing step (b), introducing step (c) and challenging step (d) may be performed in any order. While the sequence (b)-(c)- (d) will commonly applied, other sequences are also possible, e.g., introducing the reporter before the culture is established, i.e., (c)-(b)-(d), or challenging the lymphocytes before the reporter is introduced and the culture is established, i.e., (d)-(c)-(b). Any one of these steps may also be performed concurrently, e.g., (b) and (c), (b) and (d), (c) and (d), or even (b), (c) and (d). NFAT is a family of transcription factors which have been demonstrated to be important in the immune response (see e.g., Macian, 2005). This family comprises five members, namely NFAT1 (also known as NFATp or NFATc2; UniProt entries Q13469 for human and Q60591 for mouse), NFAT2 (also known as NFATc or NFATc1; UniProt entries O95644 for human and O88942 for mouse), NFAT3 (also known as NFATc4; UniProt entries Q14934 for human and Q8K120 for mouse), NFAT4 (also known as NFATx or NFATc3; UniProt entries Q12968 for human and P97305 for mouse) and NFAT5 (UniProt entries O94916 for human and Q9WV30 for mouse). In the context of the present invention, the NFAT may be selected from any one of (in particular human or murine) NFAT1, NFAT2, NFAT3, NFAT4 and NFAT5, in particular from any one of NFAT1, NFAT2, NFAT 3 and NFAT4, especially NFAT1. NFAT reporter systems as such are known e.g., from Schaft et al, 2003. NFAT reporter systems introduced with viral vectors are discussed in Examples 8 and 12 of WO 03 / 064665 A2. Along similar lines, WO 2023 / 010118 A1 discloses NFAT-responsive reporter systems for assessing chimeric antigen receptor activation and methods of making and using the same. The TCR is a protein complex which consists of six parts (Alcover et al, 2018). The ap-subunits are glycosylated heterodimers, which are localized on the cell surface on human T-cells and show homology with immunoglobulins. These heterodimers are flanked by dimers on both sides consisting of representatives of the CD3 family: CD3y, CD36 and CD3e, respectively. This complex interacts with short peptides bound to major histocompatibility complexes (MHCs). After binding of TCR to the respective antigen, intracellular Ca2+rises through multiple mechanisms and leads to calcineurin activation. Calcineurin dephosphorylates NFAT1 and allows nuclear translocation and the expression of NFAT1 response genes (cf. Vaeth & Feske, 2018. In vivo experiments showed near- instantaneous accumulation of NFAT1 in the nucleus with a halftime for maximal accumulation of ~1 minute upon contact of CD8+T cells with their respective antigen through antigen presenting cells (APCs) in a binary fashion. In the nucleus, NFAT1 together with activator-protein 1 (AP1) promotes gene transcription. Nuclear export of NFAT was reported with a half- life around 20 minutes after the disengagement of the TCR. Remarkably, Ca2+seems to decrease at a faster pace and calcineurin inhibition does not lead to faster NFAT1 export. Thus, prolonged TCR signaling after disengagement seems not to be responsible for the slow kinetics of NFAT1. This seems to be equally true through activation with sufficient (APC) or insufficient (B-cells or tumour cells) antigen presentation. Accordingly, Ca2+can be used as a short-term readout (e.g., only a few minutes) and NFAT1 as a longer-term (e.g., up to many hours) readout to identify antigen-specific T cells. Previously known identification methods to screen for antigen- specfic T cells include among others Interferon-gamma based assays and surface marker analysis (Ben-Avi et al, 2018; Sade- Feldman et al, 2018). However, in the course of the present invention, nuclear translocation of NFAT was confirmed as a particularly suitable marker for selected antigen-specific lymphocytes from a population of lymphocytes upon previous challenge with the antigen. However, in addition to T lymphocytes, the present invention is also suitable for B lymphocytes. This is because B cell receptor activation triggers NFAT translocation as well, as for instance discussed in Sana et al, 2021. Tumours are characterized by the accumulation of a variable number of genetic alterations and the loss of normal cellular regulatory processes. These events are known to result in the expression of antigens, which can lead to presentation of peptides bound to major histocompatibility class molecules (MHCI and MHCII) distinguishing them from their normal counterparts. Cancer-specific peptide-MHC complexes can be recognized e.g., by CD4+or CD8+T cells. However, even when natural T cell responses occur, they rarely provide protective immunity. For an anticancer immune response to lead to effective killing of cancer cells, a series of events must occur, described as the Cancer-Immunity Cycle (Mellmann et al, 2011). In brief, (neo)antigens are released and dendritic cells (DCs) present the captured antigens on MHC molecules to T cells, resulting in the priming and activation of effector T cell responses against the cancer-specific antigens. Finally, the activated effector T cells traffic to and infiltrate into the tumour, specifically recognize and bind to cancer cells through their TCR and its cognate antigen bound to MHC and kill their target cancer cell. Killing of the cancer cells release additional tumour-associated antigens to increase the response in subsequent cycles. However, in cancer patients, one or multiple steps are dysfunctional. Milestone accomplishments in immuno-oncology through provided evidence that T cells play a central role in cancer growth. The most direct approach of this insight is adoptive transfer of ex vivo expanded TILs, first conducted by Rosenberg and others (Dudley et al, 2003). Another option is TCR gene therapy, transferring tumour- directed TCR genes into autologous T-cells. The use of TIL therapy in refractory malign melanoma led to long-lasting responses. Taken together, it is particularly beneficial to provide antigen-reactive lymphocytes for cell- based tumour therapy, such as TIL therapy. Accordingly, in a preferred embodiment of the invention, the individual has a tumour and the at least one antigen is a tumour antigen. Preferably, the challenging step (d) comprises contacting (preferably: co-culturing) the lymphocytes with cells obtained from the tumour or cells loaded with lysate obtained from the tumour. In this connection, the biopsy sample (if used in the method) is a sample obtained from the tumour (which typically is a metastatic or secondary tumour) of the individual. Preferably, the biopsy sample (which may in particular be a tumour sample) has a volume of at least 1 mm3, preferably at least 2 mm3, more preferably at least 4 mm3, especially at least 6 mm3. In the course of the present invention, these sample sizes have turned out to be generally sufficient for the inventive method. Along similar lines, the biopsy sample (which may in particular be a tumour sample) preferably comprises at least 104, preferably at least 105, especially at least 106lymphocytes (preferably T lymphocytes, especially CD4+and / or CD8+T lymphocytes). In the course of the present invention, these cell numbers in the sample have turned out to be generally sufficient for the inventive method. According to a preferred embodiment, the obtaining step (a) comprises isolating lymphocytes, preferably T lymphocytes, especially CD4+and / or CD8+T lymphocytes, from a biopsy sample and / or blood sample obtained from the individual. For loading with tissue (tumour) lysate, autologous or heterologous cells may be used. Preferably, the cells to be loaded are dendritic cells. According to a particular preference, these dendritic cells are directly obtained from the individual or obtained by differentiating monocytes (e.g., peripheral blood mononuclear cells (PBMCs)) obtained from the individual, in particular from a blood sample obtained from the individual. The inventive method may comprise already a selection step before a primary culture is established. It is especially preferred when CD8+ T lymphocytes are selected for establishing the primary culture, as these cytotoxic T cells are particularly suitable for TIL therapy. Alternatively, or in addition thereto, CD4+T lymphocytes may be selected for establishing the primary culture, since they orchestrate the humoral immune response. In the context of the present invention, any transient reporter system that produces a signal upon NFAT translocation to the nucleus may be used. Messenger ribonucleic acid (mRNA) reporter systems are especially preferred because mRNA is inherently transient (however, transient transfection with DNA may also be employed). Transient transfection methods are for instance disclosed in Kim & Eberwine, 2010. The mRNA is translated into a protein by the translation machinery of the transfected cells. In a preferred embodiment, the introducing step (c) comprises contacting lymphocytes of the primary culture with exogenous messenger ribonucleic acid (mRNA) comprising the transient reporter system, such that the exogenous mRNA is taken up by the lymphocytes. In other words, this is an mRNA transfection step. The mRNA may be transfected e.g., by using liposomes or viruses. According to a further preferred embodiment, the transient reporter system is a fluorescent reporter system (e.g., based on green fluorescent protein (GFP) or red fluorescent protein (RFP)). In this connection, selecting step (e) preferably comprises fluorescence-activated cell sorting (FACS) of the lymphocytes. It is particularly preferred when the transient reporter system is a bimolecular fluorescence complementation (BIFC) reporter system or a Förster resonance energy transfer (FRET) reporter system. However, it has turned out that BIFC is more advantageous because it was easier to use with FACS in the context of the present invention. BIFC reporter systems are also disclosed e.g., in Pratt et al, 2016, Kudla & Bock, 2016, Kerppola, 2006, and Berendzen et al, 2012. Dimerization- dependent fluorescence protein (ddFP) reporter systems, as for instance disclosed in Ding et al, 2015, are particularly suitable BIFC reporter systems for the present invention. In yet another preferred embodiment, the transient reporter system comprises a first BIFC component with a nuclear localization signal (NLS) and a second BIFC component with NFAT or a fragment thereof. Either or both components may be fusion proteins. NFAT preferably has the sequence of any one of UniProt entries Q13469, Q60591, O95644, O88942, Q14934, Q8K120, Q12968, P97305, O94916 and Q9WV30, preferably Q13469 and Q60591, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entire sequence). The fragment preferably comprises (or is) a sequence fragment of these sequences with a length of at least 200 amino acids, preferably at least 300 amino acids, especially at least 350 or at least 400 amino acids. The NLS is a short sequence that facilitates the targeted transportation of the protein to which it is attached, into the cell nucleus. Typically, the NLS functions by serving as a recognizable tag for the cellular machinery responsible for nuclear import. The NFAT fragment is a fragment which retains its nuclear translocation capability (upon Ser / Thr dephosphorylation). NFAT domains are discussed e.g., in Shou et al, 2015 (see in particular Fig. 1). NFAT proteins comprise a Rel-homology region (RHR), the N-terminal NFAT homology region (NHR) and a C- terminal domain. Preferably, the fragment includes at least the NHR and optionally also the RHR. In particular, the fragment may comprise amino acids 1-460 of murine NFAT1 (cf. Arambaru et al, 1998; e.g., UniProt Q60591) or 4-460 of murine NFAT1 (e.g., UniProt Q60591), optionally with up to 5, preferably up to 4, more preferably up to 3, even more preferably up to 2, especially up to 1 amino acid substitutions. Preferred sequences for the reporter system are given in the following: Murine NFAT14-460 + Linker + B-GFP11(SEQ ID NO: 1) ATGCCGGAGCCGCAGCCCGACCCCGATGGCGGGGACGGCCCCGGCCACGAGCCCGGGGGCAGTCCCCAAGACGAGCT GGACTTTTCCATCCTCTTCGATTATGACTATCTGAACCCTATCGAAGAAGAACCGATCGCACATAAGGCCATCAGCT CACCCTCCGGACTCGCATACCCGGATGATGTCCTGGACTATGGCCTCAAGCCATGCAACCCCCTTGCCAGTCCCTCT GGCGAGCCCCCTGGCCGGTTCGGAGAGCCGGATAGTATAGGGTTCCAGAACTTTCTGAGCCCGGTCAAGCCAGCAGG GGCTTCGGGCCCGAGCCCTCGGATCGAGATCACTCCATCCCACGAACTGATGCAGGCAGGGGGGGCCCTCCGTGGGA GAGACGCCGGCCTGTCCCCCGAGCAGCCGGCCCTGGCCCTGGCCGGCGTGGCCGCCAGCCCGAGGTTCACACTGCCC GTGCCCGGCTACGAGGGCTACCGCGAGCCGCTTTGCTTGAGCCCCGCTAGCAGCGGCTCCTCTGCCAGCTTCATTTC TGACACCTTCTCCCCCTACACCTCGCCCTGCGTCTCACCCAATAACGCCGGGCCCGACGACCTGTGTCCCCAGTTTC AAAACATCCCTGCTCATTATTCCCCCAGAACCTCTCCAATAATGTCACCTCGAACCAGCCTCGCCGAGGACAGCTGC CTGGGCCGACACTCGCCCGTGCCCCGTCCGGCATCCCGCTCCTCCTCACCCGGTGCCAAGCGGAGGCATTCGTGCGC AGAGGCTTTGGTTGCTCCTCTGCCCGCAGCCTCACCCCAGCGCTCCCGGAGCCCCTCGCCACAGCCCTCGCCTCACG TGGCACCGCAGGACGACAGCATCCCCGCTGGGTACCCCCCCACGGCCGGCTCTGCTGTTCTCATGGATGCCCTCAAC ACCCTGGCCACCGACTCGCCCTGCGGGATCCCCTCCAAGATATGGAAGACCAGTCCTGACCCGACGCCTGTGTCCAC CGCTCCGTCCAAGGCTGGCCTGGCCCGCCACATCTACCCTACTGTGGAGTTCCTGGGGCCATGTGAGCAGGAGGAGA GGAGGAATTCCGCTCCAGAGTCCATCCTGCTGGTACCACCTACTTGGCCCAAGCAGTTGGTGCCGGCCATTCCCATC TGCAGCATCCCTGTGACTGCATCCCTCCCACCACTCGAGTGGCCACTCTCCAATCAGTCGGGCTCCTATGAGCTACG GATTGAGGTCCAACCCAAGCCCCATCACCGGGCCCACTATGAGACGGAGGGCAGCCGTGGCGCTGTCAAAGCCCCAA CAGGAGGACACCCTGTGGTGCAGCTCCACGGCTACATGGAGAACAAGCCTCTGGGGCTTCAGATCTCTGGTGGCGGA GGCTCGGGCGGAGGTGGGTCGGGTGGCGGCGGATCAGCCTCCTCCGAGGACAACAACATGGCCACCATCAAAGAGTT CATGCGCTTCAAGGTGCGCATGGAGGGCTCCATGAACGGCCACGAGTTCGAGATCGAGGGCGAGGGCGAGGGCCGCC CCTACGAGGGCACCCAGACCGCCAAGCTGAAGGTGACCAAGGGCGGCCCCCTGCCCTTCGCCTGGGACATCCTGTCC CCCCAGATCATGTACGGCTCCAAAGCGTACGTGAGGCACCCCGCCGACATCCCCGATTACAAGAAGCTGCCCTTCCC CGAGGGCTTCAAGTGGGAGCGCGTGATGAACTTCGAAGACGGCGGTCTGGTGACCGTTACCCAGGACTCCTCCCTGC AGGACGGCACGCTGATCTGCAAGGTGAAGATTCGCGGCACCAACTTCCCCCCCGACGGCCCCGTAATGCAGAAGAAG ACCATGGGCTGGGAGGCCTCCACCGAGATGCTGTACCCCAAAGACGGCGTGCTGAAGGGCCATAGCTATCAGGCCCT GAAGCTGAAGGACGGCGGCCACTACCTGGTGGAGTTCGAGACCATCTACATGGCCAAGAAGCCCGTGCAACTGCCCG GCGATTACTGTGTGGACACCAAGCTGGACATCACCTCCCACAACGAGGACTACACCATCGTGGAACAGTACGGGCGC TCCGAGGGCCGCCACCGTCTGGGCATGGACGAGCGGTACAAGGGAACGGCGGGAAGCGAT SEQ ID NO: 1 translates into the following protein (SEQ ID NO: 2): MPEPQPDPDGGDGPGHEPGGSPQDELDFSILFDYDYLNPIEEEPIAHKAISSPSGLAYPDDVLDYGLKPCNPLASPS GEPPGRFGEPDSIGFQNFLSPVKPAGASGPSPRIEITPSHELMQAGGALRGRDAGLSPEQPALALAGVAASPRFTLP VPGYEGYREPLCLSPASSGSSASFISDTFSPYTSPCVSPNNAGPDDLCPQFQNIPAHYSPRTSPIMSPRTSLAEDSC LGRHSPVPRPASRSSSPGAKRRHSCAEALVAPLPAASPQRSRSPSPQPSPHVAPQDDSIPAGYPPTAGSAVLMDALN TLATDSPCGIPSKIWKTSPDPTPVSTAPSKAGLARHIYPTVEFLGPCEQEERRNSAPESILLVPPTWPKQLVPAIPI CSIPVTASLPPLEWPLSNQSGSYELRIEVQPKPHHRAHYETEGSRGAVKAPTGGHPVVQLHGYMENKPLGLQISGGG GSGGGGSGGGGSASSEDNNMATIKEFMRFKVRMEGSMNGHEFEIEGEGEGRPYEGTQTAKLKVTKGGPLPFAWDILS PQIMYGSKAYVRHPADIPDYKKLPFPEGFKWERVMNFEDGGLVTVTQDSSLQDGTLICKVKIRGTNFPPDGPVMQKK TMGWEASTEMLYPKDGVLKGHSYQALKLKDGGHYLVEFETIYMAKKPVQLPGDYCVDTKLDITSHNEDYTIVEQYGR SEGRHRLGMDERYKGTAGSD A-GFP1-10+ 3x NLS (SEQ ID NO: 3) ATGGTGAGCAAGAGCGAGGAGGTCATCAAAGAGTTCATGCGCTTCAAGGTGCGCTTGGAGGGCTCCATGAACGGCCA CGAGTTCGAGATCGAGGGCGAGGGCGAGGGCCGCCCTTACGAGGGCACCCAGACCGCCAAGCTGAAGGTGACCAAGG GCGGCCCCCTGCCCTTCGCCTGGGACATCCTGTCCCCCCTGATCATGTACGGCTCCAAGATGTACGTGAAGCACCCC GCCGACGTCCCCGATTACATGAAGCTGTCCTTCCCCGAGGGCTTCAAGTGGGAGCGCGTGATGCACTTCGAGGACGG CGGTCTGGTGACCGCGACACAGGACTCCTCCCTGCAGGACGGCACGCTGATCTACAAGGTGAAGATGCGCGGCACCA ACTTCCCCCCCGACGGCCCCGTAATGCAGAAGAAGACCTTGGGCTGGGATTATGCCACCGAGCGCCTGTACCCCGAA GAAGGCGTGCTGAAGGGCGAGCTCCTGGGGCGCCTGAAGCTGAAGGACGGCGGCCTCAACCTGGTGGAGTCCAAGAC CATCTACATGGCCAAGAAGCCCGTGCAACTGCCCGGCTACTACTTCGTGGACACCAAGCTGGACATCACCTCCCACA ACGAGGACTACACCATCGTGGAACAGTACGAGCGCTCCGAGGGCCGCCACCACCTGGGGCATGGTACAGGTAGCGGA ACGGCGGGAAGCGATCCAAAAAAGAAGAGAAAGGTAGATCCAAAAAAGAAGAGAAAGGTAGATCCAAAAAAGAAGAG AAAGGTATAG SEQ ID NO: 3 translates into the following fusion protein (SEQ ID NO: 4): MVSKSEEVIKEFMRFKVRLEGSMNGHEFEIEGEGEGRPYEGTQTAKLKVTKGGPLPFAWDILSPLIMYGSKMYVKHP ADVPDYMKLSFPEGFKWERVMHFEDGGLVTATQDSSLQDGTLIYKVKMRGTNFPPDGPVMQKKTLGWDYATERLYPE EGVLKGELLGRLKLKDGGLNLVESKTIYMAKKPVQLPGYYFVDTKLDITSHNEDYTIVEQYERSEGRHHLGHGTGSG TAGSDPKKKRKVDPKKKRKVDPKKKRKV NFAT + GFP 11 (SEQ ID NO: 5) ATGCCTGAACCCCAACCCGACCCCGACGGTGGCGACGGCCCAGGTCATGAACCGGGCGGTTCACCGCAGGATGAATT GGATTTCTCAATTTTGTTTGACTACGATTACTTGAATCCCATAGAGGAAGAGCCCATTGCGCACAAAGCGATTAGTA GTCCTAGCGGGCTGGCTTATCCCGACGACGTGCTTGATTACGGATTGAAACCTTGTAATCCACTGGCGTCTCCTAGC GGTGAACCACCAGGGCGCTTTGGCGAACCCGACAGCATTGGTTTTCAAAATTTCTTGTCTCCAGTAAAACCTGCCGG TGCGTCCGGACCTTCTCCAAGGATAGAAATTACGCCGTCTCATGAGCTCATGCAAGCCGGTGGAGCACTGCGGGGCC GGGATGCAGGGCTCTCTCCTGAACAACCCGCACTCGCTCTTGCTGGTGTTGCTGCGTCTCCTCGATTTACTCTCCCG GTACCTGGATATGAAGGGTATAGAGAACCTCTGTGTCTGTCCCCAGCCAGTTCCGGGTCAAGTGCGTCCTTTATCAG CGATACTTTTAGCCCTTATACCAGTCCGTGTGTGAGTCCAAACAATGCAGGCCCAGATGATCTCTGCCCACAATTCC AGAATATACCAGCACACTACAGCCCTCGCACTAGCCCTATCATGAGTCCCCGGACTAGCCTGGCAGAAGATTCCTGT CTTGGTCGCCATAGCCCTGTACCACGCCCCGCTAGTCGATCTAGCTCCCCTGGCGCAAAACGCCGTCATAGCTGTGC TGAAGCACTGGTCGCGCCGTTGCCTGCCGCTAGTCCACAAAGATCAAGATCCCCAAGCCCGCAACCTTCCCCACATG TTGCTCCCCAAGATGATAGTATTCCAGCGGGCTATCCCCCAACTGCTGGTAGCGCAGTGTTGATGGACGCTCTGAAT ACTCTCGCAACAGATAGTCCATGTGGCATACCGAGCAAAATTTGGAAAACGTCACCCGATCCTACCCCCGTTTCTAC GGCCCCTTCAAAAGCGGGGCTTGCACGACATATATATCCAACAGTTGAATTTCTCGGCCCTTGCGAACAAGAAGAAA GAAGAAACTCAGCCCCCGAATCAATTCTCTTGGTGCCACCAACGTGGCCGAAACAACTGGTTCCAGCTATACCAATT TGTTCTATACCAGTCACCGCCAGCCTTCCGCCCCTGGAATGGCCTTTGTCTAACCAATCTGGGAGTTACGAACTCAG AATCGAAGTGCAGCCGAAACCTCACCATAGGGCACATTACGAAACAGAAGGAAGTAGAGGAGCGGTGAAGGCACCGA CTGGCGGTCATCCAGTCGTACAACTTCATGGTTATATGGAAAATAAACCCCTCGGCCTGCAAATTACTGGAATGCGG GATCATATGGTACTGCACGAATACGTGAACGCGGCCGGCATCACG SEQ ID NO: 5 translates into the following fusion protein (SEQ ID NO: 6): MPEPQPDPDGGDGPGHEPGGSPQDELDFSILFDYDYLNPIEEEPIAHKAISSPSGLAYPDDVLDYGLKPCNPLASPS GEPPGRFGEPDSIGFQNFLSPVKPAGASGPSPRIEITPSHELMQAGGALRGRDAGLSPEQPALALAGVAASPRFTLP VPGYEGYREPLCLSPASSGSSASFISDTFSPYTSPCVSPNNAGPDDLCPQFQNIPAHYSPRTSPIMSPRTSLAEDSC LGRHSPVPRPASRSSSPGAKRRHSCAEALVAPLPAASPQRSRSPSPQPSPHVAPQDDSIPAGYPPTAGSAVLMDALN TLATDSPCGIPSKIWKTSPDPTPVSTAPSKAGLARHIYPTVEFLGPCEQEERRNSAPESILLVPPTWPKQLVPAIPI CSIPVTASLPPLEWPLSNQSGSYELRIEVQPKPHHRAHYETEGSRGAVKAPTGGHPVVQLHGYMENKPLGLQITGMR DHMVLHEYVNAAGIT GFP2 + 3xNLS (SEQ ID NO: 7) ATGTCAAAGGGCGAGGAGCTCTTCACAGGCGTGGTACCCATCCTGGTGGAGTTGGACGGCGACGTGAATGGCCACAA ATTTTCTGTTAGGGGAGAGGGCGAGGGAGATGCGACAATCGGCAAGCTGACCCTCAAGTTTATTTGCACAACGGGGA AGCTGCCCGTTCCTTGGCCAACCCTGGTGACTACACTCACCTATGGGGTGCAATGTTTCAGTCGCTATCCGGATCAC ATGAAGAGGCACGATTTCTTCAAATCCGCCATGCCGGAAGGGTATGTTCAGGAGAGGACTATCTCCTTTAAGGACGA CGGCAAGTACAAGACCCGTGCCGTGGTGAAGTTCGAAGGGGACACACTGGTGAATCGGATCGAGTTGAAGGGCACTG ACTTCAAAGAGGACGGAAACATCCTCGGGCATAAGCTGGAGTATAACTTCAACAGCCACAATGTGTATATAACCGCA GACAAACAGAAGAATGGCATAAAGGCAAACTTTACCGTGAGACACAACGTGGAAGACGGTTCTGTGCAGCTGGCAGA TCACTATCAGCAGAATACACCGATCGGGGATGGACCAGTTCTGTTGCCCGACAACCATTATCTGTCTACCCAGACTG TGCTTTCTAAGGACCCCAACGAGAAGAGTCGCGACCCCAAGAAGAAACGAAAAGTGGACCCTAAGAAGAAACGGAAA GTCGACCCGAAGAAGAAACGGAAAGTG SEQ ID NO: 7 translates into the following fusion protein (SEQ ID NO: 8): MSKGEELFTGVVPILVELDGDVNGHKFSVRGEGEGDATIGKLTLKFICTTGKLPVPWPTLVTTLTYGVQCFSRYPDH MKRHDFFKSAMPEGYVQERTISFKDDGKYKTRAVVKFEGDTLVNRIELKGTDFKEDGNILGHKLEYNFNSHNVYITA DKQKNGIKANFTVRHNVEDGSVQLADHYQQNTPIGDGPVLLPDNHYLSTQTVLSKDPNEKSRDPKKKRKVDPKKKRK VDPKKKRKV The transient reporter system may be a ddGFP-based system. Thus, according to another preferred embodiment, the reporter system comprises the sequences identified by SEQ ID NO: 1 (or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of this sequence) and SEQ ID NO: 2 (or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of this sequence). These two sequences may be present on the same mRNA molecule or two different mRNA molecules, for instance. Along similar lines, the reporter system may code for the sequences identified by SEQ ID NO: 3 (or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of this sequence) and SEQ ID NO: 4 (or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of this sequence). The transient reporter system may be a splitGFP-based system. Thus, according to another preferred embodiment, the reporter system comprises the sequences identified by SEQ ID NO: 4 (or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of this sequence) and SEQ ID NO: 6 (or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of this sequence). These two sequences may be present on the same mRNA molecule or two different mRNA molecules, for instance. Along similar lines, the reporter system may code for the sequences identified by SEQ ID NO: 7 (or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of this sequence) and SEQ ID NO: 8 (or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of this sequence). According to another particular preference, the transient reporter system has the sequence identified by SEQ ID NO: 9 (see Example) or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entire sequence. The inventive method may be performed with the kit of the present invention. The transient reporter system provided in the kit is preferably the transient reporter system disclosed in the paragraphs above. The transient reporter system provided in the first container of the kit is ready-for-use for transfection of lymphocytes, optionally upon reconstitution in a liquid such as a buffer (e.g., if the transient reporter system is provided in lyophilized form). By way of example, this may entail that the reporter system (in particular if it is mRNA) is already provided encapsulated in a transfection vector such as liposomes, lipid nanoparticles (LNPs) or a virus, or in mixture with a transfection vector such as delivery peptides or cell- penetrating peptides. Such peptide-based delivery systems are for instance disclosed in Yokoo et al, 2022 and Foss et al, 2023. Any buffer suitable for transfection of lymphocytes with the transient reporter system (e.g., transfection based on liposomes, LNPs, peptides such as cell-penetrating peptides or virus) may be provided as transfection buffer in the inventive kit (e.g., as a stock solution or concentrate such as a 10x solution, or already in the final dilution, i.e., 1x). Suitable transfection buffers are also disclosed in e.g., US 2010 / 0074885 A1, US 2010 / 0260808 A1, US 2021 / 0047648 A1 and WO 2021 / 173729 A2 (all of which are included herein by reference). By way of example, the buffer contains NaCl, KaCl, Na2HPO4 / NaH2PO4, HEPES, mannitol and has a pH of 7.2. Any cytokine suitable to stimulate lymphocytes may be provided in the inventive kit. Preferably, the cytokine is selected from the group consisting of Granulocyte-Macrophage Colony- Stimulating Factor (GM-CSF), Interleukin-4 (IL-4), Interleukin-6 (IL-6), Interleukin-1 alpha (IL-1 alpha), and Prostaglandin E2 (PGE2). The inventive kit may also comprise an instruction manual for performing the method. According to another preferred embodiment, the inventive method comprises an additional selection step (e1) of isolating non- lymphocyte cells from the biopsy sample, co-culturing the non- lymphocyte cells with exposing the at least one antigen-reactive lymphocyte to a portion of the biopsy sample and, and selecting antigen-reactive lymphocytes for high reactivity, in particular cell-killing ability or cytokine production ability, to the non- lymphocyte cells. This additional screening step increases the likelihood of therapeutic success, as the most suitable lymphocytes are selected. By way of example, tumour cells (marked with a fluorescent dye) are isolated from the tumour biopsy and co-cultured with the lymphocytes. After certain amount of time (usually 24h), the remaining viable tumour cells are counted and a killing percentage is calculated (i.e., the cell-killing ability). Further, the supernatant is removed and IFNg or other cytokines are measured e.g., by ELISA (i.e., the cytokine production ability). Alternatively, or in addition thereto, the lymphocytes may be tested in tumour avatar models or patient-derived xenograft (PDX) models. Both tumour avatar models (also called patient-derived tumour avatars or 3D tumour avatars or 3D patient tumour avatars) and PDX Models may be used to create in vivo models of the tumour in immunocompromised animals, but while PDX models are based on implanting unaltered tumour tissue into the animals, tumour avatar models may exist in in vivo and in in vitro (or hybrid) formats, offering greater experimental flexibility and the ability to replicate the human tumour microenvironment more closely. In this connection, Bose et al, 2022, discusses how 3D patient tumour avatars enable next generation precision oncology. The present invention is suitable for cell therapy in several diseases (involving an inflammatory component). Therefore, the individual (to be treated) preferably has a cancer, preferably a solid cancer (such as melanoma, lung cancer, breast cancer, ovarian cancer or colon cancer), an infection, an autoimmune disease or an inflammatory disease. The inventive therapy may be used if the cancer is metastatic and / or unresectable (and other treatments have failed). The therapy may also be used when the cancer is refractory to anti immune-checkpoint-inhibitor, in particular anti–programmed death 1 (PD1), anti-programmed death ligand 1 (PD-L1) or anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), treatment and / or refractory to a targeted therapy. The pharmaceutical composition (obtained by the inventive method) is preferably provided as a (typically aqueous) cell suspension (in particular for intravenous administration). Excipients suitable for the pharmaceutical composition of the present invention are known to the person skilled in the art, upon having read the present specification, for example water (especially water for injection), saline, Ringer's solution, dextrose solution, buffers, Hank solution, vesicle forming compounds (e.g. lipids), fixed oils, ethyl oleate, 5% dextrose in saline, substances that enhance isotonicity and chemical stability, buffers and preservatives. Other suitable excipients include any compound that is not harmful for the patient (or individual). Examples are well tolerable proteins, polysaccharides, polylactic acids, polyglycolic acid, polymeric amino acids and amino acid copolymers. This pharmaceutical composition can (as a drug) be administered via appropriate procedures known to the skilled person (upon having read the present specification) to a patient or individual in need thereof (i.e. a patient or individual having or having the risk of developing the diseases or conditions mentioned herein). The preferred route of administration of said pharmaceutical composition is parenteral administration, in particular through intraperitoneal, subcutaneous, intramuscular and / or intravenous administration. For parenteral administration, the pharmaceutical composition of the present invention is preferably provided in injectable dosage unit form, e.g. as a solution (typically as an aqueous solution), suspension or emulsion, formulated in conjunction with the above-defined pharmaceutically acceptable excipients. The dosage and method of administration, however, depends on the individual patient or individual to be treated. Said pharmaceutical composition can be administered in any suitable dosage known from other biological dosage regimens or specifically evaluated and optimised for a given individual. For example, the active agent (i.e., the lymphocytes) may be present in the pharmaceutical composition in an amount from 106to 1014cells. The administration may occur e.g., a single time or multiple times (such as two or three times) e.g., within a period of a month, 3 months, 6 months, 9 months or 12 months. As the preferred mode of administration of the inventive pharmaceutical composition is parenteral administration, the pharmaceutical composition according to the present invention is preferably liquid. In embodiments, the pharmaceutical composition may be provided in frozen form (preferably with suitable cryoprotectants). The pharmaceutical composition is preferably for use in treatment of a disease or condition, preferably selected from a cancer (such as any one of the cancers defined hereinabove), an infection, an autoimmune disease, or an inflammatory disease. In particular, the pharmaceutical composition is for use in TIL therapy. Herein, "transient" (as used in connection to the reporter system) refers to the temporary or short-term presence and activity of the reporter system in living cells. Unlike stable reporter systems, which integrate into the host genome and provide long-term expression of a reporter gene, transient systems do not integrate into the genome. They are gradually lost or diluted out as the cells divide and grow. Preferably, “transient” means that the reporter system is only active (e.g., able to produce a fluorescence signal useful for FACS) for at most 4 weeks at physiological in vitro conditions (e.g., incubation of the cells at 37°C), preferably at most 3 weeks, more preferably at most 2 weeks, especially at most 1 week or even at most 5 days or even at most 3 days. Entries in the UniProt databases are identified by their accession codes (referred to herein e.g. as “UniProt accession code” or briefly as “UniProt” followed by the accession code), usually a code of six alphanumeric letters (e.g. “Q1HVF7”). If not specified otherwise, the accession codes used herein refer to entries in the Protein Knowledgebase (UniProtKB) of UniProt. If not stated otherwise, the UniProt database state for all entries referenced herein is of 1 March 2023 (UniProt / UniProtKB Release 2023_01). In the context of the present application, sequence variants (designated as “natural variant” in UniProt) are expressly included when referring to a UniProt database entry. “Percent (%) amino acid sequence identity” or “X% identical” (such as “70% identical”) with respect to a reference polypeptide or protein sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2, Megalign (DNASTAR) or the “needle” pairwise sequence alignment application of the EMBOSS software package. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are calculated using the sequence alignment of the computer programme “needle” of the EMBOSS software package (publicly available from European Molecular Biology Laboratory; Rice et al., 2000). The needle programme can be accessed under the web site http: / / www.ebi.ac.uk / Tools / psa / emboss_needle / or downloaded for local installation as part of the EMBOSS package from http: / / emboss.sourceforge.net / . It runs on many widely-used UNIX operating systems, such as Linux. To align two protein sequences, the needle programme is preferably run with the following parameters: Commandline: needle -auto -stdout -asequence SEQUENCE_FILE_A - bsequence SEQUENCE_FILE_B -datafile EBLOSUM62 -gapopen 10.0 - gapextend 0.5 -endopen 10.0 -endextend 0.5 -aformat3 pair - sprotein1 -sprotein2 (Align_format: pair Report_file: stdout) The % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program needle in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. In cases where “the sequence of A is more than N% identical to the entire sequence of B”, Y is the entire sequence length of B (i.e. the entire number of amino acid residues in B). Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the needle computer program. “Sequence similarity”, “sequence identity”, “sharing a se- quence” and similar terms shall also apply to the reverse complement of a sequence, i.e. the expression “sequence A is 80% identical to sequence B” shall also be true if “sequence A is 80% identical to the reverse complement (or antisense sequence) of sequence B”. Further, “T” in a sequence can also be read as “U” (and vice versa), depending on whether the molecule in question is RNA or DNA. The present invention further relates to the following embodiments: Embodiment 1. A method for providing antigen-reactive lymphocytes, comprising: (a) obtaining lymphocytes of an individual, wherein the individual harbours at least one antigen; (b) establishing a primary culture of the lymphocytes; (c) introducing a transient reporter system into lymphocytes of the primary culture, wherein the reporter system produces a signal upon nuclear translocation of Nuclear Factor of Activated T cells (NFAT); (d) challenging said lymphocytes with at least one antigen; and (e) selecting from said lymphocytes at least one antigen- reactive lymphocyte by detecting the signal. Embodiment 2. The method of embodiment 1, further comprising the step of: (f) expanding the at least one antigen-reactive lymphocyte. Embodiment 3. The method of embodiment 2, further comprising the step of: (g) formulating a pharmaceutical composition comprising expanded antigen-reactive lymphocytes for administration to the individual. Embodiment 4. The method of any one of embodiments 1 to 3, wherein the individual has a tumour and the at least one antigen is a tumour antigen; preferably wherein challenging step (d) comprises contacting the lymphocytes with cells obtained from the tumour or cells loaded with lysate obtained from the tumour, preferably wherein the cells to be loaded are dendritic cells obtained by differentiating monocytes obtained from the individual, in particular from a blood sample obtained from the individual. Embodiment 5. The method of any one of embodiments 1 to 4, wherein the lymphocytes are T lymphocytes, preferably CD4+and / or CD8+T lymphocytes, or B lymphocytes. Embodiment 6. The method of any one of embodiments 1 to 5, wherein introducing step (c) comprises contacting lymphocytes of the primary culture with exogenous messenger ribonucleic acid (mRNA) comprising the transient reporter system, such that the exogenous mRNA is taken up by the lymphocytes. Embodiment 7. The method of any one of embodiments 1 to 6, wherein the transient reporter system is a fluorescent reporter system and selecting step (e) comprises fluorescence-activated cell sorting (FACS) of said lymphocytes. Embodiment 8. The method of embodiment 7, wherein the transient reporter system is a bimolecular fluorescence complementation (BIFC) reporter system. Embodiment 9. The method of embodiment 8, wherein the transient reporter system is a dimerization-dependent fluorescence protein (ddFP) system. Embodiment 10. The method of embodiment 8 or 9, wherein the transient reporter system comprises a first BIFC component with a nuclear localization signal (NLS) and a second BIFC component with NFAT or a fragment thereof, preferably wherein the fragment comprises at least the NFAT homology region (NHR) and optionally the Rel-homology region (RHR). Embodiment 11. The method of embodiment 10, wherein the transient reporter system comprises the sequences identified by SEQ ID NO: 1, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of said sequence, and SEQ ID NO: 2, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of said sequence. Embodiment 12. The method of embodiment 10, wherein the transient reporter system codes for the sequences identified by SEQ ID NO: 3, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of said sequence, and SEQ ID NO: 4, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of said sequence. Embodiment 13. The method of embodiment 10, wherein the transient reporter system comprises the sequences identified by SEQ ID NO: 5, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of said sequence, and SEQ ID NO: 6, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of said sequence. Embodiment 14. The method of embodiment 10, wherein the transient reporter system codes for the sequences identified by SEQ ID NO: 7, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of said sequence, and SEQ ID NO: 8, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of said sequence. Embodiment 15. The method of embodiment 10, wherein the transient reporter system comprises the sequence identified by SEQ ID NO: 9, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of said sequence. Embodiment 16. The method of any one of embodiments 1 to 15, wherein obtaining step (a) comprises isolating lymphocytes, preferably T lymphocytes, especially CD4+and / or CD8+T lymphocytes, from a biopsy sample and / or blood sample obtained from the individual. Embodiment 17. The method of embodiment 16, wherein the individual has the tumour, wherein the biopsy sample is a sample obtained from the tumour of the individual. Embodiment 18. The method of embodiment 16 or 17, wherein the biopsy sample has a volume of at least 1 mm3, preferably at least 2 mm3, more preferably at least 4 mm3, especially at least 6 mm3. Embodiment 19. The method of any one of embodiments 16 to 18, wherein the biopsy sample comprises at least 104, preferably at least 105, especially at least 106lymphocytes, preferably T lymphocytes, especially CD4+and / or CD8+T lymphocytes. Embodiment 20. The method of any one of embodiments 16 to 19, further comprising an additional selection step (e1) of isolating non-lymphocyte cells from the biopsy sample, co- culturing the non-lymphocyte cells with the at least one antigen-reactive lymphocyte, and selecting antigen-reactive lymphocytes for high reactivity, in particular cell-killing ability or cytokine production ability, to the non-lymphocyte cells. Embodiment 21. The method of any one of embodiments 1 to 20, wherein the individual has a cancer, an infection, an autoimmune disease or an inflammatory disease. Embodiment 22. The method of embodiment 21, wherein the cancer is a solid cancer, preferably selected from melanoma, lung cancer, breast cancer, ovarian cancer and colon cancer. Embodiment 23. The method of embodiment 21 or 22, wherein the cancer is metastatic. Embodiment 24. The method of any one of embodiments 21 to 23, wherein the cancer is unresectable. Embodiment 25. The method of any one of embodiments 21 to 24, wherein the cancer is refractory to anti immune-checkpoint- inhibitor, in particular anti–programmed death 1 (PD1), anti- programmed death ligand 1 (PD-L1) or anti-cytotoxic T- lymphocyte-associated protein 4 (CTLA-4), treatment and / or refractory to a targeted therapy. Embodiment 26. A pharmaceutical composition comprising expanded antigen-reactive lymphocytes, preferably T lymphocytes, especially CD4+and / or CD8+T lymphocytes, obtained by the method of any one of embodiments 3 to 25 for use in therapy, preferably for use in treatment of a cancer, an infection, an autoimmune disease, or an inflammatory disease. Embodiment 27. The pharmaceutical composition of embodiment 26 for use in tumour-infiltrating lymphocyte (TIL) therapy. Embodiment 28. A method for providing and administering antigen- reactive lymphocytes to an individual in need thereof, comprising: (a) obtaining lymphocytes of an individual, wherein the individual harbours at least one antigen; (b) establishing a primary culture of the lymphocytes; (c) introducing a transient reporter system into lymphocytes of the primary culture, wherein the reporter system produces a signal upon nuclear translocation of Nuclear Factor of Activated T cells (NFAT); (d) challenging said lymphocytes with at least one antigen; (e) selecting from said lymphocytes at least one antigen- reactive lymphocyte by detecting the signal; (f) expanding the at least one antigen-reactive lymphocyte; (g) formulating a pharmaceutical composition comprising expanded antigen-reactive lymphocytes for administration to the individual; and (h) administering the pharmaceutical composition to the individual. Embodiment 29. A kit for selecting antigen-reactive lymphocytes, comprising: - a first container comprising a transient reporter system for producing a signal upon nuclear translocation of NFAT, wherein the reporter system is ready-for-use for transfection of lymphocytes, optionally upon reconstitution in a liquid such as a buffer; - a second container comprising a transfection buffer; and - a third container comprising at least one cytokine. Embodiment 30. The kit of embodiment 29, wherein the transient reporter system is as defined in any one of embodiments 7 to 15. Embodiment 31. The kit of embodiment 29 or 30, wherein the at least one cytokine is selected from the group consisting of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Interleukin-4 (IL-4), Interleukin-6 (IL-6), Interleukin-1 alpha (IL-1 alpha), and Prostaglandin E2 (PGE2). The present invention is further illustrated by the following figures and examples, without being restricted thereto. Figures 1, 2, 3, 8 and 9 were created with the software tool BioRender.com. Fig. 1: The figure shows three different reporter systems which can be used to enable a readout of NFAT translocation. Importantly, the reporter systems are introduced into the cells in a way such that they are only transiently active, e.g., by way of mRNA transfection. Fig. 2: A proposed reporter mechanism on how to visualize the NFAT translocation with a ddFP. One part of the ddFP is linked to NFAT, the other part is placed in the nucleus through a nuclear localization signal (NLS). After translocation, both parts will get together and form a fluorescent protein, thereby producing the signal (which can be detected upon illumination). Fig. 3: This figure illustrates the need for detecting NFAT translocation (and not NFAT expression in general). When using a GFP coupled to NFAT, there would be no difference in fluorescence intensity after translocation. Fig. 4: Top left: Microscopy picture of proliferating TILs. TILs mainly consist of T cells (top centre) with varying subtypes between samples (top right). IFNg production can be detected in supernatant after co-culturing TILs with tumour cells (bottom left). Results from sorting CD4+ T cells and CD8+T cells from NSCLC tumour sample are also shown (bottom centre and right). Fig. 5: Dendritic cells lose CD14 marker and gain more MHC molecules (A). The PGE2-method leads to highest activation of dendritic cells with also elevated expression of MHC-II molecules (B). Fig. 6: HeLa cells transfected with a NFAT-ddFP reporter before (A) and after ionomycin stimulation (B, C). HeLa cells transfected with NFAT-GFP before (D) and after ionomycin stimulation (E). Fig. 7: (A) HeLa Cells transfected separately with both parts of NFAT-ddFP reporter. (B) Jurkat cells transfected with NFAT reporter show GFP expression after stimulation with anti-CD3 and anti-CD28 after 24 hours (33). Fig. 8: Outline of the workflow of the inventive method. Fig. 9: Detailed outline of the in vitro workflow. Monocytes are isolated from blood of the cancer patient and differentiated into dendritic cells to be loaded with tumour lysate. A tumour sample is first cultured in IL-2 containing medium. Subsequently, mature T cells are isolated from tumours of the patient via FACS of CD3+positive cells and then transduced with the NFAT reporter system by electroporation and co-cultured with loaded dendritic cells. T lymphocytes with the NFAT translocation signal are selected by FACS and, after expansion, re-introduced into the patient (not shown in the figure). Example - Isolation of tumour-antigen-specific T cells for TIL therapy of NSCLC Introduction Lung cancer is the leading cause of cancer deaths worldwide and can be histologically divided in NSCLC and small cell lung cancer (SCLC). For metastatic NSCLC, targeted therapy and Immune checkpoint blockade (ICB) led to improvement of patient survival (Reck et al, 2021; Mok et al, 2017). Several mutations can be targeted including epidermal growth factor receptor (EGFR) which is a common targetable driver mutation in lung adenocarcinoma. Unfortunately, both targeted therapy and ICB confer resistance development and further therapy decision after treatment failure is difficult (Hosomi et al, 2020; Lei et al, 2020). Adoptive cell transfer represents a new option for those patients and clinical studies for NSCLC are currently conducted (Creelan et al, 2021). The present example represents an improvement of this treatment modality. Fluorescent proteins can be used to detect intracellular mechanisms. Among these methods are Fluorescence Resonance Energy Transfer (FRET) and biomolecular complementation of split fluorescent protein. ddFP systems are another option (Alford et al, 2012). A ddFP comprises two monomers, which form a fluorescent heterodimer after contact, whereas only one copy carries a chromophore, named GA in its green variant (GFP), RA in red variant (mCherry). GA / RA carry low fluorescence intensity, but signal gets enhanced through the heterodimerization with the second monomer (B), which acts only as an amplifier and has no inherent fluorescent property (Ding et al, 2015). A ddFP reporter was used to visualize the NFAT translocation in order to be able to sort live, activated T cells with FACS (schemes are shown in Figs. 1, 2, 3). Methods PBMC Isolation Human peripheral blood lymphocytes were isolated from healthy volunteers and NSCLC patients. Platelet rich plasma was removed by centrifugation of citrated whole blood and erythrocytes was removed by dextran sedimentation. PBMCs(containing lymphocytes) were isolated by gradient centrifugation. Nucleofection of human T cells and Jurkat cells After washing with phosphate-buffered saline (PBS), cells were nucleofected with the P3 Primary Cell 4D-Nucleofector® X Kit (Lonza Group, Basel, Switzerland). Briefly, 1x106T cells were mixed with varying amounts of plasmid DNA or mRNA before nucleofection using a commercially available electroporation device (4D-Nucleofector®, electroporation program “EH-100”; Lonza Group, Basel, Switzerland). Evaluation of transfection efficiency was carried out after 24h via flow cytometry. Isolation of primary T cells T cells were isolated from PBMCs of healthy donors using the EasySep™ Human T Cell Isolation Kit via negative selection (StemCell Technologies, Vancouver, Canada). Culture and Stimulation of Jurkat T cells Jurkat cells were cultured in RPMI with 10% FBS and 1% Penicillin / Streptomycin. Before electroporation, cells were stimulated using plates coated anti-CD3 and anti-CD28. After expression of the NFAT translocation reporter, cells were again stimulated with coated plates for 24h and GFP signal was measured via flow cytometry (Fig. 7B). mRNA in vitro transcription Linearized templates were generated via restriction digestion, and reporter plasmids were in vitro transcribed using the HiScribe® T7 Anti-Reverse Cap Analog (ARCA) mRNA Kit (with tailing) (New England Biolabs, Ipswitch, US). Synthesized ARCA capped and poly(A)-tailed mRNA were quantified on a Nanodrop ND- 1000 spectrophotometer, and stored in single-use aliquots at -80 °C. Preparation of tumour tissue Tumour tissue received within 24 hours after resection was immediately used for preparation of single cell suspension. Tissue was minced and digested in RPMI-1640 medium (Thermo Fisher Scientific Inc.) supplemented with 80 U / mL DNase I and 300 U / mL collagenase I 37°C for 30 min. Enzymatic digests were inactivated with FBS and single cell suspensions were passed through cell strainers. After RBC lysis, cells were washed and resuspended in staining buffer (1X PBS+2% FBS). Total and trypan blue-negative (i.e., viable) cells were counted with a hemocytometer. TIL culture For TIL cultures, 4-8 fragments of tumour tissue (each about 2x2x2mm) were cultured in 24-well plates in T cell media (RPMI 1640, 10% FBS, 10mM HEPES, 100 U / ml penicillin and 100 mg / ml streptomycin, 50 mg / ml gentamicin, 1x2-mercaptoethanol) in the presence of interleukin-2 (IL-2, 6,000U / ml). Co-culture and IFNg ELISA TILs (50,000 cells) were co-cultured after harvest with autologous tumour cells (100,000 cells). The supernatant was subjected to IFNg ELISA analysis following overnight co-culture. TIL only, tumour only samples and PMA / ionomycin treatment served as the controls. A two-fold increase in IFNg release was considered a positive result for tumour reactivity. Flow cytometry In brief, cells were pre-incubated with Fc receptor blocking solution to reduce nonspecific binding and subsequently stained with anti-human antibodies for 30 min on ice. Subsequently cells were stained with fixable viability dye, prior to fixation using fixation Buffer. Transfection of HeLa cells 1x106HeLa cells were seeded in each well of 6-well plates to reach a confluency between 70-90% after 24 hours. Lipofectamine transfection was carried out according to protocol. Briefly, master mixes of DNA and Lipofectamine were prepared, mixed in a 1:1 ratio and incubated for 5 minutes before adding to the cells. On the next day, medium was changed and on the following day cells were analyzed. Stimulation of NFAT translocation NFAT translocation was stimulated via the use of Ionomycin, PMA, Thapsigargin or a combination of those. For cells with a T cell receptor, plates coated with anti-CD3 and anti-CD28 were used. Constructs The transient reporter system is an mRNA and has the sequence SEQ ID NO: 9 (the sequence coding for ddGFP-A-NFAT1 is underlined and the sequence coding for ddGFP-B-NLS is bold): TCTAGAATGCCGGAGCCGCAGCCCGACCCCGATGGCGGGGACGGCCCCGGCCACGAGCCCGGGGGCAGTCCCCAAGA CGAGCTGGACTTTTCCATCCTCTTCGATTATGACTATCTGAACCCTATCGAAGAAGAACCGATCGCACATAAGGCCA TCAGCTCACCCTCCGGACTCGCATACCCGGATGATGTCCTGGACTATGGCCTCAAGCCATGCAACCCCCTTGCCAGT CCCTCTGGCGAGCCCCCTGGCCGGTTCGGAGAGCCGGATAGTATAGGGTTCCAGAACTTTCTGAGCCCGGTCAAGCC AGCAGGGGCTTCGGGCCCGAGCCCTCGGATCGAGATCACTCCATCCCACGAACTGATGCAGGCAGGGGGGGCCCTCC GTGGGAGAGACGCCGGCCTGTCCCCCGAGCAGCCGGCCCTGGCCCTGGCCGGCGTGGCCGCCAGCCCGAGGTTCACA CTGCCCGTGCCCGGCTACGAGGGCTACCGCGAGCCGCTTTGCTTGAGCCCCGCTAGCAGCGGCTCCTCTGCCAGCTT CATTTCTGACACCTTCTCCCCCTACACCTCGCCCTGCGTCTCACCCAATAACGCCGGGCCCGACGACCTGTGTCCCC AGTTTCAAAACATCCCTGCTCATTATTCCCCCAGAACCTCTCCAATAATGTCACCTCGAACCAGCCTCGCCGAGGAC AGCTGCCTGGGCCGACACTCGCCCGTGCCCCGTCCGGCATCCCGCTCCTCCTCACCCGGTGCCAAGCGGAGGCATTC GTGCGCAGAGGCTTTGGTTGCTCCTCTGCCCGCAGCCTCACCCCAGCGCTCCCGGAGCCCCTCGCCACAGCCCTCGC CTCACGTGGCACCGCAGGACGACAGCATCCCCGCTGGGTACCCCCCCACGGCCGGCTCTGCTGTTCTCATGGATGCC CTCAACACCCTGGCCACCGACTCGCCCTGCGGGATCCCCTCCAAGATATGGAAGACCAGTCCTGACCCGACGCCTGT GTCCACCGCTCCGTCCAAGGCTGGCCTGGCCCGCCACATCTACCCTACTGTGGAGTTCCTGGGGCCATGTGAGCAGG AGGAGAGGAGGAATTCCGCTCCAGAGTCCATCCTGCTGGTACCACCTACTTGGCCCAAGCAGTTGGTGCCGGCCATT CCCATCTGCAGCATCCCTGTGACTGCATCCCTCCCACCACTCGAGTGGCCACTCTCCAATCAGTCGGGCTCCTATGA GCTACGGATTGAGGTCCAACCCAAGCCCCATCACCGGGCCCACTATGAGACGGAGGGCAGCCGTGGCGCTGTCAAAG CCCCAACAGGAGGACACCCTGTGGTGCAGCTCCACGGCTACATGGAGAACAAGCCTCTGGGGCTTCAGATCGATATC ATGGCCACCATCAAAGAGTTCATGCGCTTCAAGGTGCGCATGGAGGGCTCCATGAACGGCCACGAGTTCGAGATCGA GGGCGAGGGCGAGGGCCGCCCCTACGAGGGCACCCAGACCGCCAAGCTGAAGGTGACCAAGGGCGGCCCCCTGCCCT TTGCCTGGGACATCCTGTCCCCCCAGATCATGTACGGCTCCAAAGCGTACGTGAGGCACCCCGCCGACATCCCCGAT TACAAGAAGCTGCCCTTCCCCGAGGGCTTCAAGTGGGAGCGCGTGATGAACTTCGAAGACGGCGGTCTGGTGACCGT TACCCAGGACTCCTCCCTGCAGGACGGCACGCTGATCTGCAAGGTGAAGATTCGCGGCACCAACTTCCCCCCCGACG GCCCCGTAATGCAGAAGAAGACCATGGGCTGGGAGGCCTCCACCGAGATGCTGTACCCCAAGGACGGCGTGCTGAAG GGCCATAGCTATCAGGCCCTGAAGCTGAAGGACGGCGGCCACTACCTGGTGGAGTTCGAGACCATCTACATGGCCAA GAAGCCCGTGCAACTGCCCGGCGATTACTGTGTGGACACCAAGCTGGACATCACCTCCCACAACGAGGACTACACCA TCGTGGAACAGTACGGGCGCTCCGAGGGCCGCCACCGTCTGGGCATGGACGAGCGGTACAAGGGAACGGCGGGAAGC GCTAGCATGGGTTCTGGTGCGACCAACTTCTCTCTGCTGAAACAGGCGGGTGACGTTGAAGAAAACCCGGGTCCGAT GGTGAGCAAGAGCGAGGAGGTCATCAAAGAGTTCATGCGCTTCAAGGTGCGCTTGGAGGGCTCCATGAACGGCCACG AGTTCGAGATCGAGGGCGAGGGCGAGGGCCGCCCTTACGAGGGCACCCAGACCGCCAAGCTGAAGGTGACCAAGGGC GGCCCCCTGCCCTTCGCCTGGGACATCCTGTCCCCCCTGATCATGTACGGCTCCAAGATGTACGTGAAGCACCCCGC CGACGTCCCCGATTACATGAAGCTGTCCTTCCCCGAGGGCTTCAAGTGGGAGCGCGTGATGCACTTCGAGGACGGCG GTCTGGTGACCGCGACACAGGACTCCTCCCTGCAGGACGGCACGCTGATCTACAAGGTGAAGATGCGCGGCACCAAC TTCCCCCCCGACGGCCCCGTAATGCAGAAGAAGACCTTGGGCTGGGATTATGCCACCGAGCGCCTGTACCCCGAAGA AGGCGTGCTGAAGGGCGAGCTCCTGGGGCGCCTGAAGCTGAAGGACGGCGGCCTCAACCTGGTGGAGTCCAAGACCA TCTACATGGCCAAGAAGCCCGTGCAACTGCCCGGCTACTACTTCGTGGACACCAAGCTGGACATCACCTCCCACAAC GAGGACTACACCATCGTGGAACAGTACGAGCGCTCCGAGGGCCGCCACCACCTGGGGCATGGTACAGGTAGCGGAAC GGCGGGAAGCGATGAATTCGATCCAAAAAAGAAGAGAAAGGTAGATCCAAAAAAGAAGAGAAAGGTAGATCCAAAAA AGAAGAGAAAGGTATAAAAGCTT Results TILs isolated and expanded from NSCLC patients TILs were generated from NSCLC Patients and their composition was checked by flow cytometry (Fig. 4). Tumour reactivity was measured through IFNy ELISA (also Fig. 4). These TILs may be used for transfection with the reporter system. mRNA electroporation of primary T cells In vitro transcription and mRNA (NFAT reporter system) electroporation of primary human T-cells was established. T cells were isolated from healthy donors and electroporated immediately with DNA or mRNA containing GFP with a 4D- Nucleofector (Lonza Group, Basel, Switzerland). GFP expression was measured by flow cytometry. T cell sorting from NSCLC To reduce possible skewing of the T cell repertoire through TIL- culture, cell sorting was established for CD4+and CD8+T cells out of single cell suspension of primary NSCLC tissue Cells were stained for live / dead marker, CD45, CD3, CD4 and CD8 and sorted with FACS. Differentiation of dendritic cells from monocytes isolated from blood Monocytes were isolated via negative selection from PBMCs (EasySep™ Human Monocyte Isolation Kit, StemCell Technologies, Vancouver, Canada). Monocytes were cultured for 7 days with with GM-CSF and IL-4 (Fig. 5-A). For the fast culture, at day 2, IL- 6, TNFa and IL-1B wered added and the dendritic cells were harvested at day 3. For the PGE2 method, the fast method was adopted through the addition of PGE2 at day 2. The PGE2 method achieved the highest expression of activation marker and MHC molecules (Fig. 5-B). NFAT translocation in HeLa cells HeLa cells were seeded on coverslips, transfected with HA-NFAT1- GFP, and then stimulated for 30 minutes with Ionomycin and PMA. Cells were fixed, stained with DAPI, mounted on a slide and NFAT translocation was assessed via fluorescence microscopy (Fig. 6, D and E). NFAT reporter testing A variety of ddFP-reporters were created and tested (Fig. 6, A, B and C). As expected, it was not possible to reliably detect a signal after stimulation in HeLa cells or HEK293T cells. Only after additionally transfecting the nuclear part of the reporter, a strong signal could be detected after stimulation (Fig. 7 A). TIL therapy workflow Patients with histologically confirmed NSCLC in Union for International Cancer Control (UICC) stage IV are eligible for TIL therapy after treatment failure of immune checkpoint inhibitor or targeted therapy, wherein failure is defined as tumour enlargement or occurrence of new lesions. Patients undergo resection of primary tumour or metastasis to obtain tumour biopsy samples. Furthermore, blood samples are taken from the patients. For each patient, a portion of the tumour biopsy sample is cultured in medium with IL-2 (6000 IU / ml) to expand T cells for 3 days (i.e., the primary culture of the lymphocytes). In the meantime, monocytes are isolated from the blood samples via magnetic isolation, differentiated into dendritic cells (as described above in Differentiation of dendritic cells from monocytes isolated from blood) and are loaded with tumour lysate (obtained from another portion of the tumour sample, which has been processed to a single cell suspension through 5 subsequent freeze-thaw cycles in PBS, centrifugation for 10 mins at 10000g and harvest of resulting supernatant). Afterwards, the transient NFAT reporter is subsequently introduced in the form of mRNA into the cultured T cells via electroporation (as described above in mRNA electroporation of primary T cells). After 24 hours, the T cells are challenged with the dendritic cells loaded with tumour lysate and after 16 hours, T cells in which the reporter has produced a signal are selected via FACS. Expansion of the tumour-reactive T cells is performed with a rapid expansion protocol (irradiated allogeneic peripheral blood mononuclear cells and IL-2 at a dosage of 6000 IU / ml) until reaching a cell number of at least 5x109cell with 80% viability determined by visual counting using a haemocytometer and a microscope. The expanded tumour-reactive T cells are formulated in a (otherwise sterile) pharmaceutical composition. The patients are admitted to a hospital and subjected to a nonmyeloablative, lympho-depleting chemotherapy. Subsequently, the respective pharmaceutical composition is administered to each patient intravenously in a volume of 500ml in 30 minutes (total dose: 1x1011cells). Finally, high-dose IL-2 is administered intravenously for 5 days. Non-patent references Alcover, Andrés, Balbino Alarcón, and Vincenzo Di Bartolo. "Cell biology of T cell receptor expression and regulation." Annual review of immunology 36 (2018): 103-125. 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Creelan BC, Wang C, Teer JK, Toloza EM, Yao J, Kim S, et al. Tumour-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat Med. August 2021;27(8):1410-8. Ding Y, Li J, Enterina JR, Shen Y, Zhang I, Tewson PH, et al. Ratiometric biosensors based on dimerization-dependent fluorescent protein exchange. Nat Methods. March 2015;12(3): 195-8. Dudley, Mark E., et al. "Generation of tumour-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients." Journal of immunotherapy (Hagerstown, Md.: 1997) 26.4 (2003): 332. Foss, Dana V., et al. "Peptide-mediated delivery of CRISPR enzymes for the efficient editing of primary human lymphocytes." Nature Biomedical Engineering (2023): 1-14. Gupta, Sneh Lata, et al. "B-cell-based immunotherapy: A promising new alternative." Vaccines 10.6 (2022): 879. Hosomi Y, Morita S, Sugawara S, Kato T, Fukuhara T, Gemma A, et al Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non- Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study. J Clin Oncol. 10. January 2020;38(2):115-23. Kerppola, Tom K. "Visualization of molecular interactions by fluorescence complementation." Nature reviews Molecular cell biology 7.6 (2006): 449-456. Kim, Tae Kyung, and James H. Eberwine. "Mammalian cell transfection: the present and the future." Analytical and bioanalytical chemistry 397 (2010): 3173-3178. Kudla, Jörg, and Ralph Bock. "Lighting the way to protein- protein interactions: recommendations on best practices for bimolecular fluorescence complementation analyses." The Plant Cell 28.5 (2016): 1002-1008. Lei Q, Wang D, Sun K, Wang L, Zhang Y. Resistance Mechanisms of Anti-PD1 / PDL1 Therapy in Solid Tumours. Front Cell Dev Biol. 21. July 2020;8:672. Macian, Fernando. "NFAT proteins: key regulators of T-cell development and function." Nature Reviews Immunology 5.6 (2005): 472-484. Mellman, Ira, George Coukos, and Glenn Dranoff. "Cancer immunotherapy comes of age." Nature 480.7378 (2011): 480-489. Mok, Tony S., et al. "Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer." New England Journal of Medicine 376.7 (2017): 629-640. Pratt, Evan PS, et al. "Bimolecular fluorescence complementation (BiFC) analysis of protein–protein interactions and assessment of subcellular localization in live cells." High-Resolution Imaging of Cellular Proteins: Methods and Protocols (2016): 153- 170. Reck, Martin, et al. "Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non–small-cell lung cancer with PD-L1 tumour proportion score≥ 50%." Journal of Clinical Oncology 39.21 (2021): 2339. Rice, Peter, Ian Longden, and Alan Bleasby. "EMBOSS: the European molecular biology open software suite." Trends in genetics 16.6 (2000): 276-277. Rohaan, Maartje W., et al. "Tumour-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma." New England Journal of Medicine 387.23 (2022): 2113-2125. Rosenberg, Steven A., Maria R. Parkhurst, and Paul F. Robbins. "Adoptive cell transfer immunotherapy for patients with solid epithelial cancers." Cancer cell 41.4 (2023): 646-648. Sade-Feldman, Moshe, et al. "Defining T cell states associated with response to checkpoint immunotherapy in melanoma." Cell 175.4 (2018): 998-1013. Sana, Ilenia, et al. "Role of NFAT in chronic lymphocytic leukemia and other B-cell malignancies." Frontiers in Oncology 11 (2021): 651057. Sakaguchi, Shimon, Ryoji Kawakami, and Norihisa Mikami. "Treg- based immunotherapy for antigen-specific immune suppression and stable tolerance induction: a perspective." Immunotherapy Advances (2023): ltad007. Schaft, Niels, et al. "Flexible and sensitive method to functionally validate tumor-specific receptors via activation of NFAT." 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Claims

Claims 1. A method for providing antigen-reactive lymphocytes, comprising: (a) obtaining lymphocytes, preferably T lymphocytes and / or B lymphocytes, of an individual, wherein the individual harbours at least one antigen; (b) establishing a primary culture of the lymphocytes; (c) introducing a transient reporter system into lymphocytes of the primary culture, wherein the reporter system produces a signal upon nuclear translocation of Nuclear Factor of Activated T cells (NFAT); (d) challenging said lymphocytes with at least one antigen; and (e) selecting from said lymphocytes at least one antigen- reactive lymphocyte by detecting the signal.

2. The method of claim 1, further comprising the steps of: (f) expanding the at least one antigen-reactive lymphocyte; and (g) formulating a pharmaceutical composition comprising expanded antigen-reactive lymphocytes for administration to the individual.

3. The method of claim 1 or 2, wherein the individual has a tumour and the at least one antigen is a tumour antigen; wherein challenging step (d) comprises contacting the lymphocytes with cells obtained from the tumour or cells loaded with lysate obtained from the tumour, preferably wherein the cells to be loaded are dendritic cells obtained by differentiating monocytes obtained from the individual, in particular from a blood sample obtained from the individual.

4. The method of any one of claims 1 to 3, wherein introducing step (c) comprises contacting lymphocytes of the primary culture with exogenous messenger ribonucleic acid (mRNA) comprising the transient reporter system, such that the exogenous mRNA is taken up by the lymphocytes; wherein the transient reporter system is a fluorescent reporter system, namely a bimolecular fluorescence complementation (BIFC) reporter system, and selecting step (e) comprises fluorescence- activated cell sorting (FACS) of said lymphocytes.

5. The method of claim 4, wherein the transient reporter system comprises a first BIFC component with a nuclear localization signal (NLS) and a second BIFC component with NFAT or a fragment thereof.

6. The method of claim 5, wherein the transient reporter system codes for the sequences identified by SEQ ID NO: 3, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of said sequence, and SEQ ID NO: 4, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of said sequence; or wherein the transient reporter system codes for the sequences identified by SEQ ID NO: 7, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of said sequence, and SEQ ID NO: 8, or a sequence with at least 80%, preferably at least 90%, especially at least 95% identity to the entirety of said sequence.

7. A pharmaceutical composition comprising expanded antigen- reactive lymphocytes, preferably T lymphocytes, especially CD4+and / or CD8+T lymphocytes, obtained by the method of any one of claims 2 to 6 for use in therapy, preferably for use in treatment of a cancer, an infection, an autoimmune disease, or an inflammatory disease.

8. The pharmaceutical composition of claim 7 for use in tumour- infiltrating lymphocyte (TIL) therapy.

9. A kit for selecting antigen-reactive lymphocytes, comprising: - a first container comprising a transient reporter system for producing a signal upon nuclear translocation of NFAT, wherein the reporter system is ready-for-use for transfection of lymphocytes, optionally upon reconstitution in a liquid such as a buffer; - a second container comprising a transfection buffer; and - a third container comprising at least one cytokine.

10. The kit of claim 9, wherein the transient reporter system is as defined in any one of claims 4 to 6.

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