A tumor-specific neoantigenic peptide resulting from mutations in spliceosome factor 3b subunit 1

Abstract

The present invention provides tumor-specific neoantigenic peptides resulting from mutations in spliceosome factor 3b subunit 1 (SF3B1), vaccinal compositions comprising such tumor-specific neoantigenic peptides, nucleic acids, antibodies or fragments thereof and immune cells that can be used in cancer therapy or prevention.

Description

[0001] A TUMOR-SPECIFIC NEOANTIGENIC PEPTIDE RESULTING FROM MUTATIONS IN

[0002] SPLICEOSOME FACTOR 3B SUBUNIT 1

[0003] TECHNICAL FIELD

[0004] The present disclosure provides tumor-specific neoantigenic peptides resulting from mutations in spliceosome factor 3b subunit 1 (SF3B1), vaccinal compositions comprising such tumor-specific neoantigenic peptides, nucleic acids, antibodies or fragments thereof and immune cells that can be used in cancer therapy or prevention.

[0005] BACKGROUND ART

[0006] Cancer is one of the leading causes of death throughout the whole world. There are many different types of cancer: breast cancer, bone cancer, or prostate cancer to name a few. To target cancer cells, different kinds of vaccines exist, targeting either specific cells from the immune system to induce an immune response, or targeting specific receptors or specific peptides expressed on the surface of cancer cells. These peptides, also called antigenic peptides, play a critical role in the immune system triggering a specific immunological response and will be used for vaccination. Antigenic peptides are recognized by major histocompatibility complexes (MHC) present on the surface of antigen- presenting cells (APC) such as Dendritic cells, B cells, and macrophages which are recognized by T cells to trigger an immune response and kill these cells.

[0007] Numerous antigenic peptides have been identified in various tumor samples, many of which have been synthesized and introduced into vaccine designs to elicit a therapeutic or prophylactic immune response. Thousands of antigenic peptides have been identified on the surface of cancer cells.

[0008] Splicing factor (SF) mutations represent an important class of driver mutations in human cancers and affect about 50 to 60% of patients with a myeloid neoplasm with myelodysplasia (Yoshida, K. et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478, 64-69 (2011)).

[0009] Recent advances have introduced neoantigenic peptides as possible targets against tumor cells. Neoantigenic peptides are self-antigens generated by tumor cells because of genomic mutations, or dysregulated RNA splicing to name a few. Neoantigenic peptides are recognized as non-self and trigger an immune response (Xie et al., 2023).

[0010] Mutations in SF3B1 splicing factor have been detected in different human cancers, tumors, and malignancies. SF3B1 splicing factor is considered the largest subunit of the spliceosome factor 3b (SF3B) complex. SF3B is a core component of spliceosomes (Zhou et al., 2020). Tumor mutations of the SF3B1 splicing factor (SF3Blmutinduce a 5’ shift of approximately 8 to 40 nucleotides in the acceptor site of more than 10000 intron-exon junctions (Alsafadi et al., 2016). These alterations in the splicing of specific target genes induce frameshifts in the downstream exons or an in-frame insertion of a few codons, that may both encode neoantigenic peptides.

[0011] While being generated by tumor cells, these neoantigenic peptides may still be found on the surface of healthy cells making them a risk of leading to auto-immune recognition. Moreover, some neoantigenic peptides may not lead to an appropriate immune response against cancer.

[0012] Identification of neoantigenic peptides that are particularly expressed by tumor cells and not by healthy cells is of particular relevance for driving a specific immune response against cancer.

[0013] Hence, there is a need to identify tumor-specific neoantigenic peptides that are expressed in tumor cells and recognized by the immune cells of a patient suffering from cancer, or likely to suffer from cancer. Identifying such tumor-specific neoantigenic antigens allows the administration of the corresponding peptides as a vaccine for preventing the development of tumor cells expressing such tumor-specific neoantigenic antigens; the patient's immune cells is able to specifically target tumor cells. Due to the specific selection of antigens that are not expressed in healthy cells, the risk of autoimmune recognition is lowered.

[0014] SUMMARY

[0015] In the present invention, the inventors have identified 61 tumor-specific antigens. The present disclosure thus provides a tumor-specific neoantigenic peptide comprising at least one amino acid sequence set forth in table 1, in particular at least one amino acid sequence set forth in SEQ ID No. 1 to SEQ ID No. 61.

[0016] The tumor-specific neoantigenic peptides of the invention are between 12 and 73 amino acids long and contain at least 1 aberrant amino acid.

[0017] These tumor-specific neoantigenic peptides can be presented by class I MHC on the surface of tumor cells and are not expressed in healthy cells. As normal tissues do not express these tumor-specific neoantigenic peptides, the risk of auto-immune response is lowered.

[0018] These tumor-specific neoantigenic peptides are not produced by SF3B1 wild type (SB3B1WT) cells. The Thymic negative selection does not eliminate T cells specific for these tumor-specific neoantigenic peptides. Therefore, an immune response can be mounted against these tumor-specific neoantigenic peptides upon vaccination.

[0019] Tumor-specific neoantigenic peptides of the present invention are capable of interacting with class I MHC coded by Human Leucocytes Antigens (HLA) members such as HLA-A and HLA-B alleles. This leads to the production of immune cells specifically targeting cells expressing those tumorspecific neoantigenic peptides thereby leading to the destruction of tumor cells, and the treatment or prevention of cancer or cancer relapse, in a subject in need thereof, optionally wherein the subject is suffering from an SF3B 1 mutant (SF3B lmut) cancer. SF3B 1 mutant tumors can be selected from uveal melanoma, hematological malignancies, breast cancers, skin melanoma, renal cell carcinoma, pulmonary adenocarcinoma, hepatocarcinoma, pancreatic carcinoma, endometrial cancers, and uveal melanoma, optionally wherein the tumor is SF3B1 mutant associated with uveal melanoma, hematological malignancies, and / or pulmonary adenocarcinoma. In some embodiments, the tumor is SF3B1 mutant associated with uveal melanoma.

[0020] In an embodiment, it is provided a vaccinal or immunogenic composition comprising the tumorspecific neoantigenic peptide comprising at least one amino acid sequence set forth in SEQ ID No. l to SEQ ID No. 61.

[0021] In an embodiment, it is provided a vaccinal or immunogenic composition comprising at least one tumor-specific neoantigenic peptide comprising at least one amino acid sequence set forth in SEQ ID No. 1 to SEQ ID No. 61, and at least a second tumor-specific neoantigenic peptide, said second neoantigenic peptide comprising an amino acid sequence set forth in SEQ ID No. 62 to SEQ ID No. 73.

[0022] In an embodiment, it is provided a vaccinal or immunogenic composition, wherein the tumor-specific neoantigenic peptide and / or the second neoantigenic peptide is / are encoded from a transcript associated with an SF3B1 mutation present in an SF3B1 mutant tumor.

[0023] In an embodiment, an SF3B1 mutant tumor is issued or selected from uveal melanoma, hematological malignancies, breast cancers, skin melanoma, renal cell carcinoma, pulmonary adenocarcinoma, hepatocarcinoma, pancreatic carcinoma, and endometrial cancers, optionally wherein the tumor is SF3B1 mutant associated with uveal melanoma, hematological malignancies, and / or pulmonary adenocarcinoma, preferably wherein the SF3B1 mutant tumor is from uveal melanoma.

[0024] In an embodiment said neoantigenic peptides are expressed in at least 30 %, 40 %, 50 %, 60 %, 70 % or more of subjects from a population of subjects suffering from an SF3B1 mutant tumor and more particularly from a population of subjects suffering from uveal melanoma (UM).

[0025] In an embodiment said neoantigenic peptides are expressed in at least 30 %, 40 %, 50 %, 60 %, 70 % or more of tumor cells within the subjects suffering from a cancer, and more particularly from uveal melanoma (UM). In some embodiments, it is provided a population of immune cells, in particular dendritic cells and / or antigen-presenting cells (APCs), that has been pulsed with one or more tumorspecific neoantigenic peptides comprising at least one amino acid sequence set forth in SEQ ID No. 1 to SEQ ID No. 61, or the vaccinal or immunogenic composition according to present disclosure. In another embodiment, it is provided a population of dendritic cells and / or APCs that have been transfected with a polynucleotide encoding one or more tumor-specific neoantigenic peptides comprising at least one amino acid sequence set forth in SEQ ID No. 1 to SEQ ID No. 61, or the vaccinal or immunogenic composition according to the present disclosure.

[0026] In another embodiment, it is provided an antibody, or an antigen-binding fragment thereof, a T cell receptor (TCR) or a chimeric antigen receptor (CAR) cell that specifically binds to a tumor-specific neoantigenic peptide comprising at least one amino acid sequence set forth in SEQ ID No. 1 to SEQ ID No. 61.

[0027] In another embodiment, it is provided an antibody, or an antigen-binding fragment thereof, a T cell receptor (TCR) or a chimeric antigen receptor (CAR) cell that specifically binds to a tumor-specific neoantigenic peptide as defined herein in association with an MHC class I molecule.

[0028] The present disclosure also relates a TCR that specifically binds to a tumor-specific neoantigenic peptide as defined in the present disclosure, wherein said TCR is soluble and fused to an antibody fragment directed to a T cell antigen, optionally wherein the targeted antigen is CD3 or CD 16.

[0029] The present invention further discloses an antibody or CAR or TCR as defined herein, wherein said antibody or CAR or TCR is a multispecific antibody or multispecific CAR or multispecific TCR that further targets at least an immune cell, an immune cell antigen or a tumor cell antigen. Optionally, the immune cell is a T cell, a Natural Killer (NK) cell, or a dendritic cell.

[0030] In another embodiment, it is provided a polynucleotide encoding a tumor-specific neoantigenic peptide as defined herein or an antibody, a CAR, or a TCR as defined herein. Another embodiment refers to a vector wherein the vector comprises the polynucleotide.

[0031] In another embodiment, it is provided an immune cell that specifically binds to one or more tumorspecific neoantigenic peptides as defined herein, optionally wherein the immune cell is an allogenic or autologous cell selected from T cell, NK cell, CD4+ / CD8+, TILs / tumor-derived CD8 T cells, central memory CD8+ T cells, Treg, MAIT, and y5 T cell.

[0032] In another embodiment, it is provided a T cell that comprises a TCR or a CAR, in particular a TCR, that specifically binds one or more tumor-specific neoantigenic peptides as defined herein.

[0033] In an embodiment of the invention, the tumor-specific neoantigenic peptide, the vaccine or immunogenic composition according to previous embodiments, the population of dendritic cells or APCs of the previous embodiment, the antibody, or an antigen-binding fragment thereof or T cell receptor (TCR) or chimeric antigen receptor (CAR) as defined hereabove, the polynucleotide, the vector, the immune cell, in particular the T-cell, the dendritic cell, the antigen-presenting cell, is provided for use the treatment or the prevention of cancer, in particular for use in inhibiting cancer cell proliferation, more particularly for treating cancer in a subject in need thereof or for use in cancer vaccination therapy of a subject, optionally wherein the subject is suffering from cancer with SF3B1 mutant tumor cells, more particularly a uveal melanoma with SF3B 1 mutant tumor cells, or optionally wherein the patient is at risk of suffering from a cancer, in particular a cancer with SF3B1 mutant tumor cells, more particularly an uveal melanoma with SF3B1 mutant tumor cells.

[0034] In an embodiment of the invention, the tumor-specific neoantigenic peptide, the vaccine or immunogenic composition according to previous embodiments, the population of dendritic cells or APCs of the previous embodiment, the antibody, or an antigen-binding fragment thereof or T cell receptor (TCR) or chimeric antigen receptor (CAR) a defined hereabove, the polynucleotide, the vector, the immune cell, in particular the T-cell, the dendritic cell, the antigen-presenting cell, is provided for treating or preventing a cancer with SF3B1 mutant tumor cells, in particular wherein the cancer is uveal melanoma.

[0035] In an embodiment of the invention, the tumor-specific neoantigenic peptide, the vaccine or immunogenic composition according to previous embodiments, the population of dendritic cells or APCs of the previous embodiment, the antibody, or an antigen-binding fragment thereof or T cell receptor (TCR) or chimeric antigen receptor (CAR) a defined hereabove, the polynucleotide, the vector, the immune cell, in particular the T-cell, the dendritic cell, the antigen-presenting cell, is provided for use in combination with at least one further therapeutic agent, optionally wherein the further therapeutic agent is a chemotherapeutic agent or an immunotherapeutic agent.

[0036] It is also provided a method of selecting an SF3B1 mutant tumor-specific neoantigen peptide comprising:

[0037] (1) A step of identifying neoantigenic peptides expressed in SF3B1 WT tumor cells, in SF3B1 mutant tumor cells, and in healthy cells issued from biological samples previously obtained;

[0038] (2) Among the identified neoantigenic peptides, a step of discarding the neoantigenic peptides expressed in healthy cells,

[0039] (3) Within the remaining neoantigenic peptides: a. a step of discarding those that do not specifically bind class I HLA proteins. b. a step of discarding those that have an RNA expression lower than 1 read when the expression of RNA is normalized according to RNAseq within the tumor cells; c. a step of discarding those that have a size inferior to 12 amino acid residues and over 73 amino acid residues, d. a step of discarding those that have an expression ratio (PSI) between SF3B1WTand SF3Blmuttumors equal or inferior to minus 0.001 PSI. the remaining neoantigenic peptides being an SF3B1 mutant tumor-specific neoantigenic peptide.

[0040] The present disclosure also provides a method of selecting an SF3B1 mutant tumor-specific neoantigenic peptide as defined herein, wherein the SF3B1 mutant tumor-specific neoantigenic peptide that has been selected is for use in therapy or prevention of cancer in a subject in need thereof, optionally wherein the subject is suffering from an SF3B1 mutant cancer, more particularly a uveal melanoma.

[0041] Various embodiments of the neoantigenic peptides, vaccinal or immunogenic compositions, therapeutic products, methods for using them, are described in detailed below. Except for alternatives clearly mentioned, combinations of such embodiments are encompassed by the present application.

[0042] BRIEF DESCRIPTION OF DRAWINGS

[0043] Figure 1: A) SF3Blmutant (SF3Blmut) -related alternative junction N0215 generates an in-frame amino acid insertion in STK24. Bold grey characters indicate the additional amino acids. The sequences illustrated in the figure correspond to SEQ ID No. 74 to SEQ ID No.76. B) N0898 generates an out-of-frame insertion. The resulting aberrant protein finishes with a string of 28 aberrant amino acids (in bold grey). The sequences illustrated in the figure correspond to SEQ ID No. 77 to SEQ ID No.79.

[0044] Figure 2: Neoantigenic peptides for N0215 and N0898 (underlined amino acids). The aberrant amino acids (bold grey) are flanked by 8 canonical aa (black). The sequence N0215 STK24 is referenced under SEQ ID No. 80 and sequence N0898 USP39 is referenced under SEQ ID No. 81.

[0045] Figure 3: Heat map of the 1407 differentially expressed intron-exon junctions modified in SF3Blmutuveal melanomas.

[0046] Figure 4: Comparison of RNAseq results in two independent cohorts. A) Venn diagram of the number of alternative junctions found by the same bio-informatics pipeline applied to two independent datasets. B) Expression of the 905 aberrant junctions in the SF3Blmuttumors of the two datasets. C) Delta PSI of the same junctions in the two cohorts.

[0047] Figure 5: T cells specific for UM-A2-18 peptide are able to kill SF3Blmuttumor cells. A) the cell line HLA-A2+ SF3B1WT(X) not killed by the T cell clone as the curve of the cell line alone is similar to the cells incubated with the clone (Y). This cell line is only killed by the T cell clone in the presence of exogenous peptide (Z). B) the cell line HLA-A2+ SF3Blmutis killed by the clone. C) the cell line HLA-A2- SF3Blmutis not killed by the clone. Figure 6: A) Detection of neoantigenic peptide UM-A25-81 DIKGPPWLSF (SEQ ID No. 82) coded by N0215 in an SF3Blmuttumor sample by immunopeptidomics and mass spectrometry. B) Neoantigenic polypeptides experimentally validated by in vivo immunogenicity, cytotoxicity, or immunopeptidomics. The sequences illustrated in the figure correspond to SEQ ID No.83 to SEQ ID No. 94.

[0048] Figure 7: Quantification of aberrant junction expression N0215 in healthy tissue using RNAseq GTEX database. 50 samples of each healthy tissue were included and compared with 7 SF3Blmutand 6 SF3B1WTUM. Expression of the aberrant junction is absent in the 27 tissues.

[0049] Figure 8: Distribution of the 928 junctions by the number of GTEX tissues without junction expression. The box indicated the optimal situation and the confirmed peptides that fulfill this condition. The number above each histogram indicates the number of neoantigenic polypeptides.

[0050] Figure 9: A) Calculation of the fraction of alternative junction of total junction (PSI). B) Examples of PSI and delta PSI calculation. The junctions with delta PSI near -1 are the best vaccine candidates.

[0051] Figure 10: A) Distribution of aberrant junction expression in SF3Blmuttumors. B) Mean expression of the aberrant junction in the SF3Blmuttumors (n=7).

[0052] Figure 11: Possible tumor-specific neoantigenic peptides: the insertion of 8 amino acids in N0215 (SEQ ID No. 95) allows the prediction of 16 9-mers.

[0053] Figure 12: A) Formula of Sorting Score. B) Sorting score calculation for N02015. Neo-polypeptide ID corresponds to neoantigenic peptide identification.

[0054] Figure 13: Sorting score distribution of the 928 neo-polypeptides.

[0055] Figure 14: Neo-polypeptide length (aa) distribution in the 928 junctions.

[0056] Figure 15: Pipeline to select the best candidates of tumor-specific neoantigenic peptides for a vaccine

[0057] Figure 16: Characterization of the 73 tumor-specific neoantigenic peptides selected for a vaccine. A) Comparison of junction RNA expression in two tumor cohorts. B) Comparison of delta PSI in two tumor cohorts. C) Total number of class-I binding peptides predicted. D) Distribution of tumorspecific neoantigenic peptide size.

[0058] Figure 17: Illustration of the binding between tumor-specific neoantigenic peptides and class I HLA protein. Left panel: Experimental scheme. Right panel: Examples of positive binding tests between tumor-specific neoantigenic peptides and class I HLA protein. DETAILED DESCRIPTION OF THE INVENTION

[0059] In a first aspect, it is provided a tumor-specific neoantigenic peptide comprising at least one amino acid sequence set forth in Table 1.

[0060] The amino acid sequences of the tumor-specific neoantigenic peptides are disclosed in table 1.

[0061]

[0062] Table 1 : Sequences of the tumor-specific neoantigenic peptides.

[0063] In an embodiment, it is provided a tumor-specific neoantigenic peptide comprising at least one amino acid sequence set forth in SEQ ID NO. 21, SEQ ID NO. 27, SEQ ID No. 9, SEQ ID No. 12, SEQ ID No. 13, SEQ ID No. 2, SEQ ID No. 3, SEQ ID No. 5, SEQ ID No. 7, SEQ ID No. 8, SEQ ID No. 11, SEQ ID No. 14, SEQ ID No. 15, SEQ ID No. 16, SEQ ID No. 61, SEQ ID No. 18, SEQ ID No. 19,

[0064] SEQ ID No. 20, SEQ ID No. 22, SEQ ID No. 24, SEQ ID No. 25, SEQ ID No. 26, SEQ ID No. 28,

[0065] SEQ ID No. 29, SEQ ID No. 30, SEQ ID No. 32, SEQ ID No. 33, SEQ ID No. 35, SEQ ID No. 37,

[0066] SEQ ID No. 38, SEQ ID No. 40, SEQ ID No. 42, SEQ ID No. 43, SEQ ID No. 45, SEQ ID No. 46, SEQ ID No. 47, SEQ ID No. 48, SEQ ID No. 49, SEQ ID No. 50, SEQ ID No. 51, SEQ ID No. 52,

[0067] SEQ ID No. 53, SEQ ID No. 54, SEQ ID No. 56, SEQ ID No. 58, SEQ ID No. 59, SEQ ID No. 60,

[0068] SEQ ID No. 1, SEQ ID No. 4, SEQ ID No. 6, SEQ ID No. 10, SEQ ID No. 17, SEQ ID No. 23, SEQ ID No. 31, SEQ ID No. 34, SEQ ID No. 36, SEQ ID No. 39, SEQ ID No. 41, SEQ ID No. 44, SEQ ID No. 55, or SEQ ID No. 57. In an embodiment, it is provided a tumor-specific neoantigenic peptide comprising at least one amino acid sequence set forth in SEQ ID No. 1 to SEQ ID No. 61.

[0069] The term “tumor-specific neoantigenic peptide” refers to antigens generated by tumor cells as a result of various tumor-specific alterations. In the present invention, the alterations may be a result of mutations in the splicing factor 3B subunit 1 (SF3B1). A tumor-specific neoantigenic peptide comprises or consists of at least one amino acid sequence set forth in SEQ ID No.l to SEQ ID N.61. These tumor-specific neoantigenic peptides are expressed in SF3B1 mutant tumors but not in healthy cells. Any one of these tumor-specific neoantigenic peptides being specifically expressed in tumor cells, their use in human medicine allows the provision of a vaccine composition that leads to the production of immune cells that target tumor cells with a low risk of auto-immune recognition.

[0070] “Tumor-specific neoantigenic peptide” can correspond to a single amino acid molecule or to a plurality of amino acid molecules encoding the same peptide (i.e. having the same amino acid residue sequence)

[0071] The term “SF3B1” refers to a protein (UniProtKB - 075533) encoded in humans by the SF3B1 gene (Ensembl: ENSG00000115524). This gene encodes subunit 1 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b / 3a complex binds pre- mRNA upstream of the intron's branch site in a sequence-independent manner and may anchor the U2 snRNP to the pre-mRNA. Splicing factor 3b is also a component of the minor U12-type spliceosome. The carboxy-terminal two-thirds of subunit 1 have 22 non-identical, tandem HEAT repeat domains that form rod-like, helical structures. Alternative splicing results in multiple transcript variants encoding different isoforms.

[0072] Relevant mutations of SF3B1 as per the present disclosure notably include mutations in a HEAT (Huntingtin, Elongation factor 3, protein phosphatase 2 A, Targets of rapamycin 1) repeat domains (typically in the region corresponding to residues 622-781) and / or in the U2AF2 domain. SF3B1 mutations induce an upstream shift of the splicing acceptor sites, leading to the inclusion of intronic sequences in the mRNA. The resulting additional amino acids, and the frameshift that is associated, generate a larger number of aberrant proteins.

[0073] The term “aberrant amino acid” refers to additional, atypical or unusual amino acids present in aberrant proteins as compared to their wild type version. These amino acids may be located in the intron region that in normal situations are not transcribed in the mRNA. Following mutations in the splicing acceptor sites, the RNA polymerase may transcribe one or several intronic nucleotides encoding the aberrant amino acid(s) that are thus translated into aberrant proteins. The insertion of aberrant nucleotides may lead to a frameshift. It can either be in-frame or out-of-frame. In in-frame cases, the reading frame is preserved and not disrupted. In out-of-frame cases, the reading frame is disrupted and not preserved.

[0074] Cancer-associated mutations in SF3B1 are missense mutations within the major hotspots targeting the 5-9 heat repeat domains and notably the fifth, sixth, and seventh HEAT repeats of the SF3B1 protein. These alterations affect residues that are predicted to be spatially close to one another and therefore might have a similar functional impact. (Alsafadi et al., 2016 and Quesada et al., 2011). Example of SF3B1 mutations include mutations in positions E622, Y623, R625, N626, H662, T663, K666, K700, V701, K741, G742, D984, more particularly mutations K700, E622, R625, H662, and K666. In some embodiments, mutations of SF3B1 are R625, K700 (notably K700E) and or K666.

[0075] In an embodiment of the present invention, it provides a plurality of different neoantigenic peptides, each different neoantigenic peptide having an amino acid sequence as set forth in any sequence from SEQ ID No. 1 to SEQ ID No. 61.

[0076] The tumor-specific neoantigenic peptides defined above are derived from aberrant splicing events and can be present on the surface of tumor cells, in particular as a consequence of mutations in the SF3B1 gene. These neoantigenic peptides can be presented by major histocompatibility complex (MHC) class I molecules. These neoantigenic peptides are capable of eliciting a cytotoxic T cell immune response, making them attractive candidates for immunotherapeutic interventions.

[0077] In an embodiment of the present invention, it is provided 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 or 61 different neoantigenic peptides, each different neoantigenic peptide comprising or consisting of an amino acid sequence as set forth in any sequence from SEQ ID No. 1 to SEQ ID No. 61.

[0078] In an embodiment of the present invention, it is provided one neoantigenic peptide or a plurality of neoantigenic peptides, each one having an amino acid sequence as defined above, wherein each neoantigenic peptide: a. specifically binds to a class I HLA allele, in particular a class I HLA-A allele, more particularly to HLA-A*02:01; b. has an expression over 1 read when the expression of RNA is normalized according to RNAseq within a tumor cell; c. has a size superior to 8 amino acid residues and lower than 80 amino acid residues, d. has an expression ratio (PSI) between SF3B1WT and SF3B limit tumors superior to minus

[0079] 0.001 PSI. The HLA Binding Specificity corresponds to the tumor-specific neoantigenic peptide specifically binding to a class I human leukocyte antigen (HLA) molecule. More particularly, the peptide binds to an HLA-A allele, and most particularly to HLA-A02:01. The ability of the peptide to bind HLA- A02:01 may be determined using in silico prediction tools such as NetMHCpan, NetMHCcons, or MHCflurry, or confirmed experimentally using HLA-binding assays, including but not limited to the assays disclosed in the experiments of the invention (see the last example and Figure 17).

[0080] The tumor-specific neoantigenic peptides of the invention are derived from splicing variants that are expressed in tumor cells. The presence of the aberrant RNA isoform encoding the peptide is determined by RNA sequencing (RNA-seq). To ensure that the variant is not an artifact and is present in the tumor sample, a minimum expression threshold may be applied: the aberrant transcript must be detected at greater than 1 read, after normalization for transcript abundance in the tumor. This ensures that the splicing event is biologically relevant and potentially immunogenic.

[0081] The tumor-specific neoantigenic peptides of the invention have a length of greater than 8 amino acids and less than 80 amino acids. This range encompasses typical lengths of peptides that are efficiently processed and presented by MHC class I molecules (usually 8-11 amino acids), but also allows inclusion of longer peptides or peptide constructs suitable for use in synthetic long peptide (SLP) vaccines, where proteasomal processing generates shorter epitopes for presentation.

[0082] To establish tumor specificity, the peptides are derived from aberrant splicing events that are preferentially found in tumors harboring mutations in SF3B1 compared to wild-type tumors. This differential inclusion of splice junctions or exons is quantified using Percent Spliced In (PSI) values, a standard metric in splicing analysis. The peptides included in the invention are encoded by sequences that exhibit a PSI ratio between SF3B1 wild-type (WT) and SF3B1 mutant tumors greater than -0.001, indicating selective expression in mutant tumors. This small cutoff avoids inclusion of background splicing noise and retains events enriched in the mutant context.

[0083] In a further embodiment, the tumor-specific neoantigenic peptide(s) of the invention specifically bind(s) to HLA-A molecules, a class of MHC class I molecules expressed on the surface of nucleated cells. Binding specificity can be determined via MHC -peptide binding prediction tools or validated experimentally using immunoprecipitation of HLA complexes from tumor cells followed by mass spectrometry to detect the naturally processed and presented peptide. The examples illustrating the invention may be used for assessing the binding between HLA molecules and the tumor-specific neoantigenic peptides of the invention.

[0084] In an embodiment of the present invention, it is provided a combination of different neoantigenic peptides, wherein each different peptide comprises or consists of a single amino acid sequence set forth in SEQ ID No. 1 to SEQ ID No. 61. In a second aspect, it is provided a vaccine or immunogenic composition comprising at least one tumor-specific neoantigenic peptide selected from the list consisting of amino acid sequences SEQ ID No. 1 to SEQ ID No. 61.

[0085] Typically, a vaccine or immunogenic composition comprises a pharmaceutically acceptable carrier or vehicle, a carrier substance, and / or one or more adjuvants. The pharmaceutically acceptable carriers, the carrier substances, and the adjuvants are those conventionally used. Additionally, stabilizers, diluents, excipients, and / or any other materials well-known to those skilled in the art may be used. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.

[0086] The carrier, or vehicle, is preferably an aqueous carrier but the precise nature of the carrier or other material will depend on the route of administration. A variety of aqueous carriers may be used, e.g., water, buffered water, 0.9% saline, 0.3% glycine, hyaluronic acid, and the like. These compositions may be sterilized by conventional, well-known sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution before administration.

[0087] The carrier substances are advantageously selected from the group consisting of unilamellar or multilamellar liposomes, ISCOMs, virosomes, viral pseudoparticles, saponin micelles, solid microspheres which are saccharide (poly(lactide-co-glycolide)) or gold-bearing in nature, and nanoparticles.

[0088] The adjuvants typically increase or expand the immune response of a host to an antigenic compound. Example adjuvants include emulsifiers, muramyl dipeptides, avridine, aqueous adjuvants such as aluminum hydroxide, chitosan-based adjuvants, saponins, oils, Amphigen, LPS, bacterial cell wall extracts, bacterial DNA, CpG sequences, synthetic oligonucleotides, cytokines, squalene and combinations thereof. Emulsifiers include, for example, potassium, sodium, and ammonium salts of lauric and oleic acid, calcium, magnesium, and aluminum salts of fatty acids, organic sulfonates such as sodium lauryl sulfate, cetyltrimethylammonium bromide, glycerylesters, polyoxyethylene glycol esters and ethers, and sorbitan fatty acid esters and their polyoxyethylene, acacia, gelatin, lecithin and / or cholesterol. Adjuvants that comprise an oil component include mineral oil, vegetable oil, or animal oil. Other adjuvants include Freund's Complete Adjuvant (FCA) or Freund's Incomplete Adjuvant (FI A). Cytokines useful as additional immunostimulatory agents include interferon alpha, interleukin-2 (IL-2), and granulocyte macrophage-colony stimulating factor (GM-CSF), or combinations thereof.

[0089] The compositions may further contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc. See, for example, Butterfield, BMJ. 2015 22;350 for a discussion of cancer vaccines.

[0090] In one embodiment of the present disclosure, the vaccine or immunogenic composition comprises one or more tumor-specific neoantigenic peptides as defined previously.

[0091] In another embodiment of the present disclosure, the vaccine or immunogenic composition comprises a plurality of tumor-specific neoantigenic peptides as defined previously.

[0092] In another embodiment of the present disclosure, the vaccine or immunogenic composition comprises at least two tumor-specific neoantigenic peptides as defined previously.

[0093] In another embodiment of the present disclosure, the vaccine or immunogenic composition comprises at least three tumor-specific neoantigenic peptides as defined previously.

[0094] In another embodiment of the present disclosure, the vaccine or immunogenic composition comprises at least four tumor-specific neoantigenic peptides as defined previously.

[0095] In another embodiment of the present disclosure, the vaccine or immunogenic composition comprises at least five tumor-specific neoantigenic peptides as defined previously.

[0096] In a particular aspect, it is provided a vaccine or immunogenic composition comprising a plurality of different tumor-specific neoantigenic peptides, each different tumor-specific neoantigenic peptide comprising or consisting of an amino acid sequence as set forth in sequences SEQ ID No. 1 to SEQ ID No. 61.

[0097] In a particular aspect, it is provided a vaccine or immunogenic composition comprising at least one copy, in particular a plurality of copies, of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 or 61 different tumor-specific neoantigenic peptides, each different tumor-specific neoantigenic peptide comprising or consisting of a single amino acid sequence as set forth in sequences SEQ ID No. 1 to SEQ ID No. 61.

[0098] In a particular aspect, it is provided a vaccine or immunogenic composition comprising at least one copy, in particular a plurality of copies, of at least one tumor-specific neoantigenic peptide comprising or consisting of an amino acid sequence selected from SEQ ID No. 1 to SEQ ID No. 61.

[0099] In a particular aspect , it is provided a vaccine or immunogenic composition comprising at least one copy, in particular a plurality of copies, of 61 different tumor-specific neoantigenic peptides, each different neoantigenic peptide comprising or consisting of a single amino acid sequence as set forth in sequence SEQ ID No. 1 to SEQ ID No. 61. In a specific aspect of the invention, it is provided a vaccine or immunogenic composition that comprises at least one copy, in particular a plurality of copies, of the tumor-specific neoantigenic peptides disclosed in Table 2.

[0100] Table 2: tumor-specific neoantigenic peptides that specifically bind to HLA

[0101] The tumor-specific neoantigenic peptides listed in table 2 show an efficient binding to HLA-A*02:01, as compared to control peptides in the experimental data provided herein.

[0102] In an embodiment, the tumor-specific neoantigenic peptide of the invention is selected from the peptides disclosed in table 2.

[0103] In an embodiment, it is provided a vaccine or immunogenic composition that comprises at least one, or a plurality, or each of the tumor-specific neoantigenic peptide(s) disclosed in table 2.

[0104] In one embodiment of the present invention, the vaccine or immunogenic composition comprises at least one tumor-specific antigenic peptide as previously described, and at least a second neoantigenic peptide, said second neoantigenic peptide comprising or consisting of an amino acid sequence set forth in SEQ ID No. 62 to SEQ ID No. 73.

[0105] The amino acid sequences of the second neoantigenic peptides are disclosed in table 3 here below.

[0106] Table 3: Amino acid sequences of the second neoantigenic peptides.

[0107] The term “second neoantigenic peptide” refers to neoantigenic peptides comprising or consisting of an amino acid sequence outlined in SEQ ID No. 62 to SEQ ID No. 73. They are peptides that, once presented by specific MHC alleles, can be recognized by T cells and may induce T cell reactivity. They may represent an abnormal or aberrant peptide that arises from the consequence of epigenetic, transcriptional, translational, and post-translational alterations of tumor cells. In the present disclosure, the alterations are splicing alterations induced by an SF3B1 or an SF3Bl-like mutation in cancer cells. Typically said neoantigenic peptides are specifically expressed in tumor cells with said mutation. The peptide is encoded from a transcript associated with an SF3B1 or an SB3Fl-like mutation. In a specific aspect of the invention, it is provided a vaccine or immunogenic composition that comprises at least one copy, in particular a plurality of copies, of the tumor-specific neoantigenic peptides disclosed in Table 2, and a at least one copy, in particular a plurality of copies, of the second neoantigenic peptide disclosed in table 4.

[0108] Table 4: second neoantigenic peptides that specifically binds to HLA molecules. The second neoantigenic peptides listed in table 4 show an efficient binding to HLA-A*02:01, as compared to control peptides in the experimental data provided herein.

[0109] In an embodiment, the second neoantigenic peptides is selected from the peptides disclosed in table 4. In an embodiment, it is provided a vaccine or immunogenic composition that comprises at least one, or a plurality, or each of the second neoantigenic peptide(s) disclosed in table 4.

[0110] In one embodiment of the present invention, the vaccine or immunogenic composition comprises at least one copy, in particular a plurality of copies, of tumor-specific antigenic peptides as previously described, and at least one copy, in particular a plurality of copies, of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 different second neoantigenic peptides, each different second neoantigenic peptide comprising or consisting of a single amino acid sequence set forth in SEQ ID No. 62 to SEQ ID No. 73.

[0111] In an embodiment, it is provided a vaccine or immunogenic composition which comprises a plurality of tumor-specific neoantigenic peptides as disclosed herein and a plurality of second neoantigenic peptides as disclosed herein.

[0112] In an embodiment of the invention, the vaccine composition comprises: i) a plurality of different tumor-specific neoantigenic peptides, each different tumor-specific neoantigenic peptide comprising or consisting of a single amino acid sequence as set forth in sequences SEQ ID No. 1 to SEQ ID No. 61, or i’) at least one copy, in particular a plurality of copies, of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 or 61 different tumor-specific neoantigenic peptides, each different tumor-specific neoantigenic peptide comprising or consisting of a single amino acid sequence as set forth in sequences SEQ ID No. 1 to SEQ ID No. 61, or i”) at least one copy, in particular a plurality of copies, of 61 different tumor-specific neoantigenic peptides, each different neoantigenic peptide comprising or consisting of a single amino acid sequence as set forth in sequences SEQ ID No. 1 to SEQ ID No. 61, and ii) at least a second neoantigenic peptide, said second neoantigenic peptide comprising or consisting of an amino acid sequence set forth in SEQ ID No. 62 to SEQ ID No. 73.

[0113] In an embodiment of the invention, the vaccine composition comprises: i) a plurality of different tumor-specific neoantigenic peptides, each different tumorspecific neoantigenic peptide comprising or consisting of an amino acid sequence as set forth in any sequence from SEQ ID No. 1 to SEQ ID No. 61, or i’) at least one copy of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,

[0114] 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,

[0115] 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 or 61 different tumor-specific neoantigenic peptides, each different tumor-specific neoantigenic peptide comprising or consisting of an amino acid sequence as set forth in any sequence from SEQ ID No. 1 to SEQ ID No. 61, or i”) at least one copy, in particular a plurality of copies, of 61 different tumor-specific neoantigenic peptides, each different neoantigenic peptide comprising or consisting of a single amino acid sequence as set forth in any sequence from SEQ ID No. 1 to SEQ ID No. 61, and ii) a plurality of different second neoantigenic peptides, each different second neoantigenic peptide comprising or consisting of an amino acid sequence set forth in SEQ ID No. 62 to SEQ ID No. 73.

[0116] In an embodiment of the invention, the vaccine composition comprises: i) a plurality of different tumor-specific neoantigenic peptides, each different tumorspecific neoantigenic peptide comprising or consisting of an amino acid sequence as set forth in any sequence from SEQ ID No. 1 to SEQ ID No. 61, or i’) at least one copy of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,

[0117] 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,

[0118] 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 or 61 different tumor-specific neoantigenic peptides, each different tumor-specific neoantigenic peptide comprising or consisting of an amino acid sequence as set forth in any sequence from SEQ ID No. 1 to SEQ ID No. 61, or i”) at least one copy, in particular a plurality of copies, of 61 different tumor-specific neoantigenic peptides, each different neoantigenic peptide comprising or consisting of a single amino acid sequence as set forth in any sequence from SEQ ID No. 1 to SEQ ID No. 61, and ii) at least one copy, in particular a plurality of copies, of 12 different second neoantigenic peptide, each different second neoantigenic peptide comprising or consisting of a single amino acid sequence set forth in SEQ ID No. 62 to SEQ ID No. 73.

[0119] In an embodiment of the invention, the vaccine composition comprises: i) at least one copy, in particular a plurality of copies, of 61 different tumor-specific neoantigenic peptides, each different neoantigenic peptide comprising or consisting of a single amino acid sequence as set forth in any sequence from SEQ ID No. 1 to SEQ ID No. 61, and ii) at least one copy, in particular a plurality of copies, of 12 different second neoantigenic peptide, each different second neoantigenic peptide comprising or consisting of a single amino acid sequence set forth in SEQ ID No. 62 to SEQ ID No. 73.

[0120] In one embodiment of the present disclosure, the vaccine or immunogenic composition comprises any one of the previous embodiments concerning tumor-specific neoantigenic peptides and one or more second neoantigenic peptides, said second neoantigenic peptides as defined above.

[0121] In one embodiment of the present disclosure, the vaccine or immunogenic composition comprises any one of the previous embodiments concerning tumor-specific neoantigenic peptides and a plurality of second neoantigenic peptides, said second neoantigenic peptides as defined above.

[0122] In one embodiment of the present disclosure, the vaccine or immunogenic composition comprises any one of the previous embodiments concerning tumor-specific neoantigenic peptides and at least two second neoantigenic peptides, said second neoantigenic peptides as defined above.

[0123] In one embodiment of the present disclosure, the vaccine or immunogenic composition comprises any one of the previous embodiments concerning tumor-specific neoantigenic peptides and at least three second neoantigenic peptides, said second neoantigenic peptides as defined above.

[0124] In one embodiment of the present disclosure, the vaccine or immunogenic composition comprises any one of the previous embodiments concerning tumor-specific neoantigenic peptides and at least four second neoantigenic peptides, said second neoantigenic peptides as defined above.

[0125] In one embodiment of the present disclosure, the vaccine or immunogenic composition comprises one of the previous embodiments concerning tumor-specific neoantigenic peptides and at least five second-neoantigenic peptides, said second neoantigenic peptides as defined above.

[0126] An “immunogenic composition” is to be understood as a composition that comprises or generates antigen(s) and is capable of eliciting an antigen-specific humoral or cellular immune response, e.g. T-cell response.

[0127] In one embodiment of the present disclosure, the said vaccinal or immunogenic composition comprises a plurality of tumor-specific neoantigenic peptides and / or a plurality of second neoantigenic peptides. Preferably, at least one copy, in particular a plurality of copies, of the 61 different tumor-specific neoantigenic peptides, each different tumor-specific neoantigenic peptides comprising or consisting of a single amino acid sequence set forth in sequences SEQ ID No. 1 to SEQ ID No. 61.

[0128] For purposes of the present disclosure, the terms "cancer" and "cancer disease" are used interchangeably with the terms "tumor" or "tumor disease". A cancer is a disease involving abnormal cell growth with the potential to invade or spread to other parts of the body. According to the invention, the cancer which affects or affected a patient may be selected from the list consisting of uveal melanoma, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head & neck cancers, hodgkin’s lymphoma, leukemia, liver cancer, lung cancer, carcinoma, hepatocarcinoma, melanoma, mesothelioma, multiple myeloma myelodysplastic syndrome, non-hodgkin’s lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, endometrial cancer, rectal cancer, renal cancer, sarcoma, skin cancer, testicular cancer, thyroid cancer or uterine cancer. In a particular embodiment, the cancer which affect a patient is uveal melanoma.

[0129] In a particular embodiment of the present invention, it is provided a vaccinal or immunogenic composition according to any embodiment disclosed herein, the tumor-specific neoantigenic peptide and / or the second tumor-specific neoantigenic peptide being encoded from a transcript associated with a SF3B1 mutation present in an SF3B1 mutant tumor.

[0130] As used herein, the term "tumor" refers to an abnormal growth of cells (called neoplastic cells, tumorigenic cells, or tumor cells) preferably forming a swelling or lesion. By "tumor cell" it meant an abnormal cell that grows by a rapid, uncontrolled cellular proliferation that continues to grow after the stimuli that initiated the new growth ceases. Tumors show partial or complete lack of structural organization and functional coordination with the normal tissue and usually form a distinct mass of tissue, which may be either benign, pre-malignant, or malignant.

[0131] A malignant tumor is essentially synonymous with cancer. Malignancy, malignant neoplasm, and malignant tumor are essentially synonymous with cancer.

[0132] A benign tumor is a tumor that lacks all three of the malignant properties of a cancer. Thus, by definition, a benign tumor does not grow in an unlimited, aggressive manner, does not invade surrounding tissues, and does not spread to non-adjacent tissues (metastasize).

[0133] A neoplasm is an abnormal mass of tissue as a result of neoplasia. Neoplasia (new growth in Greek) is the abnormal proliferation of cells. The growth of the cells exceeds and is uncoordinated with that of the normal tissues around them. The growth persists in the same excessive manner even after cessation of the stimuli. It usually causes a lump or tumor. Neoplasms may be benign, pre-malignant, or malignant.

[0134] In a particular embodiment, the SF3B1 mutant tumor associated with the cancer is issued or derived from uveal melanoma, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head & neck cancers, hodgkin’s lymphoma, leukemia, liver cancer, lung cancer, carcinoma, hepatocarcinoma, melanoma, mesothelioma, multiple myeloma myelodysplastic syndrome, non-hodgkin’s lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, endometrial cancer, rectal cancer, renal cancer, sarcoma, skin cancer, testicular cancer, thyroid cancer or uterine cancer.

[0135] In a particular embodiment, the SF3B1 mutant tumor associated with the cancer is issued or derived from uveal melanoma.

[0136] “SF3B1 mutant associated tumors” or “SF3B1 mutant tumors” are tumors associated with mutations of SF3B1 and / or with SF3Bl-like mutations, in particular mutations associated with mutation(s) of SF3B1 and / or SUGP1 as described above. By “associated with” it is herein intended that said tumor expresses one or more mutations. Some embodiments said one or more mutations are tumor-specific (i.e., mutation (s) found to a level below 5 %, notably below 1%, in particular, that are not found in normal tissue samples). SF3B1 mutant tumors notably include melanoma, mucosal melanoma, mesothelioma, skin or cutaneous melanoma, uveal melanoma, orbital melanoma, hematological malignancies such as acute myeloid leukemia, chronic lymphocytic leukemia, chronic B-cell leukemia, myeloid leukemia, myeloproliferative neoplasm, myelodysplastic myeloproliferative cancer, chronic myelomonocytic leukemia or PDGFRB-associated chronic eosinophilic leukemia, renal cell carcinoma, adenoid cystic carcinoma, bladder urothelial carcinoma, liver cancer (notably hepatocellular carcinoma), lung cancer, pulmonary adenocarcinoma, pancreatic adenocarcinoma, breast cancer, and progesterone negative breast cancer

[0137] Preferably, the tumor is selected from hematological malignancies, uveal melanoma, and / or pulmonary adenocarcinoma. In a preferred embodiment, the SF3B1 mutant-associated tumor is uveal melanoma.

[0138] "Growth of a tumor" or "tumor growth" according to the present disclosure relates to the tendency of a tumor to increase its size and / or to the tendency of tumor cells to proliferate.

[0139] "Metastasis" means the spread of cancer cells from their original site to another part of the body. The formation of metastasis is a very complex process and depends on the detachment of malignant cells from the primary tumor, invasion of the extracellular matrix, penetration of the endothelial basement membranes to enter the body cavity and vessels, and then after being transported by the blood, infiltration of target organs. Finally, the growth of a new tumor, i.e. a secondary tumor or metastatic tumor, at the target site depends on angiogenesis. Tumor metastasis often occurs even after the removal of the primary tumor because tumor cells or components may remain and develop metastatic potential. In one embodiment, the term "metastasis" according to the present disclosure relates to "distant metastasis" which relates to a metastasis that is remote from the primary tumor and the regional lymph node system. A relapse or recurrence occurs when a person is affected again by a condition that affected them. For example, if a patient has suffered from a tumor disease, has received a successful treatment of said disease, and again develops said disease, the newly developed disease may be considered as a relapse or recurrence. However, according to the present disclosure, a relapse or recurrence of a tumor disease may but does not necessarily occur at the site of the original tumor disease. Thus, for example, if a patient has suffered from an ovarian tumor and has received a successful treatment a relapse or recurrence may be the occurrence of an ovarian tumor or the occurrence of a tumor at a site different to the ovary. Relapse or recurrence of a tumor also includes situations wherein a tumor occurs at a site different from the site of the original tumor as well as at the site of the original tumor. Preferably, the original tumor for which the patient has received a treatment is a primary tumor and the tumor at a site different to the site of the original tumor is a secondary or metastatic tumor.

[0140] "Treatment" is meant to administer a compound or composition as described herein to a subject in order to prevent or eliminate disease, including reducing the size of a tumor or the number of tumors in a subject; arresting or slowing a disease in a subject; inhibit or slow the development of a new disease in a subject; decrease the frequency or severity of symptoms and / or recurrences in a subject who currently has or who previously has had a disease; and / or prolong, i.e. increase the lifespan of the subject. In particular, "treating cancer" includes curing, shortening the duration, easing, preventing, slowing down, inhibiting progression or worsening, or preventing or delaying the onset of a disease or the symptoms thereof.

[0141] The present disclosure also encompasses a population of dendritic cells or antigen-presenting cells (APCs) that have been pulsed with one or more of the tumor-specific neoantigenic peptide or the vaccine or immunogenic composition as previously described. The present invention also encompasses a population of dendritic cells or antigen-presenting cells (APCs) transfected with a polynucleotide encoding one or more tumor-specific neoantigenic peptides as defined previously or the vaccinal or immunogenic composition hereabove. In a preferred embodiment, the dendritic cells are autologous dendritic cells.

[0142] Preferably, the antigen-presenting cells are dendritic cells (DCs) or artificial antigen-presenting cells (aAPCs). Dendritic cells (DC) are professional antigen-presenting cells (APC) that have an extraordinary capacity to stimulate naive T-cells and initiate primary immune responses to pathogens. Indeed, the main role of mature DCs is to sense antigens and produce mediators that activate other immune cells, particularly T cells. DCs are potent stimulators for lymphocyte activation as they express MHC molecules that trigger TCRs (signal 1) and co-stimulatory molecules (signal 2) on T cells. Additionally, DCs also secrete cytokines that support T-cell expansion. T cells require presented antigens in the form of a processed peptide to recognize foreign pathogens or tumors. Presentation of peptide epitopes derived from pathogen / tumor proteins is achieved through MHC molecules. MHC class I (MHC -I) and MHC class II (MHC-II) molecules present processed peptides to CD8+ T cells and CD4+ T cells, respectively. Importantly, DCs home to inflammatory sites containing abundant T cell populations to foster an immune response. Thus, DCs can be a crucial component of any immunotherapeutic approach, as they are intimately involved with the activation of the adaptive immune response. In the context of vaccines, DC therapy can enhance T cell immune responses to a desired target in healthy volunteers or patients with infectious disease or cancer. In one embodiment, APCS are artificial APCs, which are genetically modified to express the desired T-cell co-stimulatory molecules, human HLA alleles, and / or cytokines.

[0143] Such artificial antigen-presenting cells (aAPC) can provide the requirements for adequate T-cell engagement, co-stimulation, as well as sustained release of cytokines that allow for controlled T-cell expansion. These cells are not subject to the constraints of time and limited availability and can be stored in small aliquots for subsequent use in generating T-cell lines from different donors, thus representing an off-the-shelf reagent for immunotherapy applications. Expression of potent costimulatory signals on these aAPC endows this system with higher efficiency lending to increased efficacy of adoptive immunotherapy. Furthermore, aAPC can be engineered to express genes directing the release of specific cytokines to facilitate the preferential expansion of desirable T-cell subsets for adoptive transfer; such as long-lived memory T-cells ((Hasan et al., 2015), Kim et al., 2004 or Wang et al., 2017).

[0144] Typically, the dendritic cells are autologous dendritic cells that are pulsed with one or more tumorspecific neoantigenic peptide as defined previously or vaccinal or immunogenic composition or transfected with a polynucleotide encoding one or more tumor-specific neoantigenic peptide as defined previously, or vaccine or immunogenic composition. The antigen-presenting cell (or stimulator cell) typically has MHC class I or II molecules on its surface, and in one embodiment is substantially incapable of loading the MHC class I or II molecules with the selected antigen. The MHC class I or II molecules may readily be loaded with the selected tumor-specific neoantigenic peptide in vitro.

[0145] In an embodiment, it is provided an antibody, or an antigen-binding fragment thereof, or a T cell receptor (TCR), or a chimeric antigen receptor (CAR) that specifically binds to at least one tumorspecific neoantigenic peptide as defined herein.

[0146] The term "antibody" herein is used in the broadest sense and includes polyclonal and monoclonal antibodies, including intact antibodies and functional (antigen-binding) antibody fragments, including fragment antigen binding (Fab) fragments, F(ab')2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rlgG) fragments, variable heavy chain (VH) regions capable of specifically binding the antigen, single chain antibody fragments, including single chain variable fragments (scFv), and single domain antibodies (e.g., VHH antibodies, sdAb, sdFv, nanobody) fragments. The term encompasses genetically engineered and / or otherwise variants modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, heteroconjugate antibodies, multispecific, e.g., bispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, tandem tri-scFv. Unless otherwise stated, the term "antibody" should be understood to encompass functional antibodies and fragments thereof. The term also encompasses intact or full-length antibodies, including antibodies of any class or sub-class, including IgG and subclasses thereof, IgGl, IgG2, IgG3, IgG4, IgM, IgE, IgA, and IgD. In some embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, e.g. in a scFv format.

[0147] Antibodies include variant polypeptide species that have one or more amino acid substitutions, insertions, or deletions in the native amino acid sequence, provided that the antibody retains or substantially retains its specific binding function.

[0148] In one embodiment, antibodies may be chimeric, humanized, or human antibodies. Humanized antibodies contain rodent-sequence-derived CDR regions; typically, the rodent CDRs are engrafted into a human framework, and some of the human framework residues may be back-mutated to the original rodent framework residue to preserve affinity, and / or one or a few of the CDR residues may be mutated to increase affinity. Fully human antibodies have no murine sequence and are typically produced via phage display technologies of human antibody libraries, or immunization of transgenic mice whose native immunoglobin loci have been replaced with segments of human immunoglobulin loci.

[0149] The present disclosure also encompasses a T cell receptor (TCR), in particular in association with an MHC class I molecule, that specifically binds to the tumor-specific neoantigenic peptide. A “T cell receptor” or “TCR” refers to a complex consisting of two TCR chains and six clusters of differentiation 3 (CD3) chains. This complex is triggered by MHC class I and class II molecules with the presentation of an antigen. In the present disclosure, the complex is triggered by the MHC class I molecule specifically bound to the tumor-specific neoantigenic peptide described previously. TCR molecule contains two distinct heterodimers of two variable chains: TCRa / TCRp and TCRy / TCRS. These heterodimers are associated with CD3 complexes and expressed either on the T cell surface or in a soluble form. Usually, T cells express TCRa / TCRp on their surface. TCR is usually responsible for recognizing antigen peptides bound to major histocompatibility complex (MHC) molecules. Unless otherwise stated, the term "TCR" should be understood to encompass functional TCR fragments thereof. The term also encompasses intact or full-length TCRs, including TCRs in the aP form or y5 form. In some embodiments, the TCR contains variable a and P chains. In some embodiments, said TCRs are made soluble and are fused to an antibody fragment directed to a T cell antigen, optionally the targeted antigen is CD3 or CD 16.

[0150] The term “fused to an antibody fragment directed to a T cell antigen” refers herein to a TCR with, on the N-term of the variable a and P chains portion, the presentation of the tumor-specific neoantigenic peptide by MHC molecules, preferentially MHC class I molecule, and on the C-terminal of the constant a and P chains portion, the fusion to an antibody fragment directed to a T cell antigen. By “T cell antigen”, it means that it targets a substance expressed on the surface of a T cell, in order to trigger an immune response. Preferentially, the targeted antigen is CD3 or CD 16.

[0151] “CD3” is a multi-protein complex that contains 6-8 and y-e heterodimers that contain extracellular and intracellular domains, and a homodimer that has a very short extracellular domain and a long intracellular domain. By targeting the CD3 complex, it triggers the activation of TCR of the lymphocyte. The complex contains a cryptic proline-rich sequence exposed on the cytoplasmic tail of the CD3s chain that is necessary for downstream signaling leading to T cell activation (Menon et al., 2023).

[0152] “CD16” or “FcyRIIIa” is an Immunoglobulin G (IgG) Fc receptor expressed on natural killer (NK) cells as well as phagocytes. By targeting CD 16, it triggers cytotoxicity and cytokine production. CD16 binds to the Fc portion of IgG antibodies. There are two types of CD16: CD16a and CD16b. CD16a is localized on NK cells. Upon ligation to the Fc portion of IgG antibodies, it induces a series of signals resulting in cytokine production and cytotoxic effector activity via Antibody-dependent cell-mediated cytotoxicity (ADCC). CD16b is localized on neutrophils (Romee et al., 2013).

[0153] As enclosed above, “Chimeric antigen receptor” or “CAR” refers to an engineered molecule expressed on the cell surface that can recognize specific proteins and deliver an activation signal to the cells. CAR design can be introduced in various immune cells such as NK cells, y6 T cells, mucosal-associated invariant T (MAIT) cells, dendritic cells (DC), macrophages, regulatory T cells (Treg), B cells, or T cells. In some embodiments, CAR molecules specifically bind to tumor-specific neoantigenic peptides as defined previously.

[0154] In an embodiment of the invention, it is provided an antibody, an antigen-binding fragment thereof, a CAR or a TCR as defined herein, wherein said antibody, antigen-binding fragment thereof, CAR or T-cell receptor is a multispecific antibody or antigen-binding fragment thereof or multispecific CAR or multispecific receptor, that further targets at least an immune cell, an immune cell antigen or a tumor cell antigen, optionally wherein the immune cell is a T cell, an NK cell, or a dendritic cell, optionally wherein the immune cell antigen is CD3, CD16, CD30 or a TCR. . The term “immune cell antigen" refers to a polypeptide produced in immune cells. It can either be expressed on the surface of the cell, or inside. Preferably, the polypeptide is found on the surface of the immune cell.

[0155] The term “tumor cell antigen" refers to a polypeptide produced in tumor cells. It can either be expressed on the surface of the cell, or inside. Preferably, the polypeptide is found on the surface of the tumor cell. Typically, this tumor cell antigen triggers an immune response in the host. Tumor cell antigens are separated into two categories: Tumor-Specific Antigens (TSA), and Tumor-Associated Antigens (TAA). They differentiate by their presence only on tumor cells for TSA and their presence on some tumor cells and some normal cells for TAA. They can also be classified based on their molecular structure and source.

[0156] The term “target” or “recognize” refers to the ability of an antibody or antigen-binding fragment thereof to specifically bind to an antigen or tumor cell antigen thereof.

[0157] The term “multispecific” refers herein to an antibody or an antigen-binding fragment thereof or CAR or T-cell receptor that may bind to at least one antigen. It may bind to more than one antigen and still trigger an immune response. In the preferred embodiment, it targets at least an immune cell antigen or a tumor cell antigen. In some embodiments, it targets two or more immune or tumor cell antigens. In an embodiment, it targets a plurality of immunogenic or tumor cell antigens.

[0158] In a further aspect, the present disclosure provides a polynucleotide encoding a tumor-specific neoantigenic peptide as defined previously, or an antibody or an antigen-binding fragment thereof, a CAR, or a TCR as defined in previous embodiments.

[0159] The term “polynucleotide” refers herein to a nucleic acid sequence encoding a tumor-specific neoantigenic peptide as herein disclosed. The nucleic acid may be selected from DNA, cDNA, PNA, CAN, RNA, either single- and / or double-stranded, or native or stabilized forms of nucleic acids, such as nucleic acids with a phosphorothiate backbone, or combinations thereof and it may or may not contain introns so long as it codes for the peptide. Typically, the sequence of said nucleic acid is that of the cDNA encoding said peptide polypeptide or said fusion protein.

[0160] In a further aspect, the present disclosure provides a vector comprising a polynucleotide encoding a tumor-specific neoantigenic peptide as defined previously, or an antibody or an antigen-binding fragment thereof, a CAR, or a TCR as defined in previous embodiments.

[0161] In some embodiments, the vector comprises the polynucleotide as previously defined. In some embodiments, the vector comprises one or more polynucleotide sequences encoding a tumor-specific neoantigenic peptide as previously defined. In some embodiments, the polynucleotide may be linked to a heterologous regulatory control sequence (e.g., heterologous transcriptional and / or translational regulatory control nucleotide sequences as well-known in the field). In some embodiments, the vector comprises a nucleic acid sequence encoding a tumor-specific neoantigenic peptide as previously defined.

[0162] According to the present disclosure, the term “vector” is intended to mean a nucleic acid molecule capable of transporting another nucleic acid to which it is linked. One type of vector that can be used in the present invention includes, in a non-limiting manner, a linear or circular DNA or RNA molecule consisting of chromosomal, non-chromosomal, synthetic or semi-synthetic nucleic acids, such as in particular a viral vector, a plasmid or an RNA vector.

[0163] Numerous vectors into which a nucleic acid molecule of interest can be inserted in order to introduce it into and maintain it in a eukaryotic or prokaryotic host cell are known in themselves; the choice of an appropriate vector depends on the use envisioned for this vector (for example, replication of the sequence of interest, expression of this sequence, maintaining of this sequence in extrachromosomal form, or else integration into the chromosomal material of the host), and also on the nature of the host cell. For example, naked nucleic acids (DNA or RNA) or viral vectors such as adenoviruses, retroviruses, lentiviruses, and AAVs, into which the sequence of interest has been previously inserted may be used; said sequence (isolated or inserted into a plasmid vector) can also be combined with a substance which allows it to cross the host cell membrane, such as a transporter, for instance, a nanotransporter or a preparation of liposomes, or cationic polymers, or else makes it possible to introduce it into a said host cell using physical methods such as electroporation or microinjection. In addition, these methods can advantageously be combined, for example using electroporation combined with liposomes.

[0164] Preferably, said vector is an expression vector comprising all the elements required for the expression of a neoantigenic peptide as herein disclosed. For example, said vector comprises an expression cassette including at least one polynucleotide as defined above, under the control of appropriate heterologous regulatory sequences for transcription and optionally for translation (promoter, enhancer, intron, start codon (ATG), stop codon, polyadenylation signal, splice site) recognized by the desired host. The polynucleotide encoding the tumor neoantigenic peptide may be linked to such heterologous regulatory control nucleotide sequences or may be non-adjacent yet operably linked to such heterologous regulatory control nucleotide sequences. The vector is then introduced into the host through standard techniques. Guidance can be found for example in Sambrook et al. (1989) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.

[0165] In an embodiment, it is provided an immune cell that specifically binds to one or more tumor-specific neoantigenic peptides as defined herein. In some embodiments, the immune cell specifically binds to at least two tumor-specific neoantigenic peptides as defined herein. In some embodiments, the immune cell binds to several tumor-specific neoantigenic peptides as defined herein.

[0166] In an embodiment, the immune cell is allogeneic or autologous. In a preferred embodiment, the immune cell is selected from T cell, NK cell, CD4+ / CD8+, tumour infiltrating lymphocyte (TILs) / tumor-derived CD8 T cells, central memory CD8+ T cells, Regulatory T cells (Treg), Mucosal- Associated Invariant T cell (MAIT), and Y5 T cell.

[0167] In the present disclosure, an “immune cell” is a cell involved in the immune response. They are of hematopoietic origin. Immune cells include lymphocytes such as B cells and T cells, natural killer cells, myeloid cells, such as monocytes, macrophages, eosinophils, mast cells, basophils, and granulocytes. Said immune cells may originate from a healthy donor or from a subject suffering from cancer.

[0168] Immune cells can be extracted from blood or derived from stem cells. The stem cells can be adult stem cells, embryonic stem cells, more particularly non-human stem cells, cord blood stem cells, progenitor cells, bone marrow stem cells, induced pluripotent stem cells, totipotent stem cells, or hematopoietic stem cells. Representative human cells are CD34+ cells.

[0169] In another embodiment, said cell can be derived from a healthy donor, from a subject diagnosed with cancer. The cell can be autologous or allogeneic.

[0170] In allogeneic immune cell therapy, the cells are collected from a donor other than the patient. Usually, the donor and the patient have similar HLA to reduce the likelihood of graft vs. host disease. Once the cells are collected, the immune cells as herein disclosed can be expanded in vivo or ex vivo. The immune cells, in particular T-cells, can be activated and expanded generally using methods known in the art. Generally, the T-cells are expanded by contact with a surface having attached thereto an agent that stimulates a CD3 / TCR complex associated signal and a ligand that stimulates a co-stimulatory molecule on the surface of the T cells. In some embodiments of the present disclosure, the immune cell can be modified to target tumor-specific neoantigenic peptides as previously defined.

[0171] In autologous immune cell therapy, the cells are collected from the individual itself. These cells are cultured and expanded outside the body using methods known in the art. In some embodiments of the present disclosure, the immune cell can be modified to target tumor-specific neoantigenic peptides as previously defined.

[0172] In some embodiments of the present disclosure, it is provided a T cell which comprises: a T cell receptor that specifically binds to one or more tumor-specific neoantigenic peptides as defined previously, or a CAR that specifically that specifically binds to one or more tumor-specific neoantigenic peptides as defined previously.

[0173] In an embodiment, the tumor-specific neoantigenic peptide as defined herein, the vaccine or immunogenic composition as defined herein, the population of dendritic cells or APCs of as defined herein, the antibody, or an antigen-binding fragment thereof or T cell receptor (TCR) or chimeric antigen receptor (CAR) as defined herein, the polynucleotide as defined herein, the vector as defined herein, the immune cell as defined herein, or the T-cell as defined as defined herein, for use the treatment or the prevention of cancer, or for reducing or inhibiting tumor growth, for reducing or preventing tumor metastasis, in particular for use in inhibiting cancer cell proliferation, more particularly for treating cancer in a subject in need thereof or for use in cancer vaccination therapy of a subject, optionally wherein the subject is suffering from a cancer with SF3B1 mutant tumor cells, more particularly an uveal melanoma with SF3B1 mutant tumor cells, or wherein the patient is at risk of suffering from with a cancer with SF3B1 mutant tumor cells, in particular an uveal melanoma with SF3B1 mutant tumor cells.

[0174] In an embodiment, it is provided a method for the treatment or the prevention of cancer, or for reducing or inhibiting tumor growth, for reducing or preventing tumor metastasis, in particular for use in inhibiting cancer cell proliferation, more particularly for treating cancer in a subject in need thereof or for use in cancer vaccination therapy of a subject, optionally wherein the subject is suffering from a cancer with SF3B1 mutant tumor cells, more particularly an uveal melanoma with SF3B1 mutant tumor cells, or wherein the patient is at risk of suffering from with a cancer with SF3B 1 mutant tumor cells, in particular an uveal melanoma with SF3B1 mutant tumor cells, the method comprising the administration of an effective amount of tumor-specific neoantigenic peptide as defined herein, the vaccine or immunogenic composition as defined herein, the population of dendritic cells or APCs of as defined herein, the antibody, or an antigen-binding fragment thereof or T cell receptor (TCR) or chimeric antigen receptor (CAR) as defined herein, the polynucleotide as defined herein, the vector as defined herein, the immune cell as defined herein, or the T-cell as defined herein, to a patient in need thereof.

[0175] In an embodiment, it is provided a method for treatment or the prevention of cancer, or for reducing or inhibiting tumor growth, for reducing or preventing tumor metastasis, in particular for use in inhibiting cancer cell proliferation, more particularly for treating cancer in a subject in need thereof or for use in cancer vaccination therapy of a subject, optionally wherein the subject is suffering from a cancer with SF3B 1 mutant tumor cells, more particularly an uveal melanoma with SF3B 1 mutant tumor cells, or wherein the patient is at risk of suffering from with a cancer with SF3B 1 mutant tumor cells, in particular an uveal melanoma with SF3B1 mutant tumor cells, the method comprising: detecting at least one tumor-specific neoantigenic peptide as defined herein in a biological sample previously obtained from a subject, the subject suffering from a cancer, in particular a cancer with SF3B1 tumor cells, more particularly a uveal melanoma,

[0176] - when at least one tumor-specific neoantigenic peptide as defined herein is detected in the biological sample, administering to the subject an effective amount of tumor-specific neoantigenic peptide as defined herein, the vaccine or immunogenic composition as defined herein, the population of dendritic cells or APCs of as defined herein, the antibody, or an antigen-binding fragment thereof or T cell receptor (TCR) or chimeric antigen receptor (CAR) as defined herein, the polynucleotide as defined herein, the vector as defined herein, the immune cell as defined herein, or the T-cell as defined herein.

[0177] Uveal melanoma is a malignant tumor with metastatic capacity, meaning it can spread to other places of the body. It affects the uvea, and the pigment cells, and provides nutrients and oxygen to the retina. It can have different starting points: the iris, ciliary body, and choroid.

[0178] Splicing factors mutation, especially SF3B1 splicing factors mutation, are quite frequent in uveal melanoma. Indeed, twenty percent of the uveal melanoma tumors harbor a mutation in SF3B1 splicing factors generating over 1000 new splice junctions. This mutation leads to an upstream shift of 8 to 40 nucleotides in the acceptor site of more than 1000 intron-exon junctions. It induces frameshifts in the downstream exons or an in-frame insertion of a few codons. These may encode potential neo-antigens and potential tumor-specific neoantigenic peptides as defined above. The inventors have shown an immune response towards neoantigenic peptides with the presence of memory and oligoclonal CD8+ T cells specific for splicing related neoantigenic peptides in patients bearing SF3B1 mutated Uveal melanoma.

[0179] In an embodiment of the invention, it is provided an effective amount of tumor-specific neoantigenic peptide as defined herein, the vaccine or immunogenic composition as defined herein, the population of dendritic cells or APCs of as defined herein, the antibody, or an antigen-binding fragment thereof or T cell receptor (TCR) or chimeric antigen receptor (CAR) as defined herein, the polynucleotide as defined herein, the vector as defined herein, the immune cell as defined herein, or the T-cell as defined herein, for treating or preventing cancer with SF3B1 mutant tumor cells, in particular wherein the cancer is uveal melanoma.

[0180] In an embodiment of the invention, it is provided an effective amount of tumor-specific neoantigenic peptide as defined herein, the vaccine or immunogenic composition as defined herein, the population of dendritic cells or APCs of as defined herein, the antibody, or an antigen-binding fragment thereof or T cell receptor (TCR) or chimeric antigen receptor (CAR) as defined herein, the polynucleotide as defined herein, the vector as defined herein, the immune cell as defined herein, or the T-cell as defined herein, for use in combination with at least one further therapeutic agent, optionally wherein further the therapeutic agent is a chemotherapeutic agent or an immunotherapeutic agent.

[0181] By “therapeutic agent”, the present embodiment refers to substances administered to influence the outcome of the disease, whether to cure it, to reduce, or eliminate some of its symptoms, or simply to improve the quality of life for the patient in question. Agents may be monoclonal antibodies, modulators, fusion proteins, soluble cytokine receptors, recombinant cytokines, small-molecule mimetics, peptides, proteins, or small and macromolecules.

[0182] “Chemotherapeutic agent” as used herein refers to a molecule that is destructive to a cell, it reduces the viability of the cell. It may be a cytotoxic drug. A chemotherapeutic agent contemplated includes, without limitation, alkylating agents, anthracyclines, epothilones, nitrosoureas, ethylenimines / methylmelamine, alkyl sulfonates, alkylating agents, antimetabolites, pyrimidine analogs, epipodophylotoxins, enzymes such as L-asparaginase; biological response modifiers such as IFNa, IL-2, G-CSF and GM-CSF; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin, anthracenediones, substituted urea such as hydroxyurea, methylhydrazine derivatives including N-methylhydrazine (MIH) and procarbazine, adrenocortical suppressants such as mitotane (o,p'-DDD) and aminoglutethimide; hormones and antagonists including adrenocorticosteroid antagonists such as prednisone and equivalents, dexamethasone and aminoglutethimide; progestin such as hydroxyprogesterone caproate, medroxyprogesterone acetate and megestrol acetate; estrogen such as diethylstilbestrol and ethinyl estradiol equivalents; antiestrogen such as tamoxifen; androgens including testosterone propionate and fluoxymesterone / equivalents; antiandrogens such as flutamide, gonadotropin-releasing hormone analogs and leuprolide; and non-steroidal antiandrogens such as flutamide.

[0183] “Immunotherapeutic agent” as used herein refers to an agent that uses or modifies immune mechanisms. A immunotherapeutic agent contemplated includes, without limitation, small and macromolecules such as imiquimod, MIW815 (ADU-S100), G100, CpG oligodeoxynucleotide, vidutolimod, a-gal glycolipid, peptides and proteins such as IL-2, IFN a-2a, IFN a-2b, IFNy, GM- CSF, L19-IL2, L19-TNF, anti-CTLA4, Anti-PD-1, Anti-CD40, trastuzumab-vc-MMAE, nucleic acid-based gene products such as tavokinogene telseplasmid, MEDI1191, mRNA-2752, SAR441000, TriMix mRNA, Circular mRNA, viruses such as Talimogene laherparepvec, CAVATAK, HflO, Pexastimogene devacirepvec, teserpaturev, tasadenoturev, ONCOS-102, Reolysin, PVSRIPO, bacteria such as Bacillus Calmette-Guerin, C. novyi-NT, VNP200009, and cells such as Autologous dendritic cells, Ilixadencel, tumor-infiltrating lymphocytes, Erbb-targeted CAR-T, C-Met-CAT-T, and Xenogenneic tissue, antibodies such as Abiciximab, adalimumab, Alemtuzumab,, alirocumab, atezolizumab, avelumab, basiliximab, belimumab, benzalizumab, Bevacizumab, bezlotoxumab, blinatomumab, bodalumab, Brentuximab vedotin, Brolucizumab, Burosumab, Canakinumab, Caplacizumab, Cemiplimab, Certolizumab (pegylated Fab’ fragment), Cetuximab, Crizanlizumab, Dupilumab, Durvalumab, Eculizumab, Elotuzumab, Emapalumab, Emicizumab, Enfortumab vedotin, Erenumab, Evolocumab, Fremanezumab, Galcanezumab, Gemtuzumab, Golimumab, Guselkumab, Ibalizumab, Ibritumomab tiuxetan, Idarucizumab, notuzumab, Ipilimumab, Isatuximab, Ixekizumab, Lanadelumab, Mepolizumab, Mogamulizumab, Moxetumomab pasudotox, Natalizumab, Necitumumab, Nivolumab, Obiltoxaximab, Obinutuzumab, Ocrelizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumumab, Pembrolizumab, Pertuzumab, Polatuzumab, Ramucirumab, Ranibizumab, Ravulizumab, Raxibacumab, Reslizumab, Risankizumab, Rituximab, Romosozumab, Sarilumab, Secukinumab, Siltuximab, Sotrovimab, Teprotumumab, Tildrakizumab, Tocilizumab, Tositumomab, Trastuzumab, Ustekinumab, or Vedolizumab, cellular therapy such as Axicabtagene ciloleucel (CAR T), Sipuleucel-T, Tisagenlecleucel (CAR T), and Soluble cytokine receptors such as Anakinra (IL-1 receptor antagonist).

[0184] Modulators include, without limitation, pladi enolide B, E7107, meayamycin, spliceostatin A, sudemycins, pladienolide, FR901464 (Clostridium sp. CAG:273 genomic scaffold, scfl84, whole genome shotgun sequence), herboxidiene, PRMT5 inhibitor, or indisulam.

[0185] The present invention further described a method of selecting an SF3B1 mutant tumor-specific neoantigenic comprising:

[0186] (1) A step of identifying neoantigenic peptide expressed in SF3B1 WT tumor cells, SF3B1 mutant tumor cells, and healthy cells issued from biological samples previously obtained;

[0187] (2) Among the identified neoantigenic peptides, a step of discarding the neoantigenic peptides expressed in healthy cells,

[0188] (3) Within the remaining neoantigenic peptides: a. a step of discarding those that do not specifically bind class I HLA proteins; b. a step of discarding those that have an RNA expression lower than 1 read when the expression of RNA is normalized according to RNAseq within the tumor cells c. a step of discarding those that have a size inferior to 8 amino acid residues and over 80 amino acid residues, d. a step of discarding those that have an expression ratio (PSI) between SF3B1WTand SF3Blmuttumors equal or inferior to minus 0.001 PSI. the remaining neoantigenic peptides being SF3B1 mutant tumor-specific neoantigenic peptides. In an embodiment, it is provided a method of selecting an SF3B1 mutant tumor-specific neoantigenic peptide as defined herein, wherein the SF3B1 mutant tumor-specific neoantigenic peptide obtained is for use in therapy or prevention of cancer in a subject in need thereof, optionally wherein the subject is suffering from an SF3B1 mutant cancer, more particularly an uveal melanoma.

[0189] It is also provided a method for treating a subject suffering from cancer, in particular a cancer with SF3B1 mutant tumor cells, more particularly a uveal melanoma with SF3B1 mutant tumor cells, or wherein the patient is at risk of suffering from a cancer, in particular a cancer with SF3B1 mutant tumor cells, more particularly a uveal melanoma with SF3B1 mutant tumor cells, said method comprising: a) Obtaining a biological sample, in particular a blood sample, more particularly a plasma sample, from a human patient; b) Detecting in the biological sample if memory and / or CD8+ T cells specifically bind to tumorspecific neoantigenic peptide as defined herein; c) Diagnosing the patient with a cancer, in particular a cancer with SF3B1 mutant tumor cells, more particularly a uveal melanoma with SF3B1 mutant tumor cells, when memory and / or CD8+ T cells specifically bind to tumor-specific neoantigenic peptide as defined herein; and d) Administering to the patient suffering from a cancer an effective amount of tumor-specific neoantigenic peptide as defined herein, the vaccine or immunogenic composition as defined herein, the population of dendritic cells or APCs as defined herein, the antibody, or an antigenbinding fragment thereof or T cell receptor (TCR) or chimeric antigen receptor (CAR) as defined herein, the polynucleotide as defined herein, the vector as defined herein, the immune cell as defined herein, or the T-cell as defined herein.

[0190] EXAMPLES

[0191] Nature of tumor-specific neoantigenic peptides related to SF3Blmuttumors

[0192] SF3B1 mutations induce an upstream shift of the splice acceptor sites, leading to the inclusion of intronic sequences in the mRNA. The resulting additional amino acids, and the frameshift that is associated, generate a large number of aberrant proteins.

[0193] The proteins resulting from aberrant splicing have an N-terminus identical to the canonical protein. When the nucleotide insertion in the mRNA leads to a frameshift, the C-terminal portion is composed of a novel amino acid sequence. When the insertion is in-frame the N and C terminal portions are canonical and are separated by a novel protein sequence. Figure 1 exemplifies two situations: The mutant SF3B1 leads to an alternative acceptor site in the pre-mRNA of STK24 (Figure 1 A). Twenty-four intronic nucleotides are retained in the final mRNA. The aberrant protein includes an insertion of 8 amino acids. The C-terminal portion of the aberrant protein is identical to the WT protein. For the gene USP39 (Figure IB), the alternative acceptor site is 40 nucleotide (nt) upstream of the canonical site leading to a frameshift. A string of 28 aberrant amino acids composes the C-terminus of the neo-antigenic peptide before a premature codon stop.

[0194] Vaccine peptides

[0195] The vaccine peptide may contain aberrant amino acids flanked by 8 canonical amino acids in order to provide all the possible 9-mers including at least 1 aberrant amino acid (Figure 2). These peptides are not produced by SF3B1WTcells and are not self. Thymic negative selection does not eliminate T cells specific for these peptides. Therefore, an immune response can be mounted against these aberrant peptides upon vaccination. As these peptides are not expressed by normal tissues, no risk of auto-immunity is present.

[0196] Characterization of tumor-specific neoantigenic peptides

[0197] Tumor RNAseq and Bio-informatic analyses

[0198] In order to identify all the transcripts with alternative splicing in SF3BlmutUveal Melanoma (UM) cells, RNA was isolated from 7 fresh SF3Blmuttumors and 6 fresh SF3B1WTtumor samples using a CsCl cushion. RNA-seq libraries were constructed using the TruSeq Stranded mRNA Sample Preparation Kit (Illumina) and sequenced on an Illumina HiSeq 2500 platform using 100-bp paired- end sequencing. An average depth of global sequence coverage of 111 million and a median coverage of 75 million were attained. Differential junctions using alternative acceptors were identified comparing SF3Blmutwith SF3B1WTtumors (Figure 3). Sequences of aberrant and corresponding normal transcripts were extracted using ANNO VAR and ENSEMBL databases.

[0199] Reads were aligned against the human reference genome Hg38 RefSeq (RNA sequences, GRCh38). Read counts for splicing junctions from junctions.bed TopHat output were considered. Differential analysis was performed on junction read counts using DESeq2. Only alternative acceptor splice sites (two or more 30ss with junctions to the same 50ss) were considered for this analysis. Fifty -nucleotide- long sequences surrounding the splice acceptor sites were extracted to generate sequence logos using WebLog 3 (http: / / weblogo.threeplusone.com / ) with the default parameters, the classic color scheme and the unit frequency being plotted as ‘probability’.

[0200] The bioinformatics pipeline applied in 2021 (Figure 3) yielded 1407 differentially expressed junctions. A new, improved, 2022 pipeline version yielded 928 junctions with a P < 0.001 between SF3Blmutand SF3B1WTUM. SF3B1 database

[0201] Our SF3B 1 database comprises 928 junctions and includes important information about the RNAseq analysis, the predicted HLA-binding peptides, and the expression in healthy tissues, among others.

[0202] Validation of SF3B1 database with an independent tumor cohort

[0203] As explained above, the SF3B1 database was built by comparing the RNAseq from 6 SF3B1WTand 7 SF3Blmutsamples and yielded 928 junctions differentially expressed. To validate the robustness of the SF3B1 database, the inventors applied the same bio-informatics pipeline to an independent cohort of 74 UM samples (58 SF3B1WTand 16 SF3Blmuttumors). The pipeline applied to the validation cohort detected 1021 junctions of which 905 junctions were shared between the two analyses (Figure 4). Discrepancies between the two analyses probably reflect junctions with a P around the threshold (0.001).

[0204] Neo-polypeptides validation by in vivo immunogenicity, cytotoxic assay and / or immunopeptidomics

[0205] “In vivo" validation

[0206] The inventors demonstrated the immunogenicity of SF3Blmut-related neo-polypeptides. From the RNAseq SF3B1 database they predicted the HLA-A*02:01 strong binders using NetMHCpan 4.0 and selected 43 peptides from the junctions with the higher ratio Log2 Fold Change (Mutated / WT). Then they used peptide-loaded HLA-A*02:01 tetramers to detect CD8+ T cells specific for them in the blood of UM patients with SF3Blmuttumors. In some of the patients the tetramer+ cells had a memory phenotype, indicating previous antigen encounter.

[0207] “Cytotoxicity” validation.

[0208] The inventors then selected and expanded CD8+ T cell clones from the blood of UM patients and from healthy controls. Some of these clones were able to specifically kill SF3BlmutUM cell lines (Figure 5).

[0209] To directly detect the neo-polypeptide transcribed, processed and presented on the cell surface by class I MHC, the inventors isolated the MHC -peptide complexes from the cell membranes of 7 SF3Blmutsamples (1 cell line, 1 tumor, 5 patient-derived xenografts). In collaboration with a mass spectrometry platform, they assessed the spectra of the recovered peptides. They generated a raw spectra database that was interrogated with the canonical protein database (Swissprot) and with their predicted neoantigenic peptide database (Figure 6A). This technique is not sensitive enough to detect all the peptides actually presented by class I MHC. Therefore, the failure in detecting one neo- polypeptide does not mean it is not presented. They were able to detect 6 neo-antigenic peptides with diverse HLA restrictions and corresponding to aberrant SF3Blmutsplicing. The whole list of 12 validated neoantigenic peptides is summarized in Figure 6B. The validation of each neo-polypeptide is then based on the detection of one neo-epitope of 9-10 amino acids, the detection of memory T cells in the patients and / or the capacity of T cell clones to specifically kill SF3Blmuttumor cells. The validation of a given neo-epitope allows the validation of the corresponding aberrant junction and tumor-specific neo-polypeptides.

[0210] Pipeline for the selection of tumor-specific neoantigenic peptides to put into the vaccine

[0211] Characterization of expression in healthy tissues (for exclusion)

[0212] If the aberrant junctions are expressed in other healthy tissues than the UM tumors, the reactive T cells are expected to be tolerated in the thymus and / or in the periphery. To investigate the expression of the junctions in a variety of control healthy tissues, a k-mer strategy was used: the RNAseq data of both UM RNAseq and GTEX (Genotype-Tissue Expression public resource) were fragmented in 31-mer nt sequences and aligned to the aberrant junction (intronic sequence) flanked by 24 nt exonic sequences. As threshold, we calculated the 10th percentile in the mutated samples. We considered that there was no significant expression if for a given tissue the 90th percentile was under the threshold. Then, we counted the number of tissues without junction expression. Testis was excluded because testis antigens are often expressed in tumors. The maximal number of negative tissues is 27. The results for N0215 (A3SS_hg38_0147) are depicted in Figure 7. This is an ideal case where the expression was only found in SF3BlmutUM tumors.

[0213] The majority of the junctions were expressed to some extent in healthy tissues (Figure 8). These junctions are not good candidates for the vaccine and were excluded. Surprisingly two peptides detected in immunopeptidomics were not specific for UM (peptides 11 and 79) and were also excluded. On the contrary, 18% (i.e n=171 / 928) junctions were not expressed in the 27 normal tissues tested. For the peptides 47, 26 and 37, we decided to keep the corresponding junctions as memory peptide specific T cells were found in patients with SF3B limit tumors and not in controls.

[0214] Ratio between aberrant and normal junction (PSI)

[0215] The oncogenic mutations in SF3B1 are change-of-function mutations with dominant activity. In the tumor cells, only one SF3B1 allele is mutated and the wild type SF3B1 protein maintains the normal function. Therefore, for each junction both aberrant and canonical mRNA are detected. Notably, mRNA produced by aberrant splicing and coding a premature STOP codon are targeted by nonsense mediated decay mechanism (NMD) and preferentially degraded.

[0216] PSI (Y) is the metric to measure the fraction of aberrant junction of the total junction (Figure 9A). PSI is calculated both in SF3B limit and SF3B1WT tumors (Figure 9B). In all the examples in Figure 9B the PSI of the aberrant junctions are higher in the SF3B limit than in SF3B1WT tumors. The PSI in wild-type samples is never exactly zero, there is a very low production of aberrant junction in WT samples around 0.001 (0.1% of total junction). Delta PSI (PSI WT-Mutated) in SF3Blmut dependent junctions is always negative. We established a threshold of delta PSI > -0.001 to exclude irrelevant junction as we consider that the alternative junction derived from mutation is poorly expressed.

[0217] Delta Psi is calculated from RNAseq data. First, the amounts of normally spliced mRNA and aberrantly spliced mRNA are measured in the SF3Blmutand SF3B1WTtumors. PSI is calculated in SF3Blmutand SB3B1WTtumors using the formula

[0218] PSI= RNA aberrant / (RNA aberrant + normal)

[0219] Delta PSI=PSI SF3Blmut- PSI SF3B I"1. Delta PSI is always negative.

[0220] Candidates without the difference between SF3Blmutand SFSBl"1are discarded.

[0221] Level of expression

[0222] Figure 10B shows the mRNA expression of 12 aberrant junctions in SF3Blmut tumors and Figure 10A the distribution of the mRNA expression in the 928 junctions. In order to exclude junctions with very low expression we set up a minimal threshold at 9. An expression with an expression lower than 9 signifies a normalized RNA expression by RNAseq of tumor cells.

[0223] Enrichment in HLA-binding peptides (sorting score)

[0224] With the aim of selecting the neo-polypeptides generating an important number of class-I HLA- binding peptides the inventors first calculated the possible 9-mer peptides (Figure 11).

[0225] Then they predicted using NetMHCpan 4.0 the binding of these peptides to the 7 more frequent class I HLA-A or HLA-B alleles. The predicted strong binders for each allele were summed and multiplied bythe frequency of the given allele to obtain the “Sum Allele weighted Percentage” (Figure 12A). To normalize to the neo-polypeptide size the inventors then divided by the number of possible peptides (Figure 11) to obtain the “Sorting Score”. This metrics reflects the enrichment in neoantigenic peptides predicted to bind to more frequent HLA-A and HLA-B alleles and takes into account the frequency of each allele in the population. Figure 12B shows some examples of Sorting Score calculation. Neo-polypeptide N1144 with 5 HLA strong binder predicted peptides has a sorting score of 17.67 while N0215 with only one strong binder had 1.09. In the global population of 928 alternative junctions the Sorting Score showed a distribution between 0 and of 17 (Figure 13). To enrich in neo- polypeptides generating several neo-peptides the inventors excluded the ones with a sorting score lower than 2.5.

[0226] Size of tumor-specific neoantigenic peptides The neoAg (neo-polypeptide) comprises the aberrant amino acids flanked by 8 canonical amino acids. The distribution of the neoAg sizes is shown in Figure 14. The neo-polypeptide size distribution peaks at around 24 amino acids. The neo-polypeptides >80aa were excluded as they probably represent unannotated alternative splicing events that may be present in normal tissues.

[0227] Selection of tumor-specific neo-antigenic peptides

[0228] To hierarchize the neoantigenic peptides for the vaccine, the inventors used the pipeline outlined in Figure 15. From the 928 alternative junctions detected in SF3Blmuttumors, they excluded those expressed in healthy tissues (n=757), those coding for peptides that were infrequently predicted to bind class I HLA alleles (n=87), those with low RNA expression (n=13), then checked the remaining junctions coded for neo-polypeptides shorter than 80 amino acids, then excluded the junctions whose expression was not very different between SF3B1WTand SF3Blmuttumors as shown by a delta PSI > -0.001 (n=2). Finally, they integrated some junctions (N1042, N0845, N0668, N0215) with good experimental validation that were excluded because of low sorting score or expression in one or few healthy tissues.

[0229] Therefore, this final selection includes the junctions that are the most expressed, coding for numerous HLA-binding peptides, coding for tumor-specific neoantigenic peptides smaller than 80 aa. These junctions were detected in two independent tumor cohorts (Figure 16A, B). They code for 191 class- I strong binder neo-epitopes for the most frequent class-I HLA alleles (Figure 16C). The mean tumorspecific neoantigenic polypeptide size is 24 and ranges between 13 and 74 amino acids (Figure 16D). The number of in-frame (n=39) and out-of-frame (n=34) junctions is equilibrated.

[0230] In vitro binding of the tumor-specific neoantigenic peptides disclosed herein and HLA molecules

[0231] Peptide-HLA binding tests were conducted to validate in silico predictions, as strong peptide-HLA binding is essential for antigen presentation on the surface of tumor cells, recognition by tumorantigen specific CD8+ T cells and tumor killing. We used algorithm NetMHCpan 4.0 to predict among our sequences which peptides would be able to be presented by the most frequent class I HLA allele HLA-A*02:01.

[0232] We synthetized the peptides and measured their binding to HLA binding using a flow cytometrybased assay (Figure 17). Peptides were incubated with HLA-A*02:01 monomers to allow the formation of the complex HLA-peptide-beta2microglobulin (b2m). Following incubation, stable complexes retained the folding and the association with the b2m whereas unstable complexes dissociated. Then complexes were stained using a fluorescent anti-b2m antibody. Fluorescence intensity was compared to a control CMV peptide with high HLA affinity. Results were expressed as percent of the control fluorescence. A peptide yielding at least 50% of control fluorescence was classified as binder and a peptide with less than 50% as not binder. 38 out of 61 sequences from list 1 encompassed a peptide with experimental validation of HLA-A*02:01 binding (Table 1). 6 out of 12 sequences from list 2 encompassed a peptide able to bind to HLA-A*02:01 allele. In addition, some of the sequences encompassed more than one HLA-A*02:01 binder peptide (not shown).

[0233]

[0234]

[0235] Table 5: HLA-A*02:01 binding results.

[0236] Table 6: SEP ID No. of each 9mer peptide sequence tested in the experiment

[0237] Citation List

[0238] Non-Patent Literature For any purpose, the following non-patent element(s) is (are) cited: Alsafadi, S., Houy, A., Battistella, A., Popova, T., Wassef, M., Henry, E., Tirode, F., Constantinou, A., Piperno-Neumann, S., Roman-Roman, S., Dutertre, M., Stern, M.-H., 2016. Cancer- associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. Nat. Commun. 7, 10615. https: / / doi.org / 10.1038 / ncommsl0615

[0239] Hasan, A.N., Selvakumar, A., O’Reilly, R.J., 2015. Artificial Antigen Presenting Cells: An Off the Shelf Approach for Generation of Desirable T-Cell Populations for Broad Application of Adoptive Immunotherapy. Adv. Genet. Eng. 4, 130.

[0240] Hellstrbm, K.E., Hellstrbm, I., 2002. Tumor Antigens, in: Bertino, J.R. (Ed.), Encyclopedia of Cancer (Second Edition). Academic Press, New York, pp. 459-466. https: / / doi.org / 10.1016 / B0-12- 227555-1 / 00251-3

[0241] Kim, J.V., Latouche, J.-B., Riviere, I., Sadelain, M., 2004. The ABCs of artificial antigen presentation. Nat. Biotechnol. 22, 403-410. https: / / doi.org / 10.1038 / nbt955

[0242] Menon, A.P., Moreno, B., Meraviglia-Crivelli, D., Nonatelli, F., Villanueva, H., Barainka, M., Zheleva, A., van Santen, H.M., Pastor, F., 2023. Modulating T Cell Responses by Targeting CD3. Cancers 15, 1189. https: / / doi.org / 10.3390 / cancersl5041189

[0243] Quesada, V., Conde, L., Villamor, N., Ordonez, G.R., Jares, P., Bassaganyas, L., Ramsay, A.J., Bea,

[0244] S., Pinyol, M., Martinez-Trillos, A., Lopez-Guerra, M., Colomer, D., Navarro, A., Baumann,

[0245] T., Aymerich, M., Rozman, M., Delgado, J., Gine, E., Hernandez, J.M., Gonzalez-Diaz, M., Puente, D.A., Velasco, G., Freije, J.M.P., Tubio, J.M.C., Royo, R., Gelpi, J.L., Orozco, M., Pisano, D.G., Zamora, J., Vazquez, M., Valencia, A., Himmelbauer, H., Bayes, M., Heath, S., Gut, M., Gut, I., Estivill, X., Lopez-Guillermo, A., Puente, X.S., Campo, E., Lopez-Otin, C., 2011. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat. Genet. 44, 47-52. https: / / doi.org / 10.1038 / ng.1032

[0246] Romee, R., Foley, B., Lenvik, T., Wang, Y., Zhang, B., Ankarlo, D., Luo, X., Cooley, S., Verneris, M., Walcheck, B., Miller, J., 2013. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease- 17 (ADAM17). Blood 121, 3599-3608. https: / / doi.org / 10.1182 / blood-2012-04-425397

[0247] Wang, C., Sun, W., Ye, Y., Bomba, H.N., Gu, Z., 2017. Bioengineering of Artificial Antigen Presenting Cells and Lymphoid Organs. Theranostics 7, 3504-3516. https: / / doi.org / 10.7150 / thno.19017

[0248] Xie, N., Shen, G., Gao, W., Huang, Z., Huang, C., Fu, L., 2023. Neoantigens: promising targets for cancer therapy. Signal Transduct. Target. Ther. 8, 1-38. https: / / doi.org / 10.1038 / s41392-022- 01270-x

[0249] Zarour, H.M., DeLeo, A., Finn, O.J., Storkus, W.J., 2003. Categories of Tumor Antigens, in: Holland- Frei Cancer Medicine. 6th Edition. BC Decker.

[0250] Zhou, Z., Gong, Q., Wang, Y., Li, M., Wang, L., Ding, H., Li, P., 2020. The biological function and clinical significance of SF3B1 mutations in cancer. Biomark. Res. 8, 38. https: / / doi.org / 10.1186 / s40364-020-00220-5

Claims

CLAIMS1. A tumor-specific neoantigenic peptide having an amino acid sequence set forth in any one disclosed in Table 1, in particular having an amino acid sequence set forth in SEQ ID NO. 21, SEQ ID NO. 27, SEQ ID No. 9, SEQ ID No. 12, SEQ ID No. 13, SEQ ID No. 2, SEQ ID No. 3, SEQ ID No. 5, SEQ ID No. 7, SEQ ID No. 8, SEQ ID No. 11, SEQ ID No. 14, SEQ ID No. 15, SEQ ID No. 16, SEQ ID No. 61, SEQ ID No. 18, SEQ ID No. 19, SEQ ID No. 20, SEQ ID No. 22, SEQ ID No. 24, SEQ ID No. 25, SEQ ID No. 26, SEQ ID No. 28, SEQ ID No. 29, SEQ ID No. 30, SEQ ID No. 32, SEQ ID No. 33, SEQ ID No. 35, SEQ ID No. 37, SEQ ID No. 38, SEQ ID No. 40, SEQ ID No. 42, SEQ ID No. 43, SEQ ID No. 45, SEQ ID No. 46, SEQ ID No. 47, SEQ ID No. 48, SEQ ID No. 49, SEQ ID No. 50, SEQ ID No. 51, SEQ ID No. 52, SEQ ID No. 53, SEQ ID No. 54, SEQ ID No. 56, SEQ ID No. 58, SEQ ID No. 59, SEQ ID No. 60, SEQ ID No. 1, SEQ ID No. 4, SEQ ID No. 6, SEQ ID No. 10, SEQ ID No. 17, SEQ ID No. 23, SEQ ID No. 31, SEQ ID No. 34, SEQ ID No. 36, SEQ ID No. 39, SEQ ID No. 41, SEQ ID No. 44, SEQ ID No. 55, or SEQ ID No. 57.

2. A tumor-specific neoantigenic peptide according to claim 1, which: a. specifically binds to a class I HLA allele, in particular a class I HLA-A allele, more particularly to HLA-A*02:01; b. has an expression over 1 read when the expression of RNA is normalized according to RNAseq within a tumor cell; c. has a size superior to 8 amino acid residues and lower than 80 amino acid residues, d. has an expression ratio (PSI) between SF3B1WTand SF3Blmuttumors superior to minus 0.001 PSI.

3. A tumor-specific neoantigenic peptide according to claim 1 or 2, which specifically binds to HLA-A4. A vaccinal or immunogenic composition comprising at least one tumor-specific neoantigenic peptide according to any one of claims 1 to 3.

5. The vaccine or immunogenic composition according to claim 4, further comprising at least a second neoantigenic peptide, said second neoantigenic peptide having an amino acid sequence set forth in any one of SEQ ID NO. 62 to SEQ ID No. 73.

6. The vaccine or immunogenic composition according to claim 4 or 5, which comprises a plurality of tumor-specific neoantigenic peptides according to claim 1 and / or a plurality of second neoantigenic peptides according to claim 3.

7. The vaccine or immunogenic composition according to any one of claims 4 to 6, which comprises a plurality of different tumor-specific neoantigenic peptides according to any one of claims 1 to 3, and wherein at least one copy of each different tumor-specific neoantigenic peptide having an amino acid sequence set forth in SEQ ID No. 1 to SEQ No. 61 is present.

8. The vaccine or immunogenic composition according to any one of claims 5 to 7, which comprises a plurality of different second neoantigenic peptides according to claim 5, and wherein at least one copy of each different second neoantigenic peptide having an amino acid sequence set forth in SEQ ID No. 62 to SEQ ID No. 73 is present.

9. The vaccine or immunogenic composition according to any one of claims 4 to 8, wherein the tumor-specific neoantigenic peptide and / or the second tumor-specific neoantigenic peptide is encoded from a transcript associated with an SF3B1 mutation present in an SF3B1 mutant tumor.

10. The vaccine or immunogenic composition according to claim 9, wherein the SF3B1 mutant tumor is issued or selected from uveal melanoma, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head & neck cancers, hodgkin’s lymphoma, leukemia, liver cancer, lung cancer, carcinoma, hepatocarcinoma, melanoma, mesothelioma, multiple myeloma myelodysplastic syndrome, non-hodgkin’s lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, endometrial cancer, rectal cancer, renal cancer, sarcoma, skin cancer, testicular cancer, thyroid cancer or uterine cancer, preferably wherein the SF3B1 mutant tumor is from uveal melanoma.

11. A population of dendritic cells or antigen-presenting cells (APCs) that have been pulsed with one or more tumor-specific neoantigenic peptides as defined in any one of claims 1 to 3 or the vaccine or immunogenic composition according to any one of claims 4 to 10, or transfected with a polynucleotide encoding one or more tumor-specific neoantigenic peptide as defined in any one of claims 1 to 3 or the vaccine or immunogenic composition according to any one of claims 4 to 10.

12. An antibody, an antigen-binding fragment thereof, a T cell receptor (TCR), or a chimeric antigen receptor (CAR), that specifically binds a tumor-specific neoantigenic peptide defined in any one of claims 1 to 3.

13. An antibody, an antigen-binding fragment thereof, a CAR or a TCR as defined according to claim 12, wherein said antibody, antigen-binding fragment thereof, CAR or T-cell receptor is a multispecific antibody or antigen-binding fragment thereof or multispecific CAR or multispecific receptor, that further targets at least an immune cell, an immune cell antigen or a tumor cell antigen, optionally wherein the immune cell is a T cell, an NK cell, or a dendritic cell, optionally wherein the immune cell antigen is CD3, CD16, CD30 or a TCR.

14. An immune cell that specifically binds to one or more tumor-specific neoantigenic peptides as defined in any one of claims 1 to 3 optionally wherein the immune cell is an allogenic or autologous cell selected from T cell, NK cell, CD4+ / CD8+, TILs / tumor-derived CD8 T cells, central memory CD8+ T cells, Treg, MAIT, and Y5 T cell.

15. A T cell according to claim 14, which comprises: a T cell receptor that specifically binds one or more tumor-specific neoantigenic peptides as defined in any one of claims 1 to 3, or a CAR that specifically binds one or more tumor-specific neoantigenic peptides as defined in any one of claims 1 to 3.

16. The tumor-specific neoantigenic peptide of any one of claims 1 to 3, the vaccine or immunogenic composition according to any one of claims 4 to 10, the population of dendritic cells or APCs of claim 11, the antibody, or an antigen-binding fragment thereof or T cell receptor (TCR) or chimeric antigen receptor (CAR) according to claim 12, the immune cell according to claim 14, or the T-cell according to claim 15, for use the treatment of cancer or the prevention of cancer or the relapse of cancer, in particular for use in inhibiting cancer cell proliferation, for reducing or inhibiting tumor growth, for reducing or preventing tumor metastasis, more particularly for treating cancer in a subject in need thereof or for use in cancer vaccination therapy of a subject, optionally wherein the subject is suffering from a cancer with SF3B1 mutant tumor cells, more particularly an uveal melanoma with SF3B1 mutant tumor cells, or wherein the patient is at risk of suffering from uveal melanoma with SF3B1 mutant tumor cells.

17. The tumor-specific neoantigenic peptide of any one of claims 1 to 3, the vaccine or immunogenic composition according to any one of claims 4 to 10, the population of dendritic cells or APCs of claim 11, the antibody, or an antigen-binding fragment thereof or T cell receptor (TCR) or chimeric antigen receptor (CAR) according to claim 12, the immune cell according to claim 14, or the T-cell according to claim 15, for use according to claim 16, for treating or preventing a cancer with SF3B1 mutant tumor cells, in particular wherein the cancer is uveal melanoma.

18. The tumor-specific neoantigenic peptide of any one of claims 1 to 3, the vaccine or immunogenic composition according to any one of claims 4 to 10, the population of dendritic cells or APCs of claim 11, the antibody, or an antigen-binding fragment thereof or T cell receptor (TCR) or chimeric antigen receptor (CAR) according to claim 12, the immune cell according to claim 14, or the T-cell according to claim 15, for use, in combination with at least one further therapeutic agent, optionally wherein the therapeutic agent is a chemotherapeutic agent of an immunotherapeutic agent.