Cancer vaccine comprising exosomes obtained or derived from activated and mature human b-lymphocytes

Abstract

The present invention relates to compositions comprising one or more populations of activated exosomes, which are suitable for use as cancer vaccines. The activated exosomes in a first population each display CD19 and one or more further surface molecules which are characteristic of mature or activated B-lymphocytes, and each comprise or display one or more tumour antigens selected from MAGEA4, GAGE2D and 5T4. Also provided are methods for the prevention or treatment of cancer using such compositions, and processes for the production of such compositions.

Description

[0001]489.159229 / 01 CANCER VACCINE COMPRISING EXOSOMES OBTAINED OR DERIVED FROM ACTIVATED AND MATURE HUMAN B-LYMPHOCYTES The present invention relates to compositions comprising one or more populations of activated exosomes, which are suitable for use as cancer vaccines. The activated exosomes in a first population each display CD19 and one or more further surface molecules which are characteristic of activated or mature human B-lymphocytes, and each comprise or display one or more tumour antigens selected from MAGEA4, GAGE2D and 5T4. Also provided are methods for the prevention or treatment of cancer using such compositions, and processes for the production of such compositions. Exosomes are a subpopulation of extracellular vesicles (EVs). They are small 30-150nm sized, lipid membrane bilayer structures, that are produced by almost every cell type (Théry, Zitvogel and Amigorena, 2002). The unique process of their biogenesis enables exosomes to contain molecules from the original parental cells and to modulate functions and gene expression in the recipient cells (Valadi et al., 2007) (Zhou et al., 2016). They have been found to be present in biological body fluids such as saliva, urine, breast milk and blood (Raposo and Stoorvogel, 2013), (Jakobsen et al., 2015) and they play a significant role in both physiological and pathological conditions by regulating biological processes between cells (Zaborowski et al., 2015). Due to their natural capability to pack and transport active biomolecules (such proteins, lipids and nuclei acids) from short to large distances within the human body, they are considered as a promising drug delivery system (Doyle and Wang, 2019). One of the biggest advantages of exosomes is their ability to cross physiological barriers, including the blood-lymph, blood-air, blood-brain, blood-cerebrospinal, blood-retinal and blood-placental barriers; this overcomes the critical obstacle found in the use of artificial nanoparticles as another type of delivery platform (Elliott and He, 2021). To date, there are several therapeutic cancer vaccines in development, based on different platforms such peptides, DNA / mRNAs, proteins, viruses, autologous patient-derived whole tumour vaccines, allogeneic whole-cell vaccines and vaccines based on dendritic cells (DeMaria and Bilusic, 2019) (Thomas and Prendergast, 2016). The therapeutic cancer vaccines are P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx designed to target specific signaling pathways, growth factors, or specific antigens that are highly expressed in cancer cells but not, or only to a limited amount, in the normal tissue (Tagliamonte et al., 2014; Loria et al., 2019). However, the development of cancer vaccines is very challenging due to poor immunogenicity (Mandelboim et al., 1995), transplant rejections (Aguirre et al., 2019), targeting the appropriate specific tumour antigens and the high cost of the production process; these factors all limit their applications. For example, in the case of autologous cell vaccines, the biggest obstacle is associated with the preparation of the proper amount of tumour specimen from the patient that is needed for their treatment (Morton et al., 1992). Dendritic cell-based vaccines have produced enormous levels of expectation in the field of immunotherapy; however, clinical trials have shown unconvincing results. Additionally, the process of vaccine development is expensive and is difficult to standardize; this causes problems with the stability of the vaccine, i.e. that it loses its effect during long-term storage (Muenst et al., 2016). Currently, only three non-exosomal therapeutic cancer vaccines have been approved by FDA for clinical applications in patients. These are vaccines against metastatic castration-resistant prostate cancer (PROVENGE), metastatic melanoma (IMLYGIC) and for patients with early stage of bladder cancer (TheraCys). The clinical trials have revealed only modest improvement in overall survival in the patients with early-stage of cancer (Gatti-Mays et al., 2017); however, there was no benefit in patients with advanced stages or metastatic disease (Dillman, 2017). The novel concept of a cell-free, exosome-based immunotherapy has received a great deal of attention in cancer vaccine development. Compared to peptide-based or nucleic acids–based vaccine therapies, exosomes are stable in vivo and are very well tolerated by the human body with minimal side effects and they have a long circulating half-life; this enables them to reach cells at distal tissues (Lai et al., 2013). Because of their phospholipid bilayer membrane, they are able to fuse with cell membranes and to deliver their cargos into recipient cells. For their biocompatibility, stability in blood circulation system, small size and specificity for target delivery, exosomes are very good candidates for immunological purposes and cancer vaccine applications (Temizoz, Kuroda and Ishii, 2016) (Harari et al., 2020). Additionally, it has been found that certain immune cell-derived exosomes might act as antigen-presenting structures and stimulate anti-tumour immune response (Raposo et al., 1996). Recently, the development of dendritic cell-derived exosome (DEXs) vaccines as an antigen delivery system has drawn much attention. Compared to dendritic cells, DEXs contain more MHC-I and MHC-II complexes, they are more resistant to immuno-suppressive mechanisms within the tumour (Fu et al., 2020) P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx and because of their unique lipid composition, they maintain higher stability over longer periods (Viaud et al., 2010). Preclinical in vitro and in vivo studies in mice have shown that DEXs can activate CD4+ and CD8+ T cells that can become memory T-cells (Tkach et al., 2017). However, recent clinical trials using immature dendritic cell-derived exosomes loaded with HLA- restricted melanoma-associated antigen (MAGE3A) peptides in HLA A2+ non-small cell lung cancer patients revealed only minor specific T-cell immune responses during a phase I clinical trial, and no specific CD4+ and CD8+ T-cell response during a phase II clinical trial (Morse et al., 2005). Furthermore, another study from a phase II clinical trial that used a vaccine based on exosomes derived from mature dendritic cells and loaded with IFN-γ did not show any effect on cancer-specific T-cell immune responses in non-small cell lung cancer patients (Besse et al., 2016). A non-randomized phase I / II clinical trial using exosomes derived from non-activated dendritic cells pulsed with SIRT1 biomarker initially showed very promising results. The vaccine induced a specific immune response in cytotoxic T-lymphocytes and had a prolonged 20-month stable period in one patient (from 7 patients, who developed progressive metastatic disease and died within 10 months); however after that, the responsive patient also developed lung metastasis (Narita et al., 2015). Additionally, a vaccine used in a phase I clinical trial for colorectal cancer, composed of exosomes derived from ascites (AEXs) mixed with granulocytes-macrophage colony-stimulating factor (GM-CSF), has shown a robust anti-cancer cytotoxic T-lymphocytes response (Dai et al., 2008); nevertheless, there was no follow-up results from this study. The main reason for such a low outcome of exosome-based vaccine immunotherapy from the above-mentioned clinical trials is the difficulty in identifying and targeting specific tumour antigens associated with the certain type of cancer. The above-mentioned clinical studies have not shown any convincing antigen-specific responses. There is a need therefore for more efficacious immunotherapies for preventing and / or treating cancer. The invention aims to overcome one or more of the above-mentioned problems / limitations by providing an exosome-based vaccine containing a specific combination of tumour antigens to P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx stimulate appropriate anti-cancer properties in effector T-cells, and also to target the adaptive immune system response. The invention combines two technologies: using in vitro activated exosomes derived from mature B-lymphocytes as a delivery system; and the bioengineering of those exosomes with three selected broad tumour antigens. These in vitro activated exosomes will have the same or similar capabilities as B-lymphocytes and thus they will be able to present tumour antigens in unprocessed form on their exosomal surfaces and they will directly act as antigen-presenting structures to evoke immune responses. Furthermore, bioengineering of their exosomal surfaces with three broad tumor antigens will enhance their anticancer immune response properties, thus targeting various tumour cells. Additionally, fusion of the bioengineered exosomes with dendritic cells will induce the processing of those tumour antigens for their further display on dendritic cell surfaces and the exposing of those antigens to certain immune cells. A vaccine based on the exosomes of the invention will be capable of stimulating and enhancing not only appropriate direct anti-cancer immune responses in pre-developed tumours, but also it will be capable of educating the adaptive immune system (which will recognize these tumour antigens and eliminate the cancer cells expressing them immediately after they arise). The use of in vitro activated exosomes from B-lymphocytes will bypass a few steps in the process of activation of the immune system (like for example, processing antigens, activation of B-cells after contact with antigens, producing antigen-presenting cells, etc.) and the selected tumour antigens will more effectively activate and educate immune cells which in turn will fight against a broad spectrum of tumour cells arising from various cancerous tissues. The use of the anti- cancer vaccine of the invention will target cells from both solid and liquid tumours, and also cells from metastases thereof, which express the above-mentioned tumour antigens. In some embodiments, the tumour antigens are all full-length proteins. Most tumour antigens used in vaccines are peptides with short amino acid sequences. Using full length proteins makes the vaccines of the invention highly immunogenic because immune cells can identify them with higher efficiency. The present invention relates to the development of a novel cell-free cancer vaccine based on in vitro activated exosomes derived either from activated and mature human B-lymphocytes or activated and mature human peripheral blood monocytes (PBMCs), which also contain large populations of B-lymphocytes. Both types of mature and in vitro activated exosomes (i.e., from B-lymphocytes and PBMCs) may be bioengineered with a combination of tumour-antigens (i.e., P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx GAGE2D, MAGEA4 and the extracellular domain of 5T4, ex5T4), which will also increase the immunogenic properties of the vaccine. The invention also relates to in vitro activated exosomes from genetically-engineered B-lymphocytes or PBMCs which express one or more tumour antigens (e.g., GAGE2D, MAGEA4 and extracellular domain of 5T4). As these tumour antigens are broadly expressed by cancer cells in different types of tumorous tissues, the novel cancer vaccines based thereon will enable the stimulation of broad anti-tumour responses in immune cells. Bioengineering the exosomal surface of the in vitro activated B-cells to display the three selected tumour antigens allows them to act as antigen-presenting structures for B-lymphocytes that are even able to recognize unprocessed antigens in their native form and to create adaptive memory. Furthermore, additional in vitro activation of the bioengineered exosomes will allow them to be easily taken up by other immune cells, such as dendritic cells or macrophages, which are able to process antigens and to present them on their surface to naïve T- lymphocytes. The vaccine of the invention may trigger the immune system via different mechanisms and induce high levels of an immune response at the same time. This may be achieved by the immunogenic properties of the bioengineered activated exosomes via direct display of tumour antigens on their surfaces and by a unique ability of exosomes to cross and internalize with cytoplasmic membranes of recipient cells, where tumour antigens can be processed and again displayed to the immune system. The interaction of these activated exosomes with T- and B-lymphocytes and the other immune cells results in activation and differentiation of T- and B-cells to either cytotoxic memory cell, but also activation of other types of immune cells participating in immune response. While cytotoxic T-cells are ordained to kill pathogens or diseased cells, including the cancer, the presence of memory cells in the human body is part of adaptive immunity. These cells, upon contact with the same antigen, are able to generate a very quick immune response, even many years later. In this case, the cell-free activated and tumour antigen-expressing exosome-based vaccine of the invention can be applied not only as an immunotherapeutic treatment in cancer patients but can also be used as a prophylactic vaccine to stimulate adaptive immunity in healthy populations. In one embodiment, the invention provides a composition comprising one or more populations of exosomes, wherein the exosomes in a first population of exosomes: (a) each display CD19 and one or more further surface molecules which are characteristic of mature activated B- lymphocytes, and; (b) each comprise (preferably display) one or more tumour antigens selected from MAGEA4, GAGE2D and 5T4, wherein the exosomes in the first population of exosomes collectively comprise (preferably display) all 3 of the tumour antigens. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx In another embodiment, there is provided a pharmaceutical composition comprising a composition of the invention, optionally together with one or more pharmaceutically-acceptable carriers, diluents, adjuvants or excipients. In another embodiment, there is provided a pharmaceutical composition comprising: (A) a first population of exosomes wherein the exosomes: (a) each display CD19 and one or more further surface molecules which are characteristic of mature activated B-lymphocytes; and (b) each comprise (preferably display) a first tumour antigen, wherein the first tumour antigen is MAGEA4; and (B) a second population of exosomes wherein the exosomes: (a) each display CD19 and one or more further surface molecules which are characteristic of mature activated B-lymphocytes; and (b) each comprise (preferably display) a second tumour antigen, wherein the second tumour antigen is GAGE2D; and optionally (C) a third population of exosomes wherein the exosomes: (a) each display CD19 and one or more further surface molecules which are characteristic of mature activated B-lymphocytes; and (b) each comprise (preferably display) a third tumour antigen, wherein the third tumour antigen is 5T4, preferably wherein the surface molecules, populations of exosomes and / or tumour antigens are as defined herein, as a combined preparation in a form suitable for simultaneous, separate or sequential use for the treatment or prevention of cancer, or for inducing an immune (e.g., T-cell or B-cell) response in a subject against the tumour antigens. In another embodiment, there is provided a composition of the invention for use in therapy or for use as a medicament. In another embodiment, there is provided the use of a composition of the invention in the manufacture of a medicament: (i) for preventing or treating cancer in a subject; or P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx (ii) for use in a method of inducing a T-cell or B-cell response to a cancer antigen in a subject; or (iii) for inducing an adaptive or innate immune cell response in a subject. In another embodiment, there is provided a method of preventing or treating a subject susceptible to cancer or with cancer, the method comprising administering an effective amount of a composition of the invention to the subject in need thereof. In another embodiment, there is provided a method of inducing a T-cell or B-cell response or other immune cells to cancer antigens in a subject or for inducing an adaptive or innate immune cell response in a subject, the method comprising administering an effective amount of a composition of the invention to the subject in need thereof. In another embodiment, there is provided a process for producing a population of activated CD19+ exosomes which comprise (preferably display) one or more tumour antigens, the process comprising the steps: (a) maturing immature B-lymphocytes to produce mature B-lymphocytes which display CD19; (b) producing exosomes from the mature B-lymphocytes; and (c) incorporating one or more tumour antigens into each of the exosomes (preferably into the (cell surface) membranes of the exosomes), wherein the tumour antigens are MAGEA4, GAGE2D and 5T4; in order to produce a population of activated CD19+ exosomes which each comprise (preferably display) one or more of the tumour antigens, and wherein the population of exosomes collectively comprises (preferably display) all 3 of the tumour antigens. The composition of the invention comprises one or more populations of exosomes, e.g., 1, 2, 3, 4, 5 or more populations of exosomes. As used herein, the term “exosomes” relates to cellular membrane-derived extracellular vesicles between 30-150 nm in size, with lipid bilayer outer membranes. As used herein, the term “population of exosomes” refers to a group of exosomes which have some features in common (e.g., they all display surface molecules which are characteristic of mature activated B-lymphocytes). P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx The exosomes of the invention may be described as being “activated” in that they are derived from mature B-lymphocytes and then subsequently activated by exposure to one or more tumour antigens; or they are derived from mature activated B-lymphocytes (which have activated by exposure to one or more tumour antigens). The exosomes may be described as being “in vitro activated” in that they have been activated in vitro. Exosomes may be obtained (or are obtainable), for example, from human B-lymphocytes from the blood or from conditioned B-lymphocytes cell media (from which the cells have been removed) by sequential ultracentrifugation at 2000xg for 40 min, 10,000xg for 60 min, and 100,000xg for 1.5 hours or by size-exclusion chromatography. The first population of exosomes display surface molecules which are characteristic of mature activated B-lymphocytes. These surface molecules are displayed on the outer membranes of the exosomes. Preferably, the exosomes have been obtained from or have been derived from mature activated B-lymphocytes. B lymphocytes (also known as B cells) are a type of white blood cell of the lymphocyte subtype. B lymphocytes are involved in the humoral, or antibody-mediated adaptive immune response. B lymphocytes are defined by the B cell receptor (BCR) on their cell surface. Therefore, the exosomes of the first population will, at least, display the B cell receptor as on their surface. Mature, activated B-lymphocytes are CD19 and CD138 positive. Therefore, the exosomes of the first population will also display the CD19 and CD138 proteins as some of their surface molecules. Mature, activated B-lymphocytes also express CD86 or CD80, and MHC I and MHC II proteins on their cell surfaces and thus activated exosomes of the invention might also display one or more of these proteins either on external or internal exosomal membrane. Preferably, therefore, the surface molecules which are characteristic of mature activated B-lymphocytes are BCR, CD19, CD138, CD86 or CD80, MHC I and MHC II. The presence of at least one of these surface molecules together with the tumour antigens, on the surfaces of the exosomes of the first population allows the exosomes to act as antigen-presenting structures, not only for naïve T-lymphocytes but also for B-lymphocytes and to participate in the activation of the immune response of other immune cells. (Surface molecules which are characteristic of normal mature activated B-lymphocytes are not tumour antigens.) P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx The display of such surface molecules on the cells or exosomes may readily be determined either by flow cytometry or by Western blot, using appropriate antibodies against the surface molecules. Immature B lymphocytes (e.g., isolated from the blood of a donor or from the cell line) may be matured by contacting them with CD40L in vitro. Preferably, the proliferation of the mature B- lymphocytes is then induced by IL-2. Preferably, the first population of exosomes is at least 5%, more preferably at least 10%, of the total exosomes in the composition. The composition may additionally comprise one or more other populations of exosomes which do not display surface molecules which are characteristic of mature activated B-lymphocytes. For example, the composition may additionally comprise exosomes which display surface molecules which are characteristic of PBMCs other than B-lymphocytes. In particular, the composition may additionally comprise exosomes which are obtained from or derived from PBMCs other than B-lymphocytes. For example, the composition may additionally comprise exosomes which display surface molecules which are characteristic of myeloid cells, such as monocytes and dendritic cells, and / or other lymphoid cells, such as NK cells and T- lymphocytes. In particular, the composition may additionally comprise exosomes which are obtained from or derived from myeloid cells, such as monocytes and dendritic cells, and other lymphoid cells, such as NK cells and T-lymphocytes. Whilst these other cells (and exosomes obtained from or derived from them) may not display surface molecules which are characteristic of mature activated B-lymphocytes, these other cells (and exosomes) may display one or more of the tumour antigens. The first population of exosomes also comprises (e.g., displays) one or more tumour antigens. In some embodiments, these tumour antigens are displayed on or in the outer cell membranes of the exosomes. These tumour antigens are therefore membrane-associated antigens. In other embodiments, the one or more tumour antigens are contained within the exosome. In other embodiments, some of the one or more tumour antigens are displayed on or in the outer cell membranes of the exosomes and some are contained within the exosome. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx In some embodiments, the one or more tumour antigens are independently selected from: (i) Products of mutated oncogenes and tumour suppressor genes; (ii) Products of other mutated genes; (iii) Over-expressed or aberrantly-expressed cellular proteins; (iv) Tumour antigens produced by oncogenic viruses (v) Onco-foetal antigens; (vi) Altered cell surface glycolipids and glycoproteins; and (vii) Cell type-specific differentiation antigens. In some embodiments, the one or more tumour antigens are 1, 2, 3, 4 or 5 or more (e.g., 5-10) tumour antigens. Each exosome may comprise (e.g., display) 1, 2, 3, 4 or 5 or more (e.g., 5-10) of the one or more tumour antigens, e.g., on their outer surfaces. In embodiments wherein the number of tumour antigens is two or more, the exosomes in the first population collectively comprise (e.g., display) those two or more tumour antigens, i.e., wherein each of the two or more tumour antigens are present (e.g., displayed) either individually or in combination by one or more of the exosomes in the first population. Thus, some exosomes in the first population may comprise (e.g., display) one tumour antigen; some may comprise (e.g., display) two tumour antigens; some may comprise (e.g., display) three tumour antigens; and so on. But overall, when the first population of exosomes is considered as a whole, at least some of the exosomes in the first population will comprise (e.g., display) each of the different tumour antigens. In some embodiments, one or more of the tumour antigens are tumour-associated antigens. In other embodiments, one or more of the tumour antigens are tumour-specific antigens. Examples of tumour-associated antigens include MAGEA4, GAGE2D and 5T4. Further examples of tumour-associated antigens include NYESO-1, HER-2 / NEW, MAGE family, GAGE family, XAGE family, RAGE family, BAGE family, SSX, Mammaglobulin A, Tyrosinase, WT1, MUC-1, hTERT, CA-125, gp-100, HPV, HBV, EBV, HTLV, SV40, GA7330 / EpCam, SART1, SART3, Survivin, Mesothelin, and AFP. Examples of tumour-specific antigens include PSA, PSMA, CEA, PAP, MART1 and melanA. The one or more tumour antigens are selected from MAGEA4, GAGE2D and 5T4. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx In some preferred embodiments, the exosomes in the first population collectively comprise (e.g., display) all three of the tumour antigens MAGEA4 and GAGE2D and 5T4, (i.e., wherein each of the three tumour antigens are present (e.g., displayed) either individually or in combination by one or more of the exosomes in the first population). Preferably, the tumour antigens are all full-length proteins. Most tumour antigens used in vaccines are peptides with short amino acid sequences. Using full length proteins makes the vaccines of the invention highly immunogenic because immune cells can identify them with higher efficiency. The MAGEA4 gene encodes Melanoma-associated antigen 4; it is also known as MAGEA4. The human MAGEA4 gene has the UniProtKB database accession no. P43358 (MAGA4_HUMAN). The amino acid sequence of the human MAGEA4 polypeptide is given herein as SEQ ID NO: 1. As used herein, the term “MAGEA4” or “MAGEA4 polypeptide” preferably refers to a polypeptide whose amino acid sequence comprises or consists of the amino sequence as given in SEQ ID NO: 1, or variant thereof having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto. Preferably, the variant is one which binds to histone deacetylase. The GAGE2D gene encodes G antigen 2D. The human GAGE2D gene has the UniProtKB database accession no. Q9UEU5 (GGE2D_HUMAN). The amino acid sequence of the human GAGE2D polypeptide is given herein as SEQ ID NO: 2. As used herein, the term “GAGE2D” or “GAGE2D polypeptide” preferably refers to a polypeptide whose amino acid sequence comprises or consists of the amino sequence as given in SEQ ID NO: 2, or variant thereof having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto. Preferably, the variant is a variant which binds to FLT3 (CD135 antigen). The 5T4 (TPBG) gene encodes an inhibitor of Wnt / beta-catenin signalling. The human 5T4 gene has the UniProtKB database accession no. Q13641. The amino acid sequence of the human 5T4 polypeptide is given herein as SEQ ID NO: 3. As used herein, the term “5T4” or “5T4 polypeptide” preferably refers to a polypeptide whose amino acid sequence comprises or consists of the amino sequence as given in SEQ ID NO: 3, or variant thereof having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto. Preferably, the variant is an inhibitor of Wnt / beta-catenin signalling. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx In some embodiments, the term “5T4” or “5T4 polypeptide” as used herein also encompasses just the extracellular domain of the 5T4 polypeptide. As used herein, the term “extracellular domain of the 5T4 polypeptide” preferably refers to a polypeptide whose amino acid sequence comprises or consists of the amino sequence as given in SEQ ID NO: 4, or variant thereof having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto. Preferably, the variant is an inhibitor of Wnt / beta-catenin signalling. Preferably, the one or more tumour antigens are selected from MAGEA4 and GAGE2D and 5T4. In some embodiments, exosomes in the first population comprise (e.g., display): (i) MAGEA4 ; (ii) GAGE2D (iii) 5T4 ; (iv) MAGEA4 and GAGE2D; (v) MAGEA4 and 5T4; (vi) GAGE2D and 5T4; or (vii) MAGEA4 and GAGE2D and 5T4; wherein at least some exosomes in the first population comprise (e.g., display) MAGEA4 at least some exosomes in the composition comprise (e.g., display) GAGE2D; and optionally at least some exosomes in the composition comprise (e.g., display) 5T4. In some preferred embodiments, each exosome comprises (e.g., displays): (i) MAGEA4 and GAGE2D; or (ii) MAGEA4 and GAGE2D and 5T4. The presence of such tumour antigens may readily be determined either by flow cytometry or by Western blot, using appropriate antibodies against the antigens. There are many established algorithms available to align two amino acid sequences. Typically, one sequence acts as a reference sequence, to which test sequences may be compared. The sequence comparison algorithm calculates the percentage sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters. Alignment of amino acid sequences for comparison may be conducted, for example, by computer-implemented algorithms (e.g., GAP, BESTFIT, FASTA or TFASTA), or BLAST and BLAST 2.0 algorithms. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx Percentage amino acid sequence identities and nucleotide sequence identities may be obtained using the BLAST methods of alignment (Altschul et al. (1997), "Gapped BLAST and PSI- BLAST: a new generation of protein database search programs", Nucleic Acids Res.25:3389- 3402; and http: / / www.ncbi.nlm.nih.gov / BLAST). Preferably the standard or default alignment parameters are used. Standard protein-protein BLAST (blastp) may be used for finding similar sequences in protein databases. Like other BLAST programs, blastp is designed to find local regions of similarity. When sequence similarity spans the whole sequence, blastp will also report a global alignment, which is the preferred result for protein identification purposes. Preferably the standard or default alignment parameters are used. In some instances, the "low complexity filter" may be taken off. BLAST protein searches may also be performed with the BLASTX program, score=50, wordlength=3. To obtain gapped alignments for comparison purposes, Gapped BLAST (in BLAST 2.0) can be utilized as described in Altschul et al. (1997) Nucleic Acids Res.25: 3389. Alternatively, PSI-BLAST (in BLAST 2.0) can be used to perform an iterated search that detects distant relationships between molecules. (See Altschul et al. (1997) supra). When utilizing BLAST, Gapped BLAST, PSI-BLAST, the default parameters of the respective programs may be used. With regard to nucleotide sequence comparisons, MEGABLAST, discontiguous-megablast, and blastn may be used to accomplish this goal. Preferably the standard or default alignment parameters are used. MEGABLAST is specifically designed to efficiently find long alignments between very similar sequences. Discontiguous MEGABLAST may be used to find nucleotide sequences which are similar, but not identical, to the nucleic acids of the invention. The BLAST nucleotide algorithm finds similar sequences by breaking the query into short subsequences called words. The program identifies the exact matches to the query words first (word hits). The BLAST program then extends these word hits in multiple steps to generate the final gapped alignments. In some embodiments, the BLAST nucleotide searches can be performed with the BLASTN program, score=100, wordlength=12. One of the important parameters governing the sensitivity of BLAST searches is the word size. The most important reason that blastn is more sensitive than MEGABLAST is that it uses a P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx shorter default word size (11). Because of this, blastn is better than MEGABLAST at finding alignments to related nucleotide sequences from other organisms. The word size is adjustable in blastn and can be reduced from the default value to a minimum of 7 to increase search sensitivity. A more sensitive search can be achieved by using the newly-introduced discontiguous megablast page (www.ncbi.nlm.nih.gov / Web / Newsltr / FallWinter02 / blastlab.html). This page uses an algorithm which is similar to that reported by Ma et al. (Bioinformatics.2002 Mar; 18(3): 440-5). Rather than requiring exact word matches as seeds for alignment extension, discontiguous megablast uses non-contiguous word within a longer window of template. In coding mode, the third base wobbling is taken into consideration by focusing on finding matches at the first and second codon positions while ignoring the mismatches in the third position. Searching in discontiguous MEGABLAST using the same word size is more sensitive and efficient than standard blastn using the same word size. Parameters unique for discontiguous megablast are: word size: 11 or 12; template: 16, 18, or 21; template type: coding (0), non- coding (1), or both (2). In some embodiments, the BLASTP 2.5.0+ algorithm may be used (such as that available from the NCBI) using the default parameters. In other embodiments, a BLAST Global Alignment program may be used (such as that available from the NCBI) using a Needleman-Wunsch alignment of two protein sequences with the gap costs: Existence 11 and Extension 1. As used herein, the term “sequence identity” in the context of amino acid sequences may alternatively be replaced by “sequence similarity”. The term “similarity” allows conservative substitutions of amino acid residues having similar physicochemical properties over a defined length of a given alignment. The percentage of similarity is determinable with any reasonable similarity-scoring matrix. In one embodiment, the composition is an immunogenic composition or a vaccine composition. As used herein, the term “immunogenic” is intended to refer to the ability to elicit a specific immune response against a tumour antigen. This response may, for example, be when a composition of the invention is administered at an appropriate dose and in an appropriate P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx formulation which may include / require a suitable adjuvant. A booster comprising a dose similar or less than the original dose may be required to obtain the required immunogenic response. In particular, the immunogenic composition of the invention is capable of inducing antibodies (preferably neutralising antibodies in a subject against one or more tumour antigens, preferably against MAGEA4, GAGE2D and / or 5T4, or is capable of inducing activity of T-lymphocytes, B- lymphocytes, NK cells, dendritic cells, or macrophages). The capability of a composition of the invention to induce neutralising antibodies in a subject (e.g., a human subject) may be tested by purifying sera from the blood of a subject to whom the composition has been administered. Antibodies may be measured using ELISA or a pseudotype micro-neutralisation (pMN) assay. ELISA is the most sensitive of these two assays; it quantifies all antibodies. In contrast, the pMN is less sensitive, but it quantifies neutralising antibodies. Testing for the activity of T-lymphocytes may be performed by testing (e.g., by Western blot or ELISA, or flow cytometry) for the production of specific cytokines or chemokines, as expressed by different populations of activated T-cells. For example, activation of Th1 T-helper: IL-2, IFN- gamma, TNF-gamma; Th-2 T helper: IL-4, IL-10, IL-13; Th-17 T-cell helpers: Th17. The immunogenic composition may additionally comprise one or more pharmaceutically- acceptable carriers. Substances suitable for use as pharmaceutically-acceptable carriers are known in the art. Non-limiting examples of pharmaceutically-acceptable carriers include water, saline, and phosphate-buffered saline. In some embodiments, however, the composition is in lyophilized form, in which case it may include a stabilizer, such as bovine serum albumin (BSA). In some embodiments, it may be desirable to formulate the composition with a preservative, such as thiomersal or sodium azide, to facilitate long term storage. Examples of buffering agents include, but are not limited to, sodium succinate (pH 6.5), and phosphate buffered saline (PBS; pH 7.4). In addition to a pharmaceutically-acceptable carrier, the composition of the invention can be further combined with one or more of a salt, excipient, diluent, adjuvant, immunoregulatory agent and / or antimicrobial compound. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx In one embodiment, the compositions of the invention may contain 5% to 95% of active ingredient (i.e., exosomes), such as at least 10% or 25% of active ingredient, or at least 40% of active ingredient or at least 50%, 55%, 60%, 70% or 75% active ingredient. The products of the invention may be administered in a manner compatible with the dosage formulation, and in such amount as will be prophylactically and / or therapeutically effective. Administration of the compositions of the invention is generally by conventional routes, e.g., intravenous, subcutaneous, intraperitoneal, oral or mucosal routes. The administration may be by parenteral administration; for example, a subcutaneous or intramuscular injection. Accordingly, the compositions of the invention may be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for solution in, or suspension in, liquid prior to injection may alternatively be prepared. The preparation may also be emulsified, or the peptide encapsulated in liposomes or microcapsules. The active ingredients are often mixed with excipients which are pharmaceutically-acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like and combinations thereof. In addition, if desired, the products of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, and / or pH buffering agents. Preferably, the composition of the invention is a vaccine composition, e.g., suitable for parenteral administration, optionally together with one or more adjuvants. As used herein, a vaccine is a formulation that, when administered to a subject stimulates a protective immune response. The immune response may be a humoral and / or a cell-mediated immune response. Thus, the vaccine may stimulate B-cells and / or T-cells, and other immune cell types. The composition may further comprise a surfactant. Examples of suitable surfactants include Tween (such as Tween 20), Brij and polyethylene glycol. Vaccine preparation is generally described in New Trends and Developments in Vaccines, edited by Voller et al., University Park Press, Baltimore, Maryland, U.S.A., 1978. Encapsulation within liposomes is described, for example, by Fullerton, U.S. Patent 4,235,877. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx The amount of the exosomes of the present invention present in each vaccine dose is selected as an amount which induces an immuno-protective response without significant adverse side effects in typical vaccines. Such amount will vary depending upon which specific immunogen is employed and whether or not the vaccine is adjuvanted. Generally, it is expected that each dose will comprise 1-1000µg / ml of protein, for example 1-200 µg / ml, such as 10-100µg / ml, and more particularly 10-40µg / ml. An optimal amount for a particular vaccine can be ascertained by standard studies involving observation of antibody titres and other responses in subjects. Following an initial vaccination, subjects will preferably receive a boost in about 4 weeks, followed by repeated boosts every six months for as long as a risk of infection exists. The immune response to the compositions of this invention is enhanced by the use of adjuvant and or an immunostimulant. The compositions of the invention do not comprise cells, i.e., they are cell-free. Preferably, the compositions are DNA / RNA free or substantially DNA / RNA free (except for the exosomes) Also provided is an immunogenic composition comprising two or more populations of exosomes as defined herein as a combined preparation in a form suitable for simultaneous, separate or sequential use for the treatment or prevention of cancer, or for inducing a T-cell or B-cell response in a subject against a tumour antigen, preferably against MAGEA4, GAGE2D or 5T4. In particular, the immunogenic composition may comprise: (A) a first population of exosomes wherein the exosomes: (a) each display CD19 and one or more further surface molecules which are characteristic of mature activated B-lymphocytes; and (b) each comprise (e.g., display) a first tumour antigen, wherein the first tumour antigen is MAGEA4; and (B) a second population of exosomes wherein the exosomes: (a) each display CD19 and one or more further surface molecules which are characteristic of mature activated B-lymphocytes; and (b) each comprise (e.g., display) a second tumour antigen, wherein the second tumour antigen is GAGE2D; and optionally (C) a third population of exosomes wherein the exosomes: P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx (a) each display CD19 and one or more further surface molecules which are characteristic of mature activated B-lymphocytes; and (b) each comprise (e.g., display) a third tumour antigen, wherein the third tumour antigen is 5T4; preferably wherein the surface molecules, populations of exosomes and / or tumour antigens are as defined herein, as a combined preparation in a form suitable for simultaneous, separate or sequential use for the treatment or prevention of cancer, or for inducing a T-cell or B-cell response in a subject against the tumour antigens. The invention also provides a kit of parts comprising the above-defined first, second and third populations of exosomes. In yet further embodiments, the invention provides a composition of the invention for use in therapy or for use as a medicament. In a further aspect, the invention provides a composition of the invention for use in a method of preventing or treating cancer in a subject. In further embodiments, the invention provides a composition of the invention for use in a method of inducing a T-cell, B-cell or other immune cell response to cancer antigens in a subject. In further embodiments, the invention provides the use of a composition of the invention in the manufacture of a medicament for preventing or treating cancer in a subject. In further embodiments, the invention provides the use a composition of the invention in the manufacture of a medicament for inducing a T-cell, B-cell or other immune cell response to a cancer antigen in a subject. The invention also provides a method of preventing or treating a subject susceptible to cancer or with cancer, the method comprising administering an effective amount of a composition of the invention to the subject in need thereof. The invention also provides a method of inducing a T-cell, B-cell or other immune cell response to a cancer antigen in a subject comprising administering an effective amount of a composition of the invention to the subject in need thereof. The invention also provides the use of a composition of the invention for the treatment of cancer; and a composition of the invention, when used for the treatment of cancer. The cancer antigen is preferably one of the tumour antigens as defined herein. Compositions of the invention may also be used in similar uses and methods to produce neutralising antibodies or methods of activation of T-lymphocytes in vivo against tumour antigens. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx The efficacy of the uses and methods to treat / prevent cancer may be tested (e.g., by ELISA) by establishing the presence or absence of neutralising antibodies against the tumour antigen in the subject’s blood or activity of T-lymphocytes in the subject’s blood. As used herein, the term "preventing" includes preventing the initiation of a cancer and / or reducing the severity of intensity of a cancer. Thus, "preventing" encompasses vaccination. As used herein, the term "treating" embraces therapeutic and preventative / prophylactic measures (including post-exposure prophylaxis) and includes post-infection therapy and amelioration of a cancer. Each of the above-described methods and uses can comprise the step of administering to a subject an effective amount, such as a therapeutically-effective amount, of a composition of the invention. As used herein, an effective amount is a dosage or amount that is sufficient to achieve a desired biological outcome. As used herein, a therapeutically-effective amount is an amount which is effective, upon single or multiple dose administration to a subject (such as a mammalian subject, in particular a human subject) for treating, preventing, curing, delaying, reducing the severity of, ameliorating at least one symptom of a disorder or recurring disorder (e.g., cancer), or prolonging the survival of the subject beyond that expected in the absence of such treatment. Accordingly, the quantity of active ingredient to be administered depends on the subject to be treated, capacity of the subject's immune system to generate a protective immune response, and the degree of protection required. Precise amounts of active ingredient required to be administered may depend on the judgement of the practitioner and may be particular to each subject. Administration to the subject can comprise administering to the subject a population of exosomes or a composition of the invention (i.e., a product of the invention) wherein the product of the invention is sequentially administered multiple times (for example, wherein the composition is administered two, three or four times). Thus, in one embodiment, the subject is administered a population of exosomes or a composition of the invention, and is then administered the same product of the invention (or a substantially similar product) again at a different time. In one embodiment, administration to a subject comprises administering a population of exosomes or a composition of the invention to a subject, wherein said product of the invention is P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx administered substantially prior to, simultaneously with, or subsequent to, another immunogenic composition. The invention also extends to prime-boost regimes. For example, priming and / or boosting may be affected using one or more products of the invention. The products may be administered to a subject sequentially, simultaneously or separately. The composition of the invention may be given in a single dose schedule (i.e., the full dose is given at substantially one time). Alternatively, the composition of the invention may be given in a multiple dose schedule. A multiple dose schedule is one in which a primary course of treatment (e.g., vaccination) may be with 1-6 separate doses, followed by other doses given at subsequent time intervals required to maintain and or reinforce the immune response, for example (for human subjects), at 1-4 months for a second dose, and if needed, a subsequent dose(s) after a further 1-4 months. The dosage regimen will be determined, at least in part, by the need of the individual and be dependent upon the judgment of the practitioner (e.g., doctor or veterinarian). Simultaneous administration means administration at (substantially) the same time. Sequential administration of two or more compositions of the invention means that the compositions are administered at (substantially) different times, one after the other. For example, sequential administration may encompass administration of two or more compositions of the invention at different times, wherein the different times are separated by a number of days (for example, 1, 2, 5, 10, 15, 20, 30, 60, 90, 100, 150 or 200 days). For example, in one embodiment, the composition of the present invention may be administered as a vaccine as part of a 'prime-boost' vaccination regime. In one embodiment, the composition of the invention can be administered to a subject such as a mammal in conjunction with (simultaneously or sequentially) one or more immunoregulatory agents selected from, for example, immunoglobulins, antibiotics, interleukins (e.g., IL- 2, IL-17), and / or cytokines (e.g., IFN-γ). P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx The subject is preferably a mammalian subject. The subject may be human or non-human. For example, the subject may be a farm mammal (e.g., sheep, horse, pig, cow or goat), a companion mammal (e.g., cat, dog or rabbit) or a laboratory test mammal (e.g., mouse, rat or monkey). Preferably, the subject is a human. The subject may be male or female. The human may, for example, be 0-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100 or above 100 years old. The human may be one who is suffering from or at risk from a particular disease or disorder, e.g., lung cancer. In some preferred embodiments, the subject is one who is suffering from or has previously suffered from cancer. A control subject may be defined as a non- diseased subject, a subject without cancer, a typically-developed subject or a healthy-aged subject. As used herein, the term “control subject” relates to an individual or group of individuals of the same species as the subject being tested. For example, if the subject is a human, the control will be a human. The cancer may be a malignant or benign cancer. Preferably, the cancer is selected from the group consisting of colon cancer, prostate cancer, breast cancer, lung cancer, skin cancer, liver cancer, bone cancer, ovary cancer, pancreatic cancer, brain cancer, head and neck cancers, blood cancer (e.g., leukaemia, lymphoma and myeloma). In yet further embodiments, there are provided processes to make the populations of exosomes of the invention. In particular, there is provided a process for producing a population of CD19+ exosomes which comprise (e.g., display) one or more tumour antigens, the process comprising the steps: (a) maturing immature B-lymphocytes to produce mature B-lymphocytes which display CD19 (b) producing exosomes from the mature B-lymphocytes; and (c) incorporating one or more tumour antigens into each of the exosomes (preferably into the membranes of the exosomes) where the tumour antigens are MAGEA4, GAGE2D and 5T4; in order to produce a population of activated CD19+ exosomes which each comprise (e.g., display) one or more tumour antigens, and wherein the population of exosomes collectively comprises (preferably display) all 3 of the tumour antigens. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx In yet a further embodiment, there is provided a process for producing a population of activated CD19+ exosomes which comprise (e.g., display) one or more tumour antigens, the process comprising the steps: (a) expressing one or more tumour antigens (preferably cell surface tumour antigens) in each cell in a population of cells comprising immature or mature B-lymphocytes, where the tumour antigens are MAGEA4, GAGE2D and 5T4, thereby maturing and activating the immature or B-lymphocytes to produce mature activated B-lymphocytes; and (b) producing activated CD19+ exosomes from the mature activated B-lymphocytes; in order to produce a population of activated CD19+ exosomes which each comprise (e.g., display) one or more the tumour antigens, and wherein the population of exosomes collectively comprises (preferably display) all 3 of the tumour antigens. In yet a further embodiment, there is provided a process for producing a population of activated CD19+ exosomes which comprise (e.g., display) one or more tumour antigens, the process comprising the steps: (a) maturing immature B-lymphocytes in a population of cells comprising immature B- lymphocytes to produce mature activated B-lymphocytes which display CD19+; (b) expressing one or more cell tumour antigens (preferably cell surface tumour antigens) in each of the mature B-lymphocytes, thus activating the B-lymphocytes, where the tumour antigens are MAGEA4, GAGE2D and 5T4; and (c) producing activated CD19+ exosomes from the mature activated B-lymphocytes, in order to produce a population of activated CD19+ exosomes which each comprise (e.g., display) one or more of the tumour antigens and wherein the population of exosomes collectively comprises (preferably display) all 3 of the tumour antigens. Immature B-lymphocytes may be obtained from any suitable source, including from blood samples obtained from subjects. Blood contains peripheral blood mononuclear cells (PBMCs), i.e., a mixed population of myeloid and lymphoid cells. Hence PBMCs include some mature and immature B-lymphocytes. In the context of the claimed processes, therefore, the immature B- lymphocytes may be provided in the form of PBMCs (e.g., admixed with other PBMCs). P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx B-lymphocytes and PBMCs may be obtained from blood samples by standard processes, e.g., by density gradient centrifugation. Individual cell types may be isolated from PBMCs either through standard immunomagnetic separation or FACS (fluorescence-activated cell sorting) techniques. Immature and mature activated B-lymphocytes (and PBMCs) may be engineered to express the tumour antigens (instead of being pulsed with the tumour antigens). For example, these cells may be transfected (stably or transiently) with appropriate expression constructs encoding the tumour antigens, e.g., under the control of inducible or constitutive promoters. Methods for the expression of such antigens in cells are known in the art (e.g., “Molecular Cloning: A Laboratory Manual” (Fourth Edition), Green, MR and Sambrook, J., (updated 2014)). The immature B-lymphocytes or PBMCs comprising immature B-lymphocytes may be activated by any suitable means. For example, immature B-lymphocytes may be activated by contact with CD40L (e.g., in vitro). Preferably, the proliferation of the mature activated B-lymphocytes is then induced by IL-2. As discussed above, mature, activated B-lymphocytes and exosomes derived therefrom are CD19 and CD138 positive; they might naturally also express BCR, CD86 or CD80, and MHC I and MHC II proteins on their cell (or exosomal) surfaces. Activation may be therefore being verified by determined the presence of such molecules by flow cytometry or by Western blot, using appropriate antibodies against the molecules. Exosomes may be produced from the mature activated B-lymphocytes by any suitable method. PBMCs comprising mature B-lymphocytes may also be used instead of mature B-lymphocytes. Such methods include centrifugation or ultracentrifugation; this may or may not be combined with size-exclusion chromatography (SEC). Size exclusion chromatography columns may be used, for example using porous gel columns. In such columns, the pore size is preferably 30- 150 nm in order to allow the passage of exosomes but not larger vesicles. Other methods include immunoprecipitation by using exosomal markers (e.g., CD9, CD81, CD63, Alix, TSG- 101 etc.). This may be achieved, for example, by direct immunoprecipitation using commercially-available kits. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx One or more tumour antigens may be incorporated into the exosomal surface membranes of the exosomes in order to produce exosomes which display the desired tumour antigens. Such incorporation may be achieved by any suitable means. For example, the exosomes may be electroporated, incubated, or pulsed with the tumour antigens in a shaker. A cationic polymer (e.g., polybrene) may be added in order to enhance the incorporation efficiency. Preferably, the exosomes are pulsed (e.g., incubated) with the tumour antigens at about 37oC, for about 90 minutes, under shaking condition optionally in the presence of polybrene. The invention also encompasses populations of exosomes which comprise (e.g., display) one or more tumour antigens which are obtained or obtainable by a process of the invention. The invention also provides a process for producing a pharmaceutical composition, the process comprising the process for producing a population of exosomes which comprise (e.g., display) one or more tumour antigens of the invention, and wherein the process additionally comprises the step of: (d) admixing the population of exosomes with one or more pharmaceutically- acceptable diluents, excipients, adjuvants or carriers. The invention also encompasses compositions obtained or obtainable by a process for producing a pharmaceutical composition of the invention. Preferably, the process steps are carried out (one after the other) in the order specified. In other embodiments, the invention provides one of more of the following Embodiments: Embodiment 1. A composition comprising one or more populations of exosomes, wherein the exosomes in a first population of exosomes: (a) each display surface molecules which are characteristic of mature activated B-lymphocytes; and (b) each comprise (preferably display) one or more tumour antigens. Embodiment 2. A composition as claimed in claim 1, wherein the surface molecules which are characteristic of mature activated B-lymphocytes are BCR, CD19, CD138, CD86 or CD80, MHC I and MHC II. Embodiment 3. A composition as claimed in Embodiment 1 or Embodiment 2, wherein the first population of exosomes have been obtained from or derived from: (i) mature activated B-lymphocytes; or (ii) a population of PBMCs which comprise mature activated B-lymphocytes. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx Embodiment 4. A composition as claimed in Embodiment 3, wherein: (i) the mature activated B-lymphocytes; or (ii) the population of PBMCs which comprise mature activated B- lymphocytes, have been modified to comprise (preferably display) one or more of the tumour antigens after production of the exosomes. Embodiment 5. A composition as claimed in Embodiment 3, wherein: (i) the mature activated B-lymphocytes; or (ii) the population of PBMCs which comprise mature activated B- lymphocytes, have been modified to comprise (preferably display) the one or more tumour antigens prior to the production of the exosomes. Embodiment 6. A composition as claimed in any one of the preceding Embodiments, wherein the composition additionally comprises one or more further population of exosomes which have been obtained or derived from monocytes, dendritic cells, NK cells and / or T- lymphocytes. Embodiment 7. A composition as claimed in Embodiment 6, wherein one or more of the further populations of exosomes comprise (preferably display) one or more of the tumour antigens. Embodiment 8. A composition as claimed in any one of the preceding Embodiments, wherein the exosomes in the first population of exosomes collectively comprise (preferably display) 1, 2, 3, 4 or 5 (preferably 3) of the tumour antigens. Embodiment 9. A composition as claimed in any one of the preceding Embodiments, wherein the exosomes in the first population of exosomes all comprise (preferably display) 1, 2, 3, 4 or 5 (preferably 3) of the tumour antigens. Embodiment 10. A composition as claimed in any one of the preceding Embodiments, wherein one or more of the tumour antigens are tumour-associated antigens or tumour-specific antigens. Embodiment 11. A composition as claimed in any one of the preceding Embodiments, wherein the one or more tumour antigens are selected from MAGEA4, GAGE2D and 5T4. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx Embodiment 12. A composition as claimed in Embodiment 11, wherein 5T4 is the extracellular domain of the 5T4 polypeptide. Embodiment 13. A pharmaceutical composition comprising a composition as claimed in any one of the preceding Embodiments, optionally together with one or more pharmaceutically- acceptable carriers, diluents, adjuvants or excipients. Embodiment 14. A pharmaceutical composition comprising: (A) a first population of exosomes wherein the exosomes: (a) each display surface molecules which are characteristic of mature activated B-lymphocytes; and (b) each comprise (preferably display) a first tumour antigen; and (B) a second population of exosomes wherein the exosomes: (a) each display surface molecules which are characteristic of mature activated B-lymphocytes; and (b) each comprise (preferably display) a second tumour antigen; and optionally (C) a third population of exosomes wherein the exosomes: (a) each display surface molecules which are characteristic of mature activated B-lymphocytes; and (b) each comprise (preferably display) a third tumour antigen, preferably wherein the surface molecules, populations of exosomes and / or tumour antigens are as defined in any one of Embodiments 2-12, as a combined preparation in a form suitable for simultaneous, separate or sequential use for the treatment or prevention of cancer, or for inducing a T-cell or B-cell response in a subject against a tumour antigen. Embodiment 15. A composition as claimed in any one of Embodiments 1 to 14 for use in therapy or for use as a medicament. Embodiment 16. A composition as claimed in any one of claims 1 to 14: (i) for use in a method of preventing or treating cancer in a subject; or (ii) for use in a method of inducing a T- cell or B-cell response to a cancer antigen in a subject. Embodiment 17. Use of a composition as claimed in any one of Embodiments 1 to 14 in the manufacture of a medicament: (i) for preventing or treating cancer in a subject; or (ii) for inducing a T-cell or B-cell response to a cancer antigen in a subject. Embodiment 18. A method of preventing or treating a subject susceptible to cancer or with cancer, the method comprising administering an effective amount of a composition as claimed in any one of Embodiments 1 to 14 to a subject in need thereof. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx Embodiment 19. A method of inducing a T-cell or B-cell response to a cancer antigen in a subject comprising administering an effective amount of a composition as claimed in any one of Embodiments 1 to 14 to a subject in need thereof. Embodiment 20. A composition for use, a use or a method as claimed in any one of Embodiments 16 to 19, wherein the cancer is selected from the group consisting of colon cancer, prostate cancer, breast cancer, lung cancer, skin cancer, liver cancer, bone cancer, ovary cancer, pancreatic cancer, brain cancer, head and neck cancers, and blood cancer (e.g., leukaemia, lymphoma and myeloma). Embodiment 21. A process for producing a population of exosomes which comprise (preferably display) one or more tumour antigens, the process comprising the steps: (a) activating immature B-lymphocytes to produce mature activated B-lymphocytes; (b) producing exosomes from the mature activated B-lymphocytes; and (c) incorporating one or more tumour antigens into the exosomes (preferably into the cell surface membranes of the exosomes); in order to produce a population of exosomes which comprise (preferably display) one or more tumour antigens. Embodiment 22. A process for producing a population of exosomes which comprise (preferably display) one or more tumour antigens, the process comprising the steps: (a) expressing one or more tumour antigens (preferably cell surface tumour antigens) in a population of cells comprising immature B-lymphocytes; (b) activating the immature B- lymphocytes to produce mature activated B-lymphocytes; and (c) producing exosomes from the mature activated B-lymphocytes; in order to produce a population of exosomes which comprise (preferably display) one or more tumour antigens. Embodiment 23. A process for producing a population of exosomes which comprise (preferably display) one or more tumour antigens, the process comprising the steps: (a) activating immature B-lymphocytes in a population of cells comprising immature B-lymphocytes to produce mature activated B-lymphocytes; (b) expressing one or more tumour antigens (preferably cell surface tumour antigens) in the mature activated B-lymphocytes; and (c) producing exosomes from the mature activated B-lymphocytes, in order to produce a population of exosomes which comprise (preferably display) one or more tumour antigens. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx Embodiment 24. A process as claimed in any one of Embodiments 21 to 23, wherein the immature B-lymphocytes are present in a population of PBMCs or where the population of cells comprising immature B-lymphocytes is a population of PBMCs. Embodiment 25. A process for producing a pharmaceutical composition, the process comprising the process for producing a population of exosomes which comprise (preferably display) one or more tumour antigens as claimed in any one of Embodiments 21 to 24, and wherein the process additionally comprises the step of: (d) admixing the population of exosomes with one or more pharmaceutically-acceptable diluents, excipients, adjuvants or carriers. Embodiment 26. A population of exosomes or a pharmaceutical composition obtained or obtainable by a process as claimed in any one of Embodiments 21 to 25. The disclosure of each reference set forth herein is specifically incorporated herein by reference in its entirety. BRIEF DESCRIPTION OF THE FIGURES Figure 1: Western blot analysis of stably-transfected HEK293T cells with tumour associated antigens. a. expression of GAGE2D protein (GAGE2D-His-Tag or Empty vector) in cell lysates (left) or in the conditioning media (right). b. expression of MAGEA4 protein (MAGEA4-His-Tag or Empty vector) in cell lysates (left) or in the conditioning media (right). c. expression of extracellular domain of 5T4 protein (5T4-His-Tag or Empty vector) in cell lysates (left) or in the conditioning media (right). Figure 2: Western blot analysis of tumour-associated antigens isolated from conditioning media after purification by fast protein liquid chromatography (FPLC) and size exclusion chromatography (SEC). a. expression of GAGE2D protein in the collected fractions obtained after SEC. b. expression of MAGEA4 protein in the collected fractions obtained after SEC. c. expression of extracellular domain of 5T4 protein in the collected fractions obtained after SEC. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx Figures 3a and 3b: Nanoparticle Tracking Analysis (NTA). The size distribution of exosomes isolated from conditional media either from a. activated B-lymphocytes or from b. activated PBMCs. Figures 3c and 3d: Western blot analysis of engineered activated exosomes pulsed with TAAs. c. expression profile of activated exosomes derived from mature B-lymphocytes and engineered for GAGE2D, MAGEA4 and extracellular domain 5T4. d. expression profile of exosomes derived from activated PBMCs and engineered for GAGE2D, MAGEA4 and extracellular domain 5T4. CD9 was used as a general marker for exosomes. Figure 4: 3D spheroids T-cell cytotoxicity assay (Tumour killing assay). a. GFP fluorescence expression profile of H1299 tumour spheroids co-cultured with freshly- isolated PBMCs and treated or not with activated exosomes derived from mature B-lymphocytes and engineered for GAGE2D, MAGEA4 and extracellular domain of 5T4. b. GFP fluorescence expression profile H1299 tumour spheroids co-cultured with freshly- isolated PBMCs and treated or not with activated exosomes derived from mature B-lymphocytes and engineered for GAGE2D and MAGEA4. c. GFP fluorescence expression profile of H1299 tumour spheroids co-cultured with freshly- isolated PBMCs and treated or not with activated exosomes derived from mature PBMCs and engineered for GAGE2D, MAGEA4 and extracellular domain of 5T4. Figure 5: Cytokine response assay by ELISA method. a. production of IL-2 in freshly-isolated PBMCs, or in PBMCs co-cultured with either empty activated exosomes derived from mature B-lymphocytes or with activated exosomes derived from mature B-lymphocytes and engineered for GAGE2D, MAGE4A and extracellular domain 5T4. b. production of IFN-γ in freshly-isolated PBMCs, or in PBMCs co-cultured with either empty activated exosomes derived from mature B-lymphocytes or with activated exosomes derived from mature B-lymphocytes and engineered for GAGE2D, MAGEA4 and extracellular domain 5T4. c. production of IL-17 in freshly-isolated PBMCs, or in PBMCs co-cultured with either empty activated exosomes derived from mature B-lymphocytes or with activated exosomes derived P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx from mature B-lymphocytes and engineered for GAGE2D, MAGEA4 and extracellular domain 5T4. Figure 6: Localization of tumor antigens in B-lymphocytes and PBMCs-derived and bioengineered exosomes. a. Western blot analysis of tumour antigens MAGEA4, extracellular domain of 5T4 and GAGE2D after exosomes were treated with trypsin. CD9 was used as a broad exosomal marker. EXAMPLES The present invention is further illustrated by the following Examples, in which parts and percentages are by weight and degrees are Celsius, unless otherwise stated. It should be understood that these Examples, while indicating preferred embodiments of the invention, are given by way of illustration only. From the above discussion and these Examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. The following Materials and Methods were used in one or more of the Examples. MATERIALS AND METHODS: Preparation of tumour associated antigens (TAAs) producing stable cell lines Stable HEK293T cell lines producing the proteins of interest were prepared according to Elegheert et al., 2018 (Elegheert et al., 2018). Briefly, full length and extracellular domain- coding sequences of human GAGE2D, MAGEA4 and the extracellular domain of 5T4 (TPBG) genes were cloned into lentiviral plasmid pHR-CMV-TetO2-3C-Avi-His6 (Addgene #113887), then transfected into virus-producing HEK293 Lenti-X cells together with the packaging plasmid psPAX2 (Addgene #12260) and envelope plasmid pMD2.G (Addgene #12259) using PEI transfection reagent.3 days after transfection, viral particle-containing media were collected and added to HEK293T target cells.3 days after infection, the polyclonal stable cell lines were established and protein production was verified by Western-blot from the media and cell lysates. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx Transfection of B-lymphocytes or PBMCs with TAA vectors HEK293T cells were transfected with lentiviral plasmids pHR-CMV-TetO2-3C-Avi-His6 (Addgene #113887) containing either full length of coding sequences of human GAGE2D gene, MAGEA4 gene or the extracellular domain of sequences coding for the extracellular domain of 5T4 (TPBG) gene, together with the packaging plasmid and envelope plasmid pMD2.G that allowed viral particles producing. Viral particle-containing media were collected and added to the human isolated B-lymphocytes. Stable transfection of genetically modified B-lymphocytes- producing TAAs was verified by Western blot. Genetically engineered TAAs-B-lymphocytes were activated by CD40L and induced by IL-2 for their proliferation and growth. This allowed the production of TAAs-B-cells derived activated exosomes into the media. The blood used to obtain mature human B-lymphocytes and peripheral blood monocytes was obtained, with the consent from the donor, in the Czech Republic. Preparation of lung cancer H1299 cells stably expressing GFP HEK293 cells were transfected with pHR-CMV-TetO2-EmGFP plasmid (Addgene #113892) together with the packaging plasmid psPAX2 (Addgene #12260) and envelope plasmid pMD2.G (Addgene #12259) for viral particle production. After 3 days viral particle-containing media was used to transduce H1299 cells. Another 3 days after infection, H1299 cells were FACS sorted and a polyclonal GFP-expressing cell line was established. Protein purification from the media of stable HEK293T protein expressing cell lines Stable HEK293T cells were seeded into 2xT175 cell culture flasks at about 70% confluence and cultured for 5-7 days. The media was collected, briefly centrifuged (5min, 2000xg, 4°C, Universal 320R centrifuge) then the supernatant was ultra-centrifuged for 30min at 50,000xg, 4°C (Optima XPN-90, Beckman coulter, rotor 70TI), then dialyzed overnight against PBS. Next day the dialyzed media was used for protein purification via His affinity chromatography, anion exchange chromatography and size exclusion chromatography (SEC) using an AKTA go FPLC machine (Cytiva). The quality of purified proteins was assessed by Western-blot using antibodies against His-tag and specific antibodies against the proteins of interest and Coomassie staining. Isolation of activated exosomes from mature B-lymphocytes or PBMCs PBMCs or B-lymphocytes were cultured and activated in the media according to Wu et al., 2010 (Wu et al., 2010) (1 x 107 cells / condition) up to 5 days. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx Conditioned medium was collected and EVs were isolated by sequential ultracentrifugation at 2000xg for 40 min, 10,000xg for 60 min, 100,000xg for 1.5 h in an Optima XPN-80 (Beckman Coulter®) ultracentrifuge using UltraClear Thinwall tubes. The exosomes were washed once in 1 ml of PBS and purified by centrifugation at 100,000xg for 80 min in an Optima MAX-XP Ultracentrifuge (Beckman Coulter). The pellet of exosomes was collected and run through a SEC column (IZON, 70 nm) to obtain exosomes sized between 70-150 nm. Exosomal protein concentration was measured using MicroBCA assay (Thermo Scientific). Nanoparticle Tracking Analysis (NTA) The total exosomal pellet was resuspended in 1 mL PBS (Gibco), vigorously resuspended by pipetting and kept on ice, before starting the analysis. Before starting any measurement, NanoSight NS300 (Malvern Panalytical) was washed three times by loading distilled water onto a syringe pump using a 1 mL syringe and pressing the liquid into the flow-cell top plate of the NanoSight. PBS was used to prime the instrument and to control the purity of the diluent (i.e., absence of particulate in the solution or presence of particulate in a concentration lower than detectable level). After priming, 1 mL of sample was carefully loaded on the syringe pump. Every measurement was done automatically, with the aid of the syringe pump and a script for data acquisition was generated on the NTA 3.2 software. Three recordings of 60 min each were automatically taken once each sample was loaded in the chamber and the focus on the particles in solution was adjusted manually. Bioengineering of exosomes with TAAs 1µg of exosomes were pulsed with 100µg MAGEA4, 100µg GAGE2D and 7.5-10µg 5T4 proteins in the presence of polybrene in a thermo-shaker by mixing for 90 minutes, 500 rpm at 37°C. After pulsing, the activated exosomes were washed in PBS and centrifuged at 100000g for 75 minutes at 4°C (Optima Max-XP Beckman Coulter®, rotor MLA150), then the pelleted exosomes were reconstituted in PBS and used for treatments. Isolation of PBMCs Peripheral blood mononuclear cells (PBMCs) were isolated from freshly collected EDTA-treated human female donor blood using a general Ficoll-PaqueTM protocol. Briefly, the collected blood was diluted with a saline solution of fetal bovine serum and layered over Ficoll-PaqueTM. The resulting solution was carefully centrifuged, and the resulting PBMC-containing layer was isolated from the Ficoll-PaqueTMmedium / blood plasma interface. The PBMC layer was then P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx serially washed and centrifuged to remove contaminants such as platelets and plasma. Finally, the isolated PBMCs were resuspended and cultured in T25 flasks in RPMI medium with 10% human serum AB and penicillin / streptomycin. SDS-PAGE and Western Blot Briefly, the cells or obtained exosomes were lysed and resuspended in 2x sample buffer with 1M DTT. The samples were then boiled at 100 oC for 10 minutes, 20µg of proteins were loaded onto a gel and separated by SDS-PAGE using NuPAGE® pre-cast gels (10 % or 4-12 %) (Thermo Scientific). Protein was transferred onto PVDF membrane and blocked and incubated with primary antibody in 5 % non-fat milk diluted in PBS-Tween 20. Secondary antibodies were always incubated in 5 % non-fat milk. Membranes were covered in ECL solutions from Thermo Scientific, Millipore or GE Healthcare prior to exposure to film (Fujifilm) and developed in a XoGraph developer. Cleavage of surface TAAs for Western blot analysis. B-lymphocytes or PBMCs-derived exosomes and bioengineered with TAAs were resuspended in PBS and treated with trypsin for 30 minutes at 37oC. After treatment, the exosomes were ultra-centrifuged at 100,000xg for 80 minutes to separate exosomes from cleaved surface proteins. Collected supernatant (that contained cleaved surface exosomal TAAs proteins) and exosomes after trypsinization were analyzed for Western blot with specific antibodies against certain tumour antigens. Tumour killing assay- Cytotoxic T-cell response H1299-GFP cells were generated by U-shape plate and co-cultured with or without PBMCs together with or without exosomes derived from activated B-lymphocytes / or PBMCs engineered (pulsed) with GAGE2D, MAGEA4 and extracellular domain of 5T4 at a concentration of 4 µg / ml. GFP fluorescence was measured for 24hours-120hours, by TECAN instrument according to the manufacturer’s protocol. Enzyme-linked Immunosorbent Assay, ELISA Freshly-isolated PBMCs were co-cultured with activated exosomes derived from mature B- lymphocytes / or PBMCs engineered (pulsed) with GAGE2D, MAGEA4 and the extracellular domain of 5T4 at a concentration of 4 µg / ml. Medium was collected every 24 hours and used for ELISA assay to measure the concentration of the produced cytokines according to the P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx manufacturer’s user guide (IL-17 human Elisa Kit, Millipore®, cat. No: RAB0262; IFN-γ human Elisa kit, Millipore®, cat. No: RAB0222 and IL-2 human Elisa kit, Invitrogen®, cat. No: BMS221). Example 1: Production of TAA engineered exosomes First, we prepared HEK-293T cell lines, which were stably-transfected with GAGE2D, MAGEA4 and ex5T4 extracellular domain. Both expression and production of these proteins into the media were verified by Western blot analysis (Fig.1a, b, c). The synthetized proteins from the conditioning media were collected, purified by fast protein liquid chromatography (FPLC) and after a size exclusion chromatography step (SEC), the purity of the obtained fractions containing the proteins was corroborated by specific antibodies using a Western blot technique (Fig.2a, b, c). To receive “active” mature immune cells-derived exosomes as a delivery cargo for the vaccine platform, we activated human B-lymphocytes or peripheral blood monocytes from a healthy donor by CD40L. Their expansion and proliferation were provided by additional presence of IL-2 to enhance production of exosomes. Both types of activated isolated exosomes were verified by NTA analyses to confirm their size (Fig.3a, b), followed by their bioengineering with all three tumour-associated antigens GAGE2D, MAGEA4 and ex5T4. The efficiency of the loading process was tested by immunoblotting (Fig.3c, d). Example 2: Stimulation of immune cells To investigate whether the designed vaccine can stimulate immune cells against the cancer, we performed an in vitro “tumour killing assay” on three-dimensional H1299-GFP cancer spheroids (which mimic tumours within the human body), co-cultured with immature peripheral blood monocytes (PBMCs). Three-dimensional spheroids exposed to our mature B-cells (B- lymphocytes) derived activated exosomes, pulsed with either GAGE2D, MAGEA4 and ex5T4 tumour associated antigens together (Fig.4a), or GAGE2D and MAGEA4 (Fig.4b) together displayed not only reduced size, compared to control or untreated spheroids (Fig.4a, b), but also a “shrinkage” pattern over a longer period (Fig.4a). A similar pattern was also observed when cancer spheroids were treated with activated PBMC-derived exosomes, pulsed with all three tumour associated antigens, suggesting that part of the activated PBMC- exosomes used for the vaccine contains a population of mature B-cell exosomes (Fig.4c). These results suggest that not only exosomes derived from mature immune cells are needed, but also the presence of our selected tumour-associated antigens is critical for activation of specific immune cells subtypes from PBMCs, that are actively participating in the elimination of cancer cells within the tumour. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx Example 3: Stimulation of cytokine production To further characterize the effect of the activated exosome-based TAA vaccine on the stimulation of an immune response, we investigated the impact of the treatment on T-cell activated cytokine production. We chose IL-2 and IFN-γ cytokines that represent a Type 1 T- helper (Th-1) response and thus participate in cell-cell mediated immunity and phagocyte- dependent protective mechanism. By using an ELISA method, we identified the higher production of both types of cytokines by PBMCs in the presence of the designed mature B-cell activated exosomes derived TAA vaccine compared to a control treatment, where mature B-cell exosomes were “empty,” not pulsed with the selected TAAs or no treatment at all (Fig.5a, b). Furthermore, we also observed the elevation of IL-17 cytokine produced by PBMCs after they were treated with the designed exosome-based vaccine, (Fig.5c). IL-17 cytokine expression characterizes the presence of a Th-17 T-helper cell subpopulation, i.e., cells that are involved in mediating a host defensive mechanism to various infections, including cancer cells. Example 4: Investigation of localization of TAAs in bioengineered immune exosomes. We further investigated whether immune exosomes bioengineered with tumour-associated antigens can directly stimulate and interact with surface molecules on immune cells, which are responsible for anti-cancer responses. To answer this question, we examined the localization of TAAs in our designed activated B-lymphocytes and PBMC-derived exosomes. Surprisingly, the extracellular domain of 5T4 and whole MAGEA4 protein were localized or inserted in the exosomal membrane and only GAGE2D tumour antigen remained as a cargo inside of the exosomes in both B-lymphocytes and PBMC-TAAs derived immune exosomes (Figure 6a). Our results suggest that our proposed treatment should be capable of inducing immune responses with higher effectivity by direct binding of exosomal surface localized TAAs with specific molecules on immune cells. REFERENCES Aguirre, L.E. et al. (2019) ‘Immune Checkpoint Inhibitors and the Risk of Allograft Rejection: A Comprehensive Analysis on an Emerging Issue’, The Oncologist, 24(3), pp.394–401. Available at: https: / / doi.org / 10.1634 / theoncologist.2018-0195. Besse, B. et al. (2016) ‘Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC’, Oncoimmunology, 5(4), p. e1071008. Available at: https: / / doi.org / 10.1080 / 2162402X.2015.1071008. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx Dai, S. et al. (2008) ‘Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer’, Molecular Therapy: The Journal of the American Society of Gene Therapy, 16(4), pp.782–790. Available at: https: / / doi.org / 10.1038 / mt.2008.1. DeMaria, P.J. and Bilusic, M. (2019) ‘Cancer Vaccines’, Hematology / Oncology Clinics of North America, 33(2), pp.199–214. Available at: https: / / doi.org / 10.1016 / j.hoc.2018.12.001. Dillman, R.O. (2017) ‘Is there a role for therapeutic cancer vaccines in the age of checkpoint inhibitors?’, Human Vaccines & Immunotherapeutics, 13(3), pp.528–532. Available at: https: / / doi.org / 10.1080 / 21645515.2016.1244149. Doyle, L.M. and Wang, M.Z. (2019) ‘Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis’, Cells, 8(7), p.727. Available at: https: / / doi.org / 10.3390 / cells8070727. Elegheert, J. et al. (2018) ‘Lentiviral transduction of mammalian cells for fast, scalable and high- level production of soluble and membrane proteins’, Nature Protocols, 13(12), pp.2991–3017. Available at: https: / / doi.org / 10.1038 / s41596-018-0075-9. Elliott, R.O. and He, M. (2021) ‘Unlocking the Power of Exosomes for Crossing Biological Barriers in Drug Delivery’, Pharmaceutics, 13(1), p.122. Available at: https: / / doi.org / 10.3390 / pharmaceutics13010122. Fu, C. et al. (2020) ‘DC-Based Vaccines for Cancer Immunotherapy’, Vaccines, 8(4), p.706. Available at: https: / / doi.org / 10.3390 / vaccines8040706. Gatti-Mays, M.E. et al. (2017) ‘Cancer vaccines: Enhanced immunogenic modulation through therapeutic combinations’, Human Vaccines & Immunotherapeutics, 13(11), pp.2561–2574. Available at: https: / / doi.org / 10.1080 / 21645515.2017.1364322. Harari, A. et al. (2020) ‘Antitumour dendritic cell vaccination in a priming and boosting approach’, Nature Reviews Drug Discovery, 19(9), pp.635–652. Available at: https: / / doi.org / 10.1038 / s41573-020-0074-8. Jakobsen, K.R. et al. (2015) ‘Exosomal proteins as potential diagnostic markers in advanced non-small cell lung carcinoma’, Journal of Extracellular Vesicles, 4. Available at: https: / / doi.org / 10.3402 / jev.v4.26659. Lai, R.C. et al. (2013) ‘Exosomes for drug delivery - a novel application for the mesenchymal stem cell’, Biotechnology Advances, 31(5), pp.543–551. Available at: https: / / doi.org / 10.1016 / j.biotechadv.2012.08.008. Loria, R. et al. (2019) ‘Very low intensity ultrasounds as a new strategy to improve selective delivery of nanoparticles-complexes in cancer cells’, Journal of experimental & clinical cancer research: CR, 38(1), p.1. Available at: https: / / doi.org / 10.1186 / s13046-018-1018-6. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx Mandelboim, O. et al. (1995) ‘Regression of established murine carcinoma metastases following vaccination with tumour-associated antigen peptides’, Nature Medicine, 1(11), pp.1179–1183. Available at: https: / / doi.org / 10.1038 / nm1195-1179. Morse, M.A. et al. (2005) ‘A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer’, Journal of Translational Medicine, 3(1), p.9. Available at: https: / / doi.org / 10.1186 / 1479-5876-3-9. Morton, D.L. et al. (1992) ‘Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine.’, Annals of Surgery, 216(4), pp.463– 482. Available at: https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC1242654 / (Accessed: 26 July 2022). Muenst, S. et al. (2016) ‘The immune system and cancer evasion strategies: therapeutic concepts’, Journal of Internal Medicine, 279(6), pp.541–562. Available at: https: / / doi.org / 10.1111 / joim.12470. Narita, M. et al. (2015) ‘Immune responses in patients with esophageal cancer treated with SART1 peptide-pulsed dendritic cell vaccine’, International Journal of Oncology, 46(4), pp. 1699–1709. Available at: https: / / doi.org / 10.3892 / ijo.2015.2846. Raposo, G. et al. (1996) ‘B lymphocytes secrete antigen-presenting vesicles’, The Journal of Experimental Medicine, 183(3), pp.1161–1172. Available at: https: / / doi.org / 10.1084 / jem.183.3.1161. Raposo, G. and Stoorvogel, W. (2013) ‘Extracellular vesicles: exosomes, microvesicles, and friends’, The Journal of Cell Biology, 200(4), pp.373–383. Available at: https: / / doi.org / 10.1083 / jcb.201211138. Tagliamonte, M. et al. (2014) ‘Antigen-specific vaccines for cancer treatment’, Human Vaccines & Immunotherapeutics, 10(11), pp.3332–3346. Available at: https: / / doi.org / 10.4161 / 21645515.2014.973317. Temizoz, B., Kuroda, E. and Ishii, K.J. (2016) ‘Vaccine adjuvants as potential cancer immunotherapeutics’, International Immunology, 28(7), pp.329–338. Available at: https: / / doi.org / 10.1093 / intimm / dxw015. Théry, C., Zitvogel, L. and Amigorena, S. (2002) ‘Exosomes: composition, biogenesis and function’, Nature Reviews. Immunology, 2(8), pp.569–579. Available at: https: / / doi.org / 10.1038 / nri855. Thomas, S. and Prendergast, G.C. (2016) ‘Cancer Vaccines: A Brief Overview’, Methods in Molecular Biology (Clifton, N.J.), 1403, pp.755–761. Available at: https: / / doi.org / 10.1007 / 978-1- 4939-3387-7_43. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx Tkach, M. et al. (2017) ‘Qualitative differences in T-cell activation by dendritic cell-derived extracellular vesicle subtypes’, The EMBO journal, 36(20), pp.3012–3028. Available at: https: / / doi.org / 10.15252 / embj.201696003. Valadi, H. et al. (2007) ‘Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells’, Nature Cell Biology, 9(6), pp.654–659. Available at: https: / / doi.org / 10.1038 / ncb1596. Viaud, S. et al. (2010) ‘Dendritic cell-derived exosomes for cancer immunotherapy: what’s next?’, Cancer Research, 70(4), pp.1281–1285. Available at: https: / / doi.org / 10.1158 / 0008- 5472.CAN-09-3276. Wu, C. et al. (2010) ‘Soluble CD40 ligand-activated human peripheral B cells as surrogated antigen presenting cells: A preliminary approach for anti-HBV immunotherapy’, Virology Journal, 7(1), p.370. Available at: https: / / doi.org / 10.1186 / 1743-422X-7-370. Zaborowski, M.P. et al. (2015) ‘Extracellular Vesicles: Composition, Biological Relevance, and Methods of Study’, Bioscience, 65(8), pp.783–797. Available at: https: / / doi.org / 10.1093 / biosci / biv084. Zhou, Y. et al. (2016) ‘Exosome-mediated small RNA delivery for gene therapy’, WIREs RNA, 7(6), pp.758–771. Available at: https: / / doi.org / 10.1002 / wrna.1363. SEQUENCES The Sequence Listing filed with this patent application is fully incorporated herein as part of the description. SEQ ID NO: 1 Gene name: MAGEA4_txt; Melanoma-associated antigen 4 · Homo sapiens(Human) · Gene: MAGEA4 (MAGE4); Uniprot: P43358 · MAGA4_HUMANMSSEQKSQHCKPEEGVEAQEEALGLVGAQAPTTEEQEAAVSSSSPLVPGTLEEVPAA ESAGPPQSPQGASALPTTISFTCWRQPNEGSSSQEEEGPSTSPDAESLFREALSNKV DELAHFLLRKYRAKELVTKAEMLERVIKNYKRCFPVIFGKASESLKMIFGIDVKEVD PASNTYTLVTCLGLSYDGLLGNNQIFPKTGLLIIVLGTIAMEGDSASEEEIWEELGV MGVYDGREHTVYGEPRKLLTQDWVQENYLEYRQVPGSNPARYEFLWGPRALAETSYV KVLEHVVRVNARVRIAYPSLREAALLEEEEGV SEQ ID NO: 2 Gene name: GAGE2D_txt; G antigen 2D · Homo sapiens (Human) · Gene: GAGE2D; GAGE8; Uniprot: Q9UEU5 · GGE2D_HUMAN P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx MSWRGRSTYRPRPRRYVEPPEMIGPMRPEQFSDEVEPATPEEGEPA TQRQDPAAAQEGEDEGASAGQGPKPEADSQEQGHPQTGCECEDGPD GQEMDPPNPEEVKTPEEGEKQSQC SEQ ID NO: 3 Full amino acid sequence of 5T4: MPGGCSRGPAAGDGRLRLARLALVLLGWVSSSSPTSSASSFSSSAPFLASAVSAQPPLPDQCPALCECSEAARTVKCVNRNLTEVPTDLPAYVRNLFLTGNQLAVLPAGAFARRPPLAELAALNLSGSRLDEVRAGAFEHLPSLRQLDLSHNPLADLSPFAFSGSNASVSAPSPLVELILNHIVPPEDERQNRSFEGMVVAALLAGRALQGLRRLELASNHF LYLPRDVLAQLPSLRHLDLSNNSLVSLTYVSFRNLTHLESLHLEDNALKVLHNGTLAELQGLPHIRVFLDNNPW VCDCHMADMVTWLKETEVVQGKDRLTCAYPEKMRNRVLLELNSADLDCDPILPPSLQTSYVFLGIVLALIGAIF LLVLYLNRKGIKKWMHNIRDACRDHMEGYHYRYEINADPRLTNLSSNSDV SEQ ID NO: 4 Extracellular domain of 5T4_txt; sp|Q13641|TPBG_HUMAN|32-355 OS=Homo sapiens OX=9606 GN=TPBG SSPTSSASSFSSSAPFLASAVSAQPPLPDQCPALCECSEAARTVKCVNRNLTEVPTDLPAYVRNLFLTGNQLAVLPA GAFARRPPLAELAALNLSGSRLDEVRAGAFEHLPSLRQLDLSHNPLADLSPFAFSGSNASVSAPSPLVELILNHIVP PEDERQNRSFEGMVVAALLAGRALQGLRRLELASNHFLYLPRDVLAQLPSLRHLDLSNNSLVSLTYVSFRNLTHLES LHLEDNALKVLHNGTLAELQGLPHIRVFLDNNPWVCDCHMADMVTWLKETEVVQGKDRLTCAYPEKMRNRVLLELNS ADLDCDPILPPSLQTS P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx

Claims

CLAIMS 1. A composition comprising one or more populations of exosomes, wherein the exosomes in a first population of exosomes: (a) each display CD19 and one or more further surface molecules which are characteristic of mature activated B-lymphocytes, and; (b) each comprise (preferably display) one or more tumour antigens selected from MAGEA4, GAGE2D and 5T4, wherein the exosomes in the first population of exosomes collectively comprise (preferably display) all 3 of the tumour antigens.

2. A composition as claimed in claim 1, wherein the tumour antigens are all full-length proteins.

3. A composition as claimed in claim 1 or claim 2, wherein the one or more further surface molecules are selected from BCR, CD138, CD86, CD80, MHC I and MHC II.

4. A composition as claimed in any one of the preceding claims, wherein the first population of exosomes were obtained from or derived from: (i) mature or activated B-lymphocytes; or (ii) a population of PBMCs which comprise mature or activated B-lymphocytes.

5. A composition as claimed in claim 4, wherein the exosomes which were obtained from or derived from: (i) the mature B-lymphocytes; or (ii) the population of PBMCs which comprise mature B-lymphocytes, were subsequently modified to comprise (preferably display) one or more of the tumour antigens.

6. A composition as claimed in claim 4, wherein: (i) the activated B-lymphocytes; or (ii) the population of PBMCs which comprise activated B-lymphocytes, were modified to comprise (preferably display) the tumour antigens prior to the production of the exosomes. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx7. A composition as claimed in any one of the preceding claims, wherein the mature or activated B-lymphocytes were matured in vitro, preferably by using CD40L and IL-2.

8. A composition as claimed in any one of the preceding claims, wherein: (i) the mature B-lymphocytes; or (ii) the population of PBMCs which comprise mature B-lymphocytes, obtained from healthy donors.

9. A composition as claimed in any one of the preceding claims, wherein the composition additionally comprises one or more further population of exosomes which have been obtained or derived from immune cells, preferably selected from the group consisting of monocytes, dendritic cells, NK cells and T-lymphocytes.

10. A composition as claimed in claim 9, wherein one or more of the further populations of exosomes comprise (preferably display) one or more of the tumour antigens.

11. A composition as claimed in any one of the preceding claims, wherein the exosomes in the first population of exosomes all comprise (preferably display) all 3 of the tumour antigens.

12. A composition as claimed in any one of claims 1 or 3 to 11, wherein 5T4 is the extracellular domain of the 5T4 polypeptide.

13. A pharmaceutical composition comprising a composition as claimed in any one of the preceding claims, optionally together with one or more pharmaceutically-acceptable carriers, diluents, adjuvants or excipients.

14. A tumour vaccine comprising a pharmaceutical composition as claimed in claim 13.

15. A pharmaceutical composition comprising: (A) a first population of exosomes wherein the exosomes: (a) each display CD19 and one or more further surface molecules which are characteristic of mature activated B-lymphocytes; and (b) each comprise (preferably display) a first tumour antigen, wherein the first tumour antigen is MAGEA4; and P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx(B) a second population of exosomes wherein the exosomes: (a) each display CD19 and one or more further surface molecules which are characteristic of mature activated B-lymphocytes; and (b) each comprise (preferably display) a second tumour antigen, wherein the second tumour antigen is GAGE2D; and (C) a third population of exosomes wherein the exosomes: (a) each display CD19 and one or more further surface molecules which are characteristic of mature activated B-lymphocytes; and (b) each comprise (preferably display) a third tumour antigen, wherein the third tumour antigen is 5T4; preferably wherein the surface molecules, populations of exosomes and / or tumour antigens are as defined in any one of claims 2-12, as a combined preparation in a form suitable for simultaneous, separate or sequential use for the treatment or prevention of cancer, or for inducing an immune cell response in a subject against the tumour antigens.

16. A composition as claimed in any one of claims 1 to 13 for use in therapy or for use as a medicament.

17. A composition as claimed in any one of claims 1 to 13: (i) for use in a method of preventing or treating cancer in a subject; or (ii) for use in a method of inducing a T-cell or B-cell response to cancer antigens in a subject; or (iii) for inducing an adaptive or innate immune cell response in a subject.

18. Use of a composition as claimed in any one of claims 1 to 12 in the manufacture of a medicament: (i) for preventing or treating cancer in a subject; or (ii) for inducing a T-cell or B-cell response to a cancer antigen in a subject; or (iii) for inducing an adaptive or innate immune cell response in a subject.

19. A method of preventing or treating a subject susceptible to cancer or with cancer, the method comprising administering an effective amount of a composition as claimed in any one of claims 1 to 13 to a subject in need thereof. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx20. A method of inducing a T-cell or B-cell response to cancer antigens in a subject or for inducing an adaptive or innate immune cell response in a subject, the method comprising administering an effective amount of a composition as claimed in any one of claims 1 to 13 to a subject in need thereof.

21. A composition for use, a use or a method as claimed in any one of claims 17 to 20, wherein the cancer is selected from the group consisting of colon cancer, prostate cancer, breast cancer, lung cancer, skin cancer, liver cancer, bone cancer, ovary cancer, pancreatic cancer, brain cancer, head and neck cancers, and blood cancer (e.g., leukaemia, lymphoma and myeloma).

22. A composition for use, a use or a method as claimed in claim 21, wherein the cancer is a solid tumour, a liquid cancer or a metastasis.

23. A process for producing a population of activated CD19+ exosomes which comprise (preferably display) one or more tumour antigens, the process comprising the steps: (a) maturing immature B-lymphocytes to produce mature B-lymphocytes which display CD19; (b) producing exosomes from the mature B-lymphocytes; and (c) incorporating one or more tumour antigens into each of the exosomes (preferably into the membranes of the exosomes), where the tumour antigens are MAGEA4, GAGE2D and 5T4; in order to produce a population of activated CD19+ exosomes which each comprise (preferably display) one or more of the tumour antigens, and wherein the population of exosomes collectively comprises (preferably display) all 3 of the tumour antigens.

24. A process for producing a population of activated CD19+ exosomes which comprise (preferably display) one or more tumour antigens, the process comprising the steps: (a) expressing one or more tumour antigens (preferably cell surface tumour antigens) in each cell in a population of cells comprising immature or mature B-lymphocytes, where the tumour antigens are MAGEA4, GAGE2D and 5T4, thereby maturing and activating the immature or mature B-lymphocytes to produce mature and activated B- lymphocytes which express CD19; and (b) producing activated CD19+ exosomes from the mature activated B-lymphocytes; P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docxin order to produce a population of activated CD19+ exosomes which each comprise (preferably display) one or more of the tumour antigens, and wherein the population of exosomes collectively comprises (preferably display) all 3 of the tumour antigens.

25. A process for producing a population of activated CD19+ exosomes which comprise (preferably display) one or more tumour antigens, the process comprising the steps: (a) maturing immature B-lymphocytes in a population of cells comprising immature B- lymphocytes to produce mature activated B-lymphocytes which display CD19; (b) expressing one or more tumour antigens (preferably cell surface tumour antigens) in each of the mature B-lymphocytes, thus activating the B-lymphocytes, where the tumour antigens are MAGEA4, GAGE2D and 5T4; and (c) producing activated CD19+ exosomes from the mature activated B-lymphocytes, in order to produce a population of activated CD19+ exosomes which each comprise (preferably display) one or more of the tumour antigens, and wherein the population of exosomes collectively comprises (preferably display) all 3 of the tumour antigens.

26. A process as claimed in any one of claims 23 to 25, wherein the immature B- lymphocytes are present in a population of PBMCs or where the population of cells comprising immature B-lymphocytes is a population of PBMCs.

27. A process as claimed in any one of claims 23 to 26, wherein the immature B- lymphocytes are obtained from healthy subjects.

28. A process as claimed in any one of claims 23 to 27, wherein the immature B- lymphocytes are matured in vitro using CD40L and IL-2.

29. A process for producing a pharmaceutical composition, the process comprising the process for producing a population of exosomes which comprise (preferably display) one or more tumour antigens as claimed in any one of claims 23 to 28, and wherein the process additionally comprises the step of: (d) admixing the population of exosomes with one or more pharmaceutically-acceptable diluents, excipients, adjuvants or carriers.

30. A population of exosomes or a pharmaceutical composition obtained or obtainable by a process as claimed in any one of claims 23 to 29. P:\1592\159229-01\Specs\159229-012023-08-29 - PCT des cls abs.docx

Images