Vaccine compositions and uses thereof

Abstract

The present invention generally relates to vaccine compositions and their use in methods of treating cancer, such as melanoma, in a subject. The vaccine composition comprises one or more nucleic acids encoding a plurality of tumour antigen T cell epitopes, wherein the T cell epitopes comprise GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), SVYDFFVWL (SEQ ID NO: 2) and WNRQLYPEWTEAQRLD (SEO ID NO: 3), and is administered to the subject in combination with (a) a programmed death-1 (PD-1) inhibitor such as nivolumab; and (b) a cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor, such as ipilimumab. The one or more nucleic acids may encode an antibody, comprising a heavy chain and a light chain, into which the T cell epitopes are inserted or substituted.

Description

[0001] VACCINE COMPOSITIONS AND USES THEREOF Field of the invention The present invention generally relates to vaccine compositions and their use in methods of treating cancer in a subject. Background Immunotherapy with checkpoint inhibitors (CPI), including programmed death 1 (PD-1) inhibitors given alone and in combination with cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors, has transformed first-line treatment outcomes in patients with unresectable or metastatic advanced melanoma (J.Larkin et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma N Engl J Med 2019; 381:1535-1546; Jedd D. Wolchok et al. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma Journal of Clinical Oncology 202240:2, 127-137). In the pivotal trial, Checkmate-067, the surrogate endpoints for survival such as overall response rate (ORR) and PFS at 3 years were 58% and 34% respectively (Errico, A. CheckMate 067—frontline nivolumab improves PFS alone or in combination with ipilimumab. Nat Rev Clin Oncol 12, 435 (2015)). In the real-world setting, the ORR that is achieved with the combination of Nivolumab and Ipilimumab is nearer to 50% (P. Serra-Bellver et al. Real-world outcomes with ipilimumab and nivolumab in advanced melanoma: a multicentre retrospective study European Journal of Cancer 176 (2022) 121e132) and some skilled in the art have reported 28% in the real-world setting (Parakh S, Randhawa M, Nguyen B, Warburton L, Hussain MA, Cebon J, Millward M, Yip D, Ali S. Real-world efficacy and toxicity of combined nivolumab and ipilimumab in patients with metastatic melanoma. Asia Pac J Clin Oncol. 2019 Feb;15(1):26-30). Recently, a nucleic acid therapeutic vaccine in melanoma showed efficacy in the unresectable stage of the disease in combination with pembrolizumab in delaying time to recurrence (L.J Albrecht et al., The Latest Option: Nivolumab and Relatlimab in Advanced Melanoma the Latest Option: Nivolumab and Relatlimab in Advanced Melanoma. Curr Oncol Rep 25, 647–657 (2023)). However, in the unresectable stage of the disease, nucleic acid vaccines have not shown a meaningful effect in reducing tumour burden. Summary of the invention In one aspect, the present invention provides a composition for use in a method of treating cancer in a subject, wherein the composition (i) is a vaccine composition comprising one or more nucleic acids encoding a plurality of tumour antigen T cell epitopes, wherein the T cell epitopes comprise GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), SVYDFFVWL (SEQ ID NO: 2) and WNRQLYPEWTEAQRLD (SEQ ID NO: 3), and wherein the method comprises administering the composition to the subject in combination with (a) a programmed death-1 (PD-1) inhibitor; and (b) a cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor; (ii) comprises a programmed death-1 (PD-1) inhibitor, and wherein the method comprises administering the PD-1 inhibitor to the subject in combination with (a) a vaccine composition comprising one or more nucleic acids encoding a plurality of tumour antigen T cell epitopes, wherein the T cell epitopes comprise GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), SVYDFFVWL (SEQ ID NO: 2) and WNRQLYPEWTEAQRLD (SEQ ID NO: 3); and (b) a cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor; or (iii) comprises a cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor, and wherein the method comprises administering the CTLA-4 inhibitor to the subject in combination with (a) a vaccine composition comprising one or more nucleic acids encoding a plurality of tumour antigen T cell epitopes, wherein the T cell epitopes comprise GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), SVYDFFVWL (SEQ ID NO: 2) and WNRQLYPEWTEAQRLD (SEQ ID NO: 3); and (b) a programmed death-1 (PD-1) inhibitor. In another aspect, the present invention provides a composition comprising one or more nucleic acids encoding a plurality of tumour antigen T cell epitopes, for use in a method of treating cancer in a subject, wherein the T cell epitopes comprise GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), SVYDFFVWL (SEQ ID NO: 2) and WNRQLYPEWTEAQRLD (SEQ ID NO: 3), and wherein the method comprises administering the composition to the subject in combination with (a) a programmed death-1 (PD-1) inhibitor; and (b) cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor. In another aspect, the present invention provides a composition comprising a programmed death-1 (PD-1) inhibitor, for use in a method of treating cancer in a subject, wherein the method comprises administering the PD-1 inhibitor to the subject in combination with (a) a vaccine composition comprising one or more nucleic acids encoding a plurality of tumour antigen T cell epitopes, wherein the T cell epitopes comprise GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), SVYDFFVWL (SEQ ID NO: 2) and WNRQLYPEWTEAQRLD (SEQ ID NO: 3); and (b) cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor. In another aspect, the present invention provides a composition comprising a cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor, for use in a method of treating cancer in a subject, wherein the method comprises administering the CTLA-4 inhibitor to the subject in combination with (a) a vaccine composition comprising one or more nucleic acids encoding a plurality of tumour antigen T cell epitopes, wherein the T cell epitopes comprise GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), SVYDFFVWL (SEQ ID NO: 2) and WNRQLYPEWTEAQRLD (SEQ ID NO: 3); and (b) programmed death-1 (PD-1) inhibitor. In another aspect, the present invention provides a method of treating cancer in a subject, wherein the method comprises administering a vaccine composition to the subject, wherein the vaccine comprises one or more nucleic acids encoding a plurality of tumour antigen T cell epitopes, wherein the T cell epitopes comprise GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), SVYDFFVWL (SEQ ID NO: 2) and WNRQLYPEWTEAQRLD (SEQ ID NO: 3) and wherein the vaccine composition is administered to the subject in combination with (a) a programmed death-1 (PD-1) inhibitor; and (b) cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor. The present invention is predicated, at least in part, on the present inventors’ surprising finding that patients with melanoma who were administered a nucleic acid (called “SCIB1”) encoding the three T cell epitopes GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), SVYDFFVWL (SEQ ID NO: 2) and WNRQLYPEWTEAQRLD (SEQ ID NO: 3), in combination with ipilimumab and nivolumab, unexpectedly had an overall response rate of 81.8%. This is far higher than the approximately 50% overall response rate reported previously for the combination of ipilimumab and nivolumab without the nucleic acid. In another aspect, the present invention provides a vaccine composition comprising a DNA molecule encoding an antibody, into which a plurality of tumour antigen T cell epitopes are inserted or substituted, for use in a method of treating unresectable stage III melanoma or stage IV melanoma in a subject, wherein the antibody comprises the T cell epitope of GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1) inserted or substituted in CDR-H1, the T cell epitope of SVYDFFVWL (SEQ ID NO: 2) inserted or substituted in CDR-H2, and the T cell epitope of WNRQLYPEWTEAQRLD (SEQ ID NO: 3) inserted or substituted in CDR-L1, wherein a first dose of the vaccine composition is administered to the subject at week 0 and then subsequent doses are administered during weeks 4, 7, 13, 25 and then every 12 weeks thereafter, and wherein the vaccine composition is administered intramuscularly in a total amount of DNA of about 8 mg per dose, wherein the vaccine composition is administered in combination with nivolumab and ipilimumab, wherein nivolumab is administered to the subject in a first phase of four doses of about 1 mg / kg every three weeks, followed by a second phase of doses of (i) about 240 mg every two weeks, wherein the first dose of the second phase is administered about three weeks after the fourth dose of the first phase; or (ii) about 480 mg every four weeks, wherein the first dose of the second phase is administered about six weeks after the fourth dose of the first phase, wherein ipilimumab is administered to the subject in four doses of about 3 mg / kg every three weeks and wherein each dose of ipilimumab is administered on the same day as each dose in the first phase of four doses of nivolumab, and wherein the first dose of ipilimumab and the first dose of nivolumab are administered about one week after the first dose of the vaccine composition. In another aspect, the present invention provides a method of treating unresectable stage III melanoma or stage IV melanoma in a subject wherein the method comprises administering a vaccine composition comprising a DNA molecule encoding an antibody, into which a plurality of tumour antigen T cell epitopes are inserted or substituted, to the subject, wherein the antibody comprises the T cell epitope of GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1) inserted or substituted in CDR-H1, the T cell epitope of SVYDFFVWL (SEQ ID NO: 2) inserted or substituted in CDR-H2, and the T cell epitope of WNRQLYPEWTEAQRLD (SEQ ID NO: 3) inserted or substituted in CDR-L1, wherein a first dose of the vaccine composition is administered to the subject at week 0 and then subsequent doses are administered during weeks 4, 7, 13, 25 and then every 12 weeks thereafter, and wherein the vaccine composition is administered intramuscularly in a total amount of DNA of about 8 mg per dose, wherein the vaccine composition is administered in combination with nivolumab and ipilimumab, wherein nivolumab is administered to the subject in a first phase of four doses of about 1 mg / kg every three weeks, followed by a second phase of doses of (i) about 240 mg every two weeks, wherein the first dose of the second phase is administered about three weeks after the fourth dose of the first phase; or (ii) about 480 mg every four weeks, wherein the first dose of the second phase is administered about six weeks after the fourth dose of the first phase, wherein ipilimumab is administered to the subject in four doses of about 3 mg / kg every three weeks and wherein each dose of ipilimumab is administered on the same day as each dose in the first phase of four doses of nivolumab, and wherein the first dose of ipilimumab and the first dose of nivolumab are administered about one week after the first dose of the vaccine composition. These and other aspects of the invention are described in further detail below. Features of each aspect of the invention are as for each of the other aspects mutatis mutandis, unless context requires otherwise. Detailed description of the invention As described above, the invention is predicated, in part, on positive interim data from the first stage in a Phase 2 trial called “SCOPE”, investigating “SCIB1” in combination with checkpoint inhibitors (CPIs), Ipilimumab and nivolumab, in advanced melanoma. Initial data from 11 patients showed an 82% objective response rate (ORR) to treatment. The Phase 2 SCOPE trial was designed to determine if the ORR in patients with unresectable metastatic melanoma could be improved by SCIB1 in combination with CPIs. The concept is that the vaccine induces new, or boosts existing, immune responses which are subsequently protected in the tumour environment by the CPIs. During the first stage of the SCOPE trial patients received SCIB1 via a needle-free device in combination with the most efficacious treatment currently available, namely the CPIs nivolumab and ipilimumab. The first milestone in the SCOPE trial was to achieve responses in more than 8 out of 15 patients which would suggest that SCIB1 in combination with doublet CPI therapy might meaningfully improve current outcomes for these patients. 16 stage IV metastatic patients had received this combination. To date, 11 of these study patients have reached 13 weeks and been evaluated at radiological imaging and nine have already shown an objective response, equating to an ORR of 82% with no increase in toxicity. At this time point, the reduction in tumour volume was 31%-94%. Four patients reaching the 25 weeks imaging evaluation and two reaching the 37 weeks evaluation have shown a 69%-94% and a 87%-94% reduction in total tumour burden, respectively. This is significantly better than an ORR of 50% reported in patients just receiving this doublet CPI therapy (without SCIB1) in the real world setting with a progression free survival time of 11.5 months. Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in immunology, molecular biology, cancer therapy, and / or biochemistry). Unless otherwise indicated, the techniques utilized in the present invention are standard procedures, well known to those skilled in the art. Such techniques are described and explained throughout the literature in sources such as, J. Perbal, A Practical Guide to Molecular Cloning, John Wiley and Sons (1984), J. Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbour Laboratory Press (1989), T.A. Brown (editor), Essential Molecular Biology: A Practical Approach, Volumes 1 and 2, IRL Press (1991), D.M. Glover and B.D. Hames (editors), DNA Cloning: A Practical Approach, Volumes 1-4, IRL Press (1995 and 1996), and F.M. Ausubel et al., (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley - Interscience (1988, including all updates until present), Ed Harlow and David Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbour Laboratory, (1988), and J.E. Coligan et al., (editors) Current Protocols in Immunology, John Wiley & Sons (including all updates until present). As used herein, the term “about”, unless stated to the contrary, includes + / - 10%, more preferably + / - 5%, of the designated value. Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. In one aspect, the present invention relates to a vaccine composition for use in a method of treating cancer in a subject. The term “vaccine composition” refers to a composition that is capable of promoting an immune response, preferably a CD8+ and / or CD4+ T cell response. The vaccine composition for use in the invention comprises one or more nucleic acids that encode the following tumour antigen T cell epitopes: GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), SVYDFFVWL (SEQ ID NO: 2) and WNRQLYPEWTEAQRLD (SEQ ID NO: 3). The term “T cell epitope” refers to a peptide comprising an amino acid sequence that is capable of being recognised by a T cell (preferably a CD8+ or CD4+ T cell), when the amino acid sequence is presented by major histocompatibility complex (MHC). As used herein, the term “T cell epitope” encompasses a peptide that may comprise multiple different shorter amino acid sequences recognised by T cells within the whole peptide sequence. However, the term “T cell epitope” does not include larger polypeptide sequences, for example sequences greater than 40 amino acids. For example, the “T cell epitope” of GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), contains at least three confirmed epitope sequences within its whole peptide sequence, as shown in the table below. Source antigen Epitope sequence HLA / DR HLA Frequency REFERENCE Amino Acid coordinates (% population) gp100 GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1) 173-190 (Accession No. MLGTHTMEV (178-186) (SEQ ID NO: 21) A2 44 Tsai, 1997 NP_008859) TGRAMLGTHTMEVTVYH (174-190) (SEQ ID DR7 25 Lapointe, 2001 NO: 22) GRAMLGTHTMEVTVY (175-189) (SEQ ID NO: DR53 / DQ6 49 / 63 Kobayashi, 2001 23) TRP2 SVYDFFVWL (SEQ ID NO: 2) A2 44 Parkhurst, 1998 180-188 (Accession No. NP_001123361) gp100 WNRQLYPEWTEAQRLD (SEQ ID NO: 3) DR4 24 Touloukian, 2000 44-59 References in the table above are provided below: Tsai V, Southwood S, Sidney J, Sakaguchi K, Kawakami Y, Appella E, Sette A, Celis E. Identification of subdominant CTL epitopes of the GP100 melanoma-associated tumor antigen by primary in vitro immunization with peptide-pulsed dendritic cells. J Immunol.1997 Feb 15;158(4):1796- 802. PMID: 9029118. Lapointe R, Royal RE, Reeves ME, Altomare I, Robbins PF, Hwu P. Retrovirally transduced human dendritic cells can generate T cells recognizing multiple MHC class I and class II epitopes from the melanoma antigen glycoprotein 100. J Immunol. 2001 Oct 15;167(8):4758-64. doi: 10.4049 / jimmunol.167.8.4758. PMID: 11591807. Kobayashi H, Lu J, Celis E. Identification of helper T-cell epitopes that encompass or lie proximal to cytotoxic T-cell epitopes in the gp100 melanoma tumor antigen. Cancer Res. 2001 Oct 15;61(20):7577-84. PMID: 11606397. Parkhurst MR, Fitzgerald EB, Southwood S, Sette A, Rosenberg SA, Kawakami Y. Identification of a shared HLA-A*0201-restricted T-cell epitope from the melanoma antigen tyrosinase-related protein 2 (TRP2). Cancer Res.1998 Nov 1;58(21):4895-901. PMID: 9809996. Touloukian CE, Leitner WW, Topalian SL, Li YF, Robbins PF, Rosenberg SA, Restifo NP. Identification of a MHC class II-restricted human gp100 epitope using DR4-IE transgenic mice. J Immunol. 2000 Apr 1;164(7):3535-42. doi: 10.4049 / jimmunol.164.7.3535. PMID: 10725708; PMCID: PMC2241739. The nucleic acid(s) is / are administered to the subject in a vaccine composition to be taken up by cells such that the T cell epitopes can be expressed and presented to T cells in the subject. The T cell epitopes can be encoded by multiple different nucleic acids, e.g., two or three nucleic acid molecules in total, or preferably are all encoded in a single nucleic acid molecule. Thus the term “nucleic acid” is used herein to refer to a nucleic acid molecule which has a polynucleotide sequence. For example, the vaccine composition may comprise a single nucleic acid molecule comprising polynucleotide sequences encoding the three T cell epitopes. The nucleic acid(s) may be DNA, cDNA, or RNA such as mRNA, e.g., obtained by cloning or produced wholly or partly by chemical synthesis. Preferably, the nucleic acid is DNA. For therapeutic use, the nucleic acid is preferably in a form capable of being expressed in the subject to be treated. The nucleic acid may be recombinant or provided as an isolate, in isolated and / or purified form. It may be free or substantially free of nucleic acid flanking the gene(s) encoding the T cell epitopes, except possibly one or more regulatory sequence(s) for expression. Where nucleic acid includes RNA, reference to the sequences shown herein should be construed as reference to the RNA equivalent, with U substituted for T. Suitable nucleic acids can be readily prepared by the skilled person, for example using the information and references contained herein and techniques known in the art (for example, see Sambrook, Fritsch and Maniatis, “Molecular Cloning”, A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1989, and Ausubel et al, Short Protocols in Molecular Biology, John Wiley and Sons, 1992), given the nucleic acid sequences and clones available. These techniques include (i) the use of the polymerase chain reaction (PCR) to amplify samples of such nucleic acid, e.g. from genomic sources, (ii) chemical synthesis, or (iii) preparing cDNA sequences. DNA encoding the polypeptide may be generated and used in any suitable way known to those of skill in the art, including by taking encoding DNA, identifying suitable restriction enzyme recognition sites either side of the portion to be expressed, and cutting out said portion from the DNA. The portion may then be operably linked to a suitable promoter in a standard commercially available expression system. Another recombinant approach is to amplify the relevant portion of the DNA with suitable PCR primers. Modifications to the sequences can be made, e.g. using site directed mutagenesis, to lead to the expression of modified peptide or to take account of codon preferences in the host cells used to express the nucleic acid. In order to obtain expression of the nucleic acid sequences, the sequences can be incorporated into a vector having one or more control sequences (e.g., a promoter) operably linked to the sequence(s) encoding the T cell epitopes to control its expression. The vectors may include other sequences such as promoters or enhancers to drive the expression of the nucleic acid sequences. The nucleic acid may encode secretion signals (also referred to herein as “leader sequence”) so that the T cell epitopes produced in the host cell are secreted from the cell. A preferred leader sequence comprises the amino acid sequence provided in SEQ ID NO: 16. The promoters may be non-specific (promoters that are active regardless of the cellular environment) and / or constitutive promoters, which do not require certain cell types or tissue types to drive expression of the T cell epitopes or a polypeptide comprising the T cell epitopes. The promoter may be a CMV-IE promoter, preferably a promoter comprising the nucleotide sequence provided in SEQ ID NO: 15, or a functional variant thereof. If desired, polypeptides encoded by the nucleic acid(s) can be obtained by transforming the vectors into host cells in which the vector is functional, culturing the host cells so that the polypeptide is produced and recovering the polypeptide from the host cells or the surrounding medium. Prokaryotic and eukaryotic cells are used for this purpose in the art, including strains of E. coli, yeast, and eukaryotic cells such as insect cells, and animal cells, for example, COS, CHO cells, Bowes Melanoma and other suitable human cells. Where the present invention relates to nucleic acid(s) encoding the heavy and light chains of an antibody, the respective nucleic acids may be present in the same expression vector, driven by the same or different promoters, or in separate expression vectors. Preferably, the heavy and light chain sequences of the antibody are encoded in the same nucleic acid (e.g., vector) driven by separate promoters. The nucleic acids are used to stimulate an immune response against the T cell epitopes in a patient such as a mammal, including human. Helper and / or cytotoxic T cell responses may be stimulated. The T cell response against a particular epitope may have a higher avidity than that obtained by immunisation with the same epitope as a simple peptide, or by immunisation with the same epitope encoded within an antigen either as a peptide or a nucleic acid. The nucleic acids may be administered as a combination therapy, i.e. a nucleic acid encoding the light chain and nucleic acid encoding the heavy chain. The nucleic acid may be administered intravenously, intradermally, intramuscularly, orally or by other routes. Intradermal or intramuscular administration is particularly suitable because these tissues contain dendritic cells. Preferably, the vaccine composition comprising the nucleic acid(s) is administered intramuscularly. Preferably the vaccine composition is administered via needle-free injection. The nucleic acid(s) may be a vector. Vectors may be used for expression of the T cell epitopes encoded by the nucleic acid. The nucleic acid(s) may be DNA molecule(s). For example, the nucleic acid(s) may be DNA vector(s). Preferably, the nucleic acid is a DNA plasmid. Preferably a single DNA plasmid encodes all of the T cell epitopes. Alternatively, the nucleic acid may be a doggybone vector. The nucleic acid or vector may be employed in combination with a pharmaceutically acceptable carrier or carriers. Such carriers may include, but are not limited to, saline, buffered saline, dextrose, liposomes, water, glycerol, ethanol and combinations thereof. The nucleic acids and / or vectors useful in the invention can be formulated in pharmaceutical compositions. These compositions may comprise, in addition to one or more of the above substances, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material may depend on the route of administration, e.g. intradermal, oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes. The formulation is preferably nucleic acid as a stable dry powder precipitated onto the surface of microscopic gold particles and suitable for injection via a gene gun or a solution of DNA mixed with GET peptides. The formulation may be suitable for intradermal or intramuscular administration using electroporation. The formulation may be suitable for administration using needle- free injection. The compositions described herein are preferably administered to an individual in a “therapeutically effective amount”, this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. The nucleic acids of the invention are particularly relevant to the treatment of existing cancer and in the prevention of the recurrence of cancer after initial treatment or surgery. Examples of the techniques and protocols mentioned above can be found in Remington’s Pharmaceutical Sciences, 16th edition, Oslo, A. (ed), 1980. Preferably, the nucleic acid stimulates helper and / or cytotoxic T cells that can kill tumour when administered to a human in an effective amount. The optimal dose can be determined by physicians based on a number of parameters including, for example, age, sex, weight, severity of the condition being treated, the active ingredient being administered and the route of administration. For example, a dose of 1-10,000 ug of DNA may be sufficient to stimulate both helper and cytotoxic T cell responses. The vaccine composition described herein is administered in combination with a programmed death-1 (PD-1) inhibitor; and a cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor. These may be administered either simultaneously or sequentially dependent upon the condition to be treated. They may also be administered in combination with other treatments. Other cancer treatments include other monoclonal antibodies, other chemotherapeutic agents, other radiotherapy techniques or other immunotherapy known in the art. The dose of nucleic acid will be dependent upon the properties of the agent employed, e.g. its binding activity and in vivo plasma half-life, the concentration of the nucleic acid in the formulation, the administration route, the site and rate of dosage, the clinical tolerance of the patient involved, the pathological condition afflicting the patient and the like, as is well within the skill of the physician. Different dosages may be utilised during a series of sequential inoculations; the practitioner may administer an initial inoculation and then boost with relatively smaller doses of nucleic acid. The vaccine composition may be administered in a total amount of nucleic acid in the range of 1 to 20 mg, 5 to 15 mg, or 6 to 10 mg per dose. The vaccine composition may be administered to the subject in a total amount of nucleic acid of about 8 mg per dose. Preferably, the vaccine composition is administered to the subject in a total amount of nucleic acid of 8 mg per dose. The term “dose” refers to the total quantity of active ingredient administered to the subject, which may be administered in multiple separate injections, for example. For example, the dose of 8 mg may be administered as four separate 2 mg injections at separate injection sites. Timing of dosing the vaccine composition can be determined by one skilled in the art. Preferably, a first dose of the vaccine composition is administered to the subject at week 0 and then subsequent doses are administered during weeks 4, 7, 13, 25 and then every 12 weeks thereafter. Herein, “week 0” refers to the week in which the subject receives the first dose. Similarly, “week 4” refers to a time which is about four weeks later than week 0, and so forth. Even more preferably, a first dose of the vaccine composition is administered to the subject on day 1 and then subsequent doses are administered on days 29, 50, 92, 176 and then every 84 days thereafter. In this context “day 1” refers to the day on which the subject receives the first dose and “day 29” refers to a time which is 28 days (i.e., four weeks) later, and so forth. Preferably, the vaccine composition is administered to the subject in accordance with the dosing schedule described for “SCIB1” in the clinical trial protocol provided herein as Example 3 (the “SCOPE” trial). The nucleic acid may be introduced into a host cell. The introduction, which may (particularly for in vitro introduction) be generally referred to without limitation as “transformation”, may employ any available technique. For eukaryotic cells, suitable techniques may include calcium phosphate transfection, DEAE-Dextran, electroporation, liposome-mediated transfection and transduction using retrovirus or other virus, e.g. vaccinia or, for insect cells, baculovirus. For bacterial cells, suitable techniques may include calcium chloride transformation, electroporation and transfection using bacteriophage. As an alternative, direct injection of the nucleic acid could be employed. Marker genes such as antibiotic resistance or sensitivity genes may be used in identifying clones containing nucleic acid of interest, as is well known in the art. The introduction may be followed by causing or allowing expression from the nucleic acid, e.g. by culturing host cells (which may include cells actually transformed although more likely the cells will be descendants of the transformed cells) under conditions for expression of the gene, so that the encoded polypeptide (or peptide) is produced. If the polypeptide is expressed coupled to an appropriate signal leader peptide it may be secreted from the cell into the culture medium. Following production by expression, a polypeptide or peptide may be isolated and / or purified from the host cell and / or culture medium, as the case may be, and subsequently used as desired, e.g. in the formulation of a composition which may include one or more additional components, such as a pharmaceutical composition which includes one or more pharmaceutically acceptable excipients, vehicles or carriers (e.g. see below). The pharmaceutical composition may comprise, in addition to active ingredient, pharmaceutically acceptable excipient, diluent, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g., intradermal or intramuscular. It is envisaged that injections will be the primary route for therapeutic administration of the compositions, although delivery through a catheter or other surgical tubing is also used. Some suitable routes of administration include intravenous, subcutaneous, intraperitoneal and intramuscular administration. Liquid formulations may be utilised after reconstitution from powder formulations. A preferred route of administration is intramuscular administration, e.g., by needle-free injection. The nucleic acid, vector, peptide and / or vaccine of the invention may be administered to the subject using needle-free injection. As will be known by those skilled in the art, needle-free injectors (also known as “jet injectors”) use a narrow, high-pressure stream of liquid that penetrates the outermost layer of the skin (stratum corneum) to deliver a composition to underlying tissues of the epidermis or dermis (i.e., intradermal injection), fat (i.e., subcutaneous injection), or muscle (i.e., intramuscular injection). For intravenous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilisers, buffers, antioxidants and / or other additives may be included, as required. Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may comprise a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. Where the formulation is a liquid it may be for example, a physiologic salt solution containing non phosphate buffer at pH 6.87.6, or a lyophilised powder. The vaccine composition may comprise a concentration of about 4 mg / mL nucleic acid. The vaccine composition may comprise disodium hydrogen phosphate in an amount of about 8.1 mM, potassium dihydrogen phosphate in an amount of about 1.5^mM, potassium chloride in an amount of about 2.7^mM, and sodium chloride in an amount of about 137 mM, and wherein the vaccine composition has a pH^of about 7.4. The vaccine composition may comprise the nucleic acid in Dulbecco’s phosphate buffered saline, without calcium or magnesium. Nucleic acids encoding the T cell epitopes can be administered to the patient using any of a number of methods known in the art. For instance, the nucleic acid can be delivered directly, as “naked DNA”. This approach is described, for instance, in Wolff et al., Science 247: 1465-1468 (1990) as well as U.S. Patent Nos. 5,580,859 and 5,589,466. The nucleic acids can also be administered using ballistic delivery as described, for instance, in U.S. Patent No. 5,204,253. Particles comprised solely of DNA can be administered. Alternatively, DNA can be adhered to particles, such as gold particles. Generally, a plasmid for a vaccine or immunological composition can comprise DNA encoding an antigen (e.g., one or more neoantigens) operatively linked to regulatory sequences which control expression or expression and secretion of the antigen from a host cell, e.g., a mammalian cell; for instance, from upstream to downstream, DNA for a promoter, such as a mammalian virus promoter (e.g., a CMV promoter such as an hCMV or mCMV promoter, e.g., an early-intermediate promoter, or an SV40 promoter— see documents cited or incorporated herein for useful promoters), DNA for a eukaryotic leader peptide for secretion (e.g., tissue plasminogen activator), DNA for the neoantigen(s), and DNA encoding a terminator (e.g., the 3' UTR transcriptional terminator from the gene encoding Bovine Growth Hormone or bGH polyA). A composition can contain more than one plasmid or vector, whereby each vector contains and expresses a different T cell epitope, but preferably all epitopes are encoded by a single nucleic acid (e.g., vector). Mention is also made of Wasmoen U.S. Pat. No.5,849,303, and Dale U.S. Pat. No. 5,811,104. DNA or DNA plasmid formulations can be formulated with or inside cationic lipids; and, as to cationic lipids, as well as adjuvants, mention is also made of Loosmore U.S. Patent Application 2003 / 0104008. Also, teachings in Audonnet U.S. Pat. Nos.6,228,846 and 6,159,477 may be relied upon for DNA plasmid teachings that can be employed in constructing and using DNA plasmids that contain and express in vivo sequences encoding the T cell epitopes. The nucleic acids can also be delivered complexed to cationic compounds, such as cationic lipids. Lipid- mediated gene delivery methods are described, for instance, in WO 1996 / 18372; WO 1993 / 24640; Mannino & Gould-Fogerite, BioTechniques 6(7): 682-691 (1988); U.S. Patent No. 5,279,833; WO 1991 / 06309; and Feigner et ak, Proc. Natl. Acad. Sci. USA 84: 7413-7414 (1987). RNA encoding the peptide of interest (e.g., mRNA) can also be used for delivery (see, e.g., Kiken et al, 2011; Su et al, 2011; see also US 8278036; Halabi et al. J Clin Oncol (2003) 21 : 1232-1237; Petsch et al, Nature Biotechnology 2012 Dec 7;30(12): 1210-6). The nucleic acids may administered as part of a viral vectors, such as a adenovirus, lentivirus or AAV vector or any other viral vector known in the art. The composition may also be administered via microspheres, liposomes, other microparticulate delivery systems or sustained release formulations placed in certain tissues including blood. Suitable examples of sustained release carriers include semi-permeable polymer matrices in the form of shared articles, e.g., suppositories or microcapsules. Implantable or microcapsular sustained release matrices include polylactides (US Patent No.3, 773, 919; EP A 0058481) copolymers of L glutamic acid and gamma ethyl L glutamate, poly (2 hydroxyethyl methacrylate). Liposomes containing the polypeptides are prepared by well known methods:; EP A 0052522; EP A 0036676; EP A 0088046; EP A 0143949; EP A 0142541; JP A 8311808; US Patent Nos 4,485,045 and 4,544,545. Ordinarily, the liposomes are of the small (about 200800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. % cholesterol, the selected proportion being adjusted for the optimal rate of the polypeptide leakage. The composition may be administered in a localised manner to a tumour site or other desired site or may be delivered in a manner in which it targets tumour or other cells. The present invention also relates to use of constructs in the form of plasmids, vectors, transcription or expression cassettes which comprise the nucleic acid(s) as described above. The present invention also provides a recombinant host cell which comprises one or more constructs as above. Systems for cloning and creating suitable constructs in a variety of different host cells are well known. Suitable host cells include bacteria, mammalian cells, yeast and baculovirus systems. Suitable vectors can be chosen or constructed, containing appropriate regulatory sequences, including promoter sequences, terminator sequences, polyadenylation sequences, enhancer sequences, marker genes and other sequences as appropriate. Vectors may be plasmids, viral e.g., 'phage, or phagemid, as appropriate. Many known techniques and protocols for manipulation of nucleic acid, for example in preparation of nucleic acid constructs, mutagenesis, sequencing, introduction of DNA into cells and gene expression, and analysis of proteins, are described in detail in Ausubel et al. , 1992. The nucleic acid may be introduced into a host cell. The introduction may employ any available technique. For eukaryotic cells, suitable techniques may include calcium phosphate transfection, DEAE Dextran, electroporation, liposome mediated transfection and transduction using retrovirus or other virus, e.g., vaccinia or, for insect cells, baculovirus. For bacterial cells, suitable techniques may include calcium chloride transformation, electroporation and transfection using bacteriophage. The introduction may be followed by causing or allowing expression from the nucleic acid, e.g., by culturing host cells under conditions for expression of the gene. In one embodiment, the nucleic acid of the invention is integrated into the genome (e.g., chromosome) of the host cell. Integration may be promoted by inclusion of sequences which promote recombination with the genome, in accordance with standard techniques. The present invention also provides a method which comprises using a construct as stated above in an expression system in order to express the T cell epitope(s) above. The one or more nucleic acids in the vaccine composition may encode an antibody, comprising a heavy chain and a light chain, into which the T cell epitopes are inserted or substituted. In this regard, the T cell epitopes are heterologous to the antibody. The terms “insertion or substitution” do not require physical cloning steps of replacing sequences. These terms are merely used to identify that the T cell epitope sequences are present in the antibody sequence in a heterologous manner. Such antibodies having been engineered to contain heterologous T cell epitopes for use in stimulating an immune response may be referred to in the art as an “immunobody”. Suitable antibodies are described in WO 2008 / 116937, which is incorporated herein by reference. A suitable antibody which may be encoded by the nucleic acid(s) in the vaccine composition is the antibody referred to as “DCIB68” in WO 2008 / 116937. The antibody comprises a heavy chain and light chain, each of which preferably comprise a variable and a constant region. Suitable antibody sequences and the structures and locations of immunoglobulin domains therein are well known in the art and may be determined with reference to Throughout the specification the residue numbering refers to the standardised IMGT system for the numbering of antibody sequences, as disclosed in Lefranc et al., 2009. Other suitable numbering systems are known to the skilled person. The antibody may be monoclonal or polyclonal and may be IgA, IgD, IgE, IgG or IgM, although IgG is preferred. The IgG antibody may be any IgG subclass, such as human IgG1, IgG2, IgG3 or IgG4, or mouse IgG1, IgG2a, IgG2b or IgG3. The IgG antibody is preferably a human IgG1 antibody. The antibody may have the constant region of a human antibody, and the variable or hypervariable region of a mouse or human monoclonal antibody into which the T cell epitopes have been inserted. The variable region other than the hypervariable region may also be derived from the variable region of a human antibody. Such an antibody is said to be humanised. Methods for making humanised antibodies are known in the art. Methods are described, for example, in Winter, U.S. Patent No.5,225,539. The variable region of the antibody outside of the mouse hypervariable region may also be derived from a mouse monoclonal antibody. In such case, the entire variable region is derived from murine monoclonal antibody and the antibody is said to be chimerised. Methods for making chimerised antibodies are known in the art. Such methods include, for example, those described in U.S. patents by Boss (Celltech) and by Cabilly (Genentech). See also U.S. Patent Nos. 4,816,397 and 4,816,567, respectively. The nucleic acid of certain aspects of the invention is such that the heavy chain, light chain or antibody expressed therefrom has at least one heterologous T cell epitope therein so that the heavy chain, light chain or the immunoglobulin molecule may not take its native conformation. The T cell epitope may disrupt the expressed protein so that the heavy chain or the immunoglobulin molecule can no longer bind to its antigen, so that the heavy and light chains (where present) can no longer associate, or so that the heavy chain or immunoglobulin molecule cannot be secreted properly, for example. The disruption may be in the tertiary structure of the immunoglobulin molecule which may prevent formation of the disulphide bonds. The T cell epitope(s) may be inserted into or substituted for the CDR regions of the antibody. CDR1 and CDR2 form part of the antibody beta sheet conformation and are partially submerged within the folded molecule. Any change to their length, amino acid composition or charge may disrupt this structure and prevent heavy and light chain folding and association. CDRH3 is exposed on the surface of the immunoglobulin molecule and is therefore more permissive of alterations. In the present invention, it is preferred if at least CDR1 and / or CDR2 are substituted with T cell epitope(s). Indeed, in certain embodiments, loss of framework regions at the CDRH junctions completely disrupts antibody folding yet insertion of epitopes in these regions gives good T cell responses. Incorporation of any epitope within the CDRH1 (5 amino acids in length) or CDRH2 (17 amino acids in length) causes sufficient disruption to allows secretion of heavy chain but only very low amounts of intact antibody, even if the light chain has its native sequence. This shows that the secondary structure is important for heavy and light chain pairing. Incorporation of any epitope within CDRL1 of the light chain results in low level secretion of light chain, even if there is only a single epitope incorporated into the CDRH3 of the heavy chain. “Heterologous T cell epitope” is intended to mean a T cell epitope which is heterologous to the antibody. For example, a heterologous T cell epitope may be one which was not previously present in the antibody. The heterologous T cell epitope may be inserted as a whole, although it may be made up from an inserted amino acid sequence, together with flanking amino acids of the second portion. This is to ensure that the inserted epitope has a similar processing profile in the heterologous nucleic as from the original antigen. One or more CTL / helper epitopes can be inserted within the same variable region. The T cell epitope(s) can be inserted anywhere in the heavy chain or light chain. It is preferred if the or each epitope is inserted in the variable region of the heavy chain and / or light chain, although nucleic acids encoding heavy chains or antibodies having T cell epitopes inserted in just the constant region, or in the constant region and the variable region of a heavy chain and / or light chain are included within the invention. In the nucleic acids of the present invention, the sequence(s) encoding the T cell epitopes may be inserted into (i.e. added to) the sequence encoding the heavy chain and / or light chain, or may be substituted into the sequence encoding the heavy chain and / or light chain. In the variable region, the T cell epitope(s) may be inserted in, or substituted for, any one or more the CDRs of the heavy and / or light chain, i.e. L1, L2, L3, H1, H2, or H3. Of these, L1, H1 and H2 are currently preferred. In certain embodiments, the T cell epitopes are inserted in, or substituted for, CDRL1 and / or H1 and / or H2. Preferably the incorporated T cell epitopes are not of similar size and charge to the amino acids of the original CDR of the antibody so that the antibody does not take its native conformation, e.g. does not fold and is not secreted correctly. Alternatively or additionally, they may be inserted in, or substituted for, the framework region surrounding the CDRs. The epitopes may inserted using complementary oligonucleotides that encode the antigenic epitopes, which are annealed and cloned into specific sites of the antibody framework where CDR’s (or other region) have been replaced with unique restriction enzyme sites. The ability of the recombinant antibody to stimulate helper and cytotoxic T cell responses can be screened as exemplified herein. Various combinations are possible within the present invention. In certain embodiments, one or a plurality of CD8 epitopes is / are inserted in, and / or substituted for, the CDR H1 and / or H2, or in the non- CDR variable region, of the heavy chain or the antibody. Additionally or alternatively, one or a plurality of CD4 epitopes may be inserted in, and / or substituted for, the CDR L1, or in the non-CDR variable region, of the light chain or the antibody. Where there is a plurality of T cell epitopes, the T cell epitopes may be the same or different. Those of skill in the art will appreciate that numerous combinations are possible, including: • a CD8 epitope in CDR H1, and a CD4 epitope in CDR L1; • a CD8 epitope in CDR H2, and a CD4 epitope in CDR L1; • a CD8 epitope in CDR H1 and CDR H2, and a CD4 epitope in CDR L1; • 2 CD8 epitopes in CDR H1, and a CD4 epitope in CDR L1; • 2 CD8 epitopes in CDR H2, and a CD4 epitope in CDR L1; etc Nucleic acids of the present invention can incorporate multiple T cell epitopes from a single target antigen that can bind to the majority of both class I and class II MHC molecules. This may create a vaccine that can be used in widespread population vaccination. Alternatively nucleic acids useful in the invention can incorporate multiple T cell epitopes from multiple target antigens that can bind to the most common class I and class II phenotypes. This may create a vaccine that may prevent selection of antigen loss variants. Target antigens may be from a single pathogen or tumour type or may be selected to give an immune response against a variety of pathogens or cancers. Nucleic acids useful in the present invention targeting specific common HLA phenotypes may incorporate numerous T cell epitopes from a wide variety of cancers and / or pathogens, providing a single vaccine to prevent disease. The antibody encoded by the nucleic acid(s) in the vaccine composition may comprise: (i) the T cell epitope of GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1) in CDR-H1; (ii) the T cell epitope of SVYDFFVWL (SEQ ID NO: 2) in CDR-H2; and (iii) the T cell epitope of WNRQLYPEWTEAQRLD (SEQ ID NO: 3) in CDR-L1. Preferably, the antibody comprises: (i) the T cell epitope of GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1) in each of CDR-H1 and CDR-L3; (ii) the T cell epitope of SVYDFFVWL (SEQ ID NO: 2) in CDR-H2; and (iii) the T cell epitope of WNRQLYPEWTEAQRLD (SEQ ID NO: 3) in each of CDR-H3 and CDR-L1. An alternative preferred antibody comprises: (i) the T cell epitope of GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1) in CDR-H1; (ii) the T cell epitope of SVYDFFVWL (SEQ ID NO: 2) in CDR-H2; (iii) the T cell epitope of VPLDCVLYRYGSFSVTLDIVQG (SEQ ID NO: 4) in CDR-H3; (iii) the T cell epitope of WNRQLYPEWTEAQRLD (SEQ ID NO: 3) in CDR-L1; (iv) the T cell epitope of ANCSVYDFFVWLHYYSVRDTLLGPGRPYR (SEQ ID NO: 5) in CDR- L2; and (v) the T cell epitope of QCTEVRADTRPWSGPYILRNQDDRELWPRKFF (SEQ ID NO: 6) in CDR-L3. The antibody may comprise a VH comprising the amino acid sequence provided in SEQ ID NO: 7 or 9, or an amino acid sequence at least 80%, at least 90%, at least 95% or at least 98% identical to the amino acid sequence provided in SEQ ID NO: 7 or 9, and a VL comprising the amino acid sequence provided in SEQ ID NO: 8 or 10, or an amino acid sequence at least 80%, at least 90%, at least 95% or at least 98% identical to the amino acid sequence provided in SEQ ID NO: 8 or 10. The antibody may comprise a heavy chain comprising the amino acid sequence provided in SEQ ID NO: 11 or 13, or an amino acid sequence at least 80%, at least 90%, at least 95% or at least 98% identical to the amino acid sequence provided in SEQ ID NO: 11 or 13, and a light chain comprising the amino acid sequence provided in SEQ ID NO: 12 or 14, or an amino acid sequence at least 80%, at least 90%, at least 95% or at least 98% identical to the amino acid sequence provided in SEQ ID NO: 12 or 14. Preferred antibodies to be encoded by the nucleic acid(s) in the vaccine composition include the antibody referred to as “DCIB68” in WO 2008 / 116937 and the antibodies encoded by the DNA vectors referred to as “SCIB1” and iSCIB1+ in WO 2022 / 043400. In this regard, the entire contents of WO 2008 / 116937 and WO 2022 / 043400 are incorporated herein by reference. The antibody sequences described above may comprise a leader sequence (i.e., a “signal peptide” or “section signal”) for promoting secretion of the antibody upon expression of the one or more nucleic acids in the vaccine composition. The leader sequence may be at the N-terminus of the heavy chain and / or the N-terminus of the light chain of the antibody. Preferably, the leader sequence comprises the amino acid sequence provided in SEQ ID NO: 16, or a functional variant thereof. Preferably, the vaccine composition comprises a single nucleic acid encoding the plurality of tumour antigen T cell epitopes. Preferably the nucleic acid is a DNA vector. As described herein, the DNA vector may comprise, a first non-specific promoter sequence operably linked to a sequence encoding a heavy chain of an antibody and a second non-specific promoter sequence operably linked to a sequence encoding a light chain of the antibody, wherein the T cell epitopes are inserted or substituted in one or more CDRs of the antibody. The first and second promoter sequences may be the same or different. The heavy and light chain sequences may both comprise a leader sequence (secretion signal) a their respective N-termini. This arrangement of sequences is shown in a feature map of an exemplary vector “SCIB1” in Figure 1 and another exemplary vector “iSCIB1+” in Figure 3. Preferred DNA sequences are the sequences of “SCIB1” and “iSCIB1+” (also referred to herein as “SCIB1plus iV1”) provided herein as SEQ ID NO: 17 and 18 respectively. Thus, the nucleic acid may be SCIB1 or iSCIB1+ as described in WO 2022 / 043400 or any other suitable nucleic acid described in WO 2022 / 043400. The vaccine composition described herein is administered in combination with a programmed death-1 (PD-1) inhibitor and a cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor. The PD-1 inhibitor and CTLA-4 inhibitor act as immune checkpoint inhibitors. Immune checkpoints are crucial signaling pathways in the immune system that maintain self-tolerance and modulate the duration and amplitude of physiological immune responses. Under normal conditions, these pathways prevent excessive effector activity by T cells. Two important examples of this pathway are the cell surface receptors CTLA-4 and PD-1 (Teft, 2006; Keir, 2008). In some cases, tumors express or over-express inhibitory immune checkpoint pathways as a major mechanism of immune evasion. Because many of the immune checkpoints are initiated by ligand-receptor interactions, these signals can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors (Pardoll, 2012). Immune checkpoint proteins are important targets for pharmacologic blockade (Teft, 2006; Keir, 2008)., and dramatic clinical responses have been observed after treatment with antibodies blocking PD-1 and CTLA-4 (See, e.g., Brahmer, 2010; Robert, 2011; Topalian, 2012; Powles, 2014; Topalian, 2014; Brahmer, 2015; Le, 2015; Robert, 2015; Reck, 2016; Langer, 2017). Accordingly, the present invention features in exemplary embodiments, novel combinations of a nucleic acid-based vaccine and one or more CTLA-4 and PD-1 inhibitors. The CTLA-4 inhibitor may be an anti-CTLA-4 antibody. The anti-CTLA-4 antibody may be Ipilimumab or Tremelimumab for example. The anti-CTLA-4 antibody binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80 / CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor-infiltrating T effector cells. Inhibition of CTLA-4 signaling can also reduce T regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response. Ipilimumab is an IgGl kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab (Yervoy®’ Bristol -Meyers Squibb, New York, NY) is a recombinant, human mAh produced in mammalian (Chinese hamster ovaries) cell culture. CTLA-4 serves to regulate early T cell activation and Programmed Death-1 (PD-1) signaling functions in part to regulate T cell activation in peripheral tissues. The PD-1 receptor refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is expressed on a number of cell types including Tregs, activated B cells, and natural killer (NK) cells, and is expressed predominantly on previously activated T cells in vivo, and binds to two ligands, PD-L1 and PD-L2. PD1 's endogenous ligands, PD-L1 and PD- L2, are expressed in activated immune cells as well as nonhematopoietic cells, including tumor cells. PD-1 as used herein is meant to include human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1. The complete hPD- 1 sequence can be found under GENBANK Accession No. U64863. Programmed Death Ligand-1 (PD- L1“is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that downregulate T cell activation and cytokine secretion upon binding to PD-1. PD-L3 as used herein includes human PD- L1 (hPD-Ll ), variants, isoforms, and species homologs of hPD-Ll, and analogs having at least one common epitope with hPD-Ll. The complete hPD-Ll sequence can be found under GENBAN Accession No. Q9NZQ7. Tumors have been demonstrated to escape immune surveillance by expressing PD- L1 / L2, thereby suppressing tumor-infiltrating lymphocytes via PD-1 / PD~L1,2 interactions (Dong et al. Nat. Med.8:793-800.2002). The PD-1 inhibitor may be an anti-PD1 antibody. The anti-PD-1 antibody may be nivolumab, Pembrolizumab or Pidilizumab, for example. Nivolumab (Opdivo®, Bristol-Myers Squibb Company, NY) is a human immunoglobulin G4 (IgG4) mAb that binds to the programmed death 1 (PD-1) receptor and blocks its interaction with PD-L1 and programmed death ligand 2 (PD-L2), reversing PD-1 pathway- mediated inhibition of the immune response, including the anti-tumor immune response. Binding of PD- L1 and PD-L2 to the PD-1 receptor expressed on T cells inhibits T-cell proliferation and cytokine production. Up-regulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. The antibodies of the invention includes, but are not limited to, all of the anti-PD-1 and anti-PD-Ll Abs disclosed in U.S. Pat. Nos. 8,008,449 and 7,943,743, respectively. Other anti-PD-1 mAbs have been described in, for example, U.S. Pat. Nos.7,488,802 and 8,168,757, and anti-PD-Ll mAbs have been described in, for example, U.S. Pat. Nos.7,635,757 and 8,217,149, and U.S. Publication No.2009 / 0317368. U.S. Pat. No.8,008,449 exemplifies seven anti-PD-1 HuMAbs: 1708.2D3, 4M, 5C4 (also referred to herein as nivolumab or BMS-936558), 4A11, 7D3 and 5F4. Nivolumab (Opdivo®) has been approved by the Food & Drug Administration of the United States (FDA) and the European Medicines Agency (EMA) for the treatment of melanoma in combination with ipilimumab (Yervoy®) and vice-versa. The Opdivo® EMA product information (incorporated herein by reference) obtained from the EMA website here: states that the recommended dosing is as follows: “In adults and adolescents 12 years of age and older and weighing at least 50 kg, the recommended dose is 1 mg / kg nivolumab in combination with 3 mg / kg ipilimumab administered intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 240 mg every 2 weeks or at 480 mg every 4 weeks (see sections 5.1 and 5.2), as presented in Table 2. For the monotherapy phase, the first dose of nivolumab should be administered: - 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mg every 2 weeks; or - 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mg every 4 weeks. In adolescents 12 years of age and older and weighing less than 50 kg, the recommended dose is 1 mg / kg nivolumab in combination with 3 mg / kg ipilimumab administered intravenously every 3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 3 mg / kg every 2 weeks or 6 mg / kg every 4 weeks (see sections 5.1 and 5.2), as presented in Table 2. For the monotherapy phase, the first dose of nivolumab should be administered: - 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 3 mg / kg every 2 weeks; or - 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 6 mg / kg every 4 weeks.” The table below is reproduced from the Opdivo® EMA product information referred to above and provides recommended doses and infusion times for intravenous administration of nivolumab in combination with ipilimumab for treating melanoma: The recommended dosing schedule for the combination of nivolumab and ipilimumab described above is also indicated on the Yervoy® EMA product information (incorporated herein by reference) obtained from the EMA website here: https: / / www.ema.europa.eu / en / documents / product-information / yervoy- For the present invention, when the PD-1 inhibitor is nivolumab and the CTLA-4 inhibitor is ipilimumab, these antibodies may be administered to the subject in accordance with the recommended dosing schedule (for the combination therapy for melanoma) on the Yervoy® EMA product information (also referred to as the “product label”) or the Opdivo® EMA product information. Preferably, ipilimumab and nivolumab are administered to the subject in accordance with the dosing schedule described in the clinical trial protocol provided herein as Example 3 (the “SCOPE” trial). Preferably, each dose of the CTLA-4 inhibitor (e.g., ipilimumab) is administered on the same day as a dose of the PD-1 inhibitor (e.g., nivolumab). Thus, the CTLA-4 inhibitor (e.g., ipilimumab) and PD-1 inhibitor (e.g., nivolumab) may be administered in separate compositions or in the same composition. The first dose of the CTLA-4 inhibitor and the PD-1 inhibitor is preferably administered to the subject about one week after the first dose of the vaccine composition. The vaccine composition described herein, in combination with the CTLA-4 inhibitor and the PD-1 inhibitor, is particularly suitable for the treatment of melanoma (especially advanced melanoma), as demonstrated by the interim clinical trial results described in Example 4. In particular, the melanoma may be stage III or stage IV melanoma. The melanoma may be metastatic melanoma. In this regard, “metastatic” melanoma refers to melanoma in which primary melanoma cells have spread to organs away from the original tumour site, such as lymph nodes, lungs, liver, brain, and bones, for example. The melanoma may be unresectable (i.e., not capable of being surgically removed). For example, the melanoma may be unresectable stage III or stage IV melanoma. Preferably, the subject has received no prior systemic treatment for advanced melanoma. Preferably, the melanoma is unresectable stage III or stage IV melanoma and the subject (a) is at least 18 years of age; (b) had received no prior systemic treatment for advanced disease; and (c) does not have brain metastases, ocular melanoma, mucosal melanoma or autoimmune disease. Preferably, the subject also (d) has a Class I HLA serotype of HLA-A*02 (i.e., HLA-A2); and (e) has a Class II HLA serotype selected from HLA-DR4, HLA-DR7, HLA-DR53 and HLA-DQ6. The prior art documents mentioned herein are incorporated to the fullest extent permitted by law. Other features or advantages of the present invention will be apparent from the following drawings, Examples, numbered embodiments, and also from the appending claims. Description of the sequences T cell epitopes SEQ ID NO: 1: GTGRAMLGTHTMEVTVYH HLA-DQ6 restricted gp100173-190 CD4 epitope SEQ ID NO: 2: SVYDFFVWL HLA-A0201 TRP2180-188 epitope SEQ ID NO: 3: WNRQLYPEWTEAQRLD HLA-DR4 restricted gp10044-59 CD4 epitope SEQ ID NO: 4: VPLDCVLYRYGSFSVTLDIVQG gp100471-492 sequence - a HLA-A1, B35 and predicted HLA-DP4 epitope SEQ ID NO: 5: ANCSVYDFFVWLHYYSVRDTLLGPGRPYR TRP2177-205 sequence – comprising HLA- A2 / DP4 / A31 / A33 / A3 epitopes SEQ ID NO: 6: QCTEVRADTRPWSGPYILRNQDDRELWPRKFF TRP260-91 sequence – comprising HLA- DR3 / B35 / B44 epitopes Exemplary antibody sequences SEQ ID NO: 7 - SCIB1 antibody heavy chain variable region (VH): QVQLVETGGGLIQPGGSLRMSCGTGRAMLGTHTMEVTVYHWVRQAPGKGLEWIAYIGSGGSV YDFFVWLRFTISRDNSKNTLYLQLNSLRAEDTAVYYCARWNRQLYPEWTEAQRLDWGQGTTV TVSS SEQ ID NO: 8 - SCIB1 antibody light chain variable region (VL): DVLMTQSPLSLPVTPGEPASISCWNRQLYPEWTEAQRLDWYLQKPGQSPQLLIYKVSNRFSG VPDRFSGSGSGTDFTLKISRVEAEDTGVYYCGTGRAMLGTHTMEVTVYHFGGGTKVEIK SEQ ID NO: 9 - SCIB1+ antibody heavy chain variable region (VH): QVQLVETGGGLIQPGGSLRMSCGTGRAMLGTHTMEVTVYHWVRQAPGKGLEWIAYIGSGGSV YDFFVWLRFTISRDNSKNTLYLQLNSLRAEDTAVYYCARVPLDCVLYRYGSFSVTLDIVQGW GQGTTVTVSS SEQ ID NO: 10 - SCIB1+ antibody light chain variable region (VL): DVLMTQSPLSLPVTPGEPASISCWNRQLYPEWTEAQRLDWYLQKPGQSPQLLIYANCSVYDF FVWLHYYSVRDTLLGPGRPYRGVPDRFSGSGSGTDFTLKISRVEAEDTGVYYCQCTEVRADT RPWSGPYILRNQDDRELWPRKFFFGGGTKVEIK SEQ ID NO: 11 - SCIB1 antibody whole heavy chain: QVQLVETGGGLIQPGGSLRMSCGTGRAMLGTHTMEVTVYHWVRQAPGKGLEWIAYIGSGGSV YDFFVWLRFTISRDNSKNTLYLQLNSLRAEDTAVYYCARWNRQLYPEWTEAQRLDWGQGTTV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 12 - SCIB1 antibody whole light chain: DVLMTQSPLSLPVTPGEPASISCWNRQLYPEWTEAQRLDWYLQKPGQSPQLLIYKVSNRFSG VPDRFSGSGSGTDFTLKISRVEAEDTGVYYCGTGRAMLGTHTMEVTVYHFGGGTKVEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 13 - SCIB1+ antibody whole heavy chain: QVQLVETGGGLIQPGGSLRMSCGTGRAMLGTHTMEVTVYHWVRQAPGKGLEWIAYIGSGGSV YDFFVWLRFTISRDNSKNTLYLQLNSLRAEDTAVYYCARVPLDCVLYRYGSFSVTLDIVQGW GQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHTAWTQPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKPKGRAQTPQVYTIPPPR EQMSKKKVSLTCLVTNFFSEAISVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 14 - SCIB1+ antibody whole light chain: DVLMTQSPLSLPVTPGEPASISCWNRQLYPEWTEAQRLDWYLQKPGQSPQLLIYANCSVYDF FVWLHYYSVRDTLLGPGRPYRGVPDRFSGSGSGTDFTLKISRVEAEDTGVYYCQCTEVRADT RPWSGPYILRNQDDRELWPRKFFFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC SEQ ID NO: 15 – CMV IE promoter sequence: GTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGC CCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAA CGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTT TCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTG TATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTA TGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCG CTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCA CGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCA ACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTG TACGGTGGGAGGTCTATATAAGCAGAGCTCSEQ ID NO: 16 - Leader sequence:MGWSCIILFLVATATGVHS SEQ ID NO: 19 - Human Kappa Constant region Acc No : P01834 (Amino Acids, 1-107): RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 20 - HuIgG1 CH1-Hinge-CH2-CH3 sequence with “iV1” murine IgG323 AA substitutions in bold, Acc No : P01857 (Amino Acids, 1-330): ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHTAWTQPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKPKGRAQTPQVYTIPPPREQMSKKKVSL TCLVTNFFSEAISVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK Exemplary whole DNA vector sequences Entire SCIB1 DNA plasmid sequence (SEQ ID NO: 17 – see also Example 1): GCTGCTTCGCGATGTACGGGCCAGATATACGCGTTGACATTGATTATTGACTAGTTATTAATAGTAAT CAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGC CCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAAC GCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTAC ATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCAT TATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTAT TACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTC CAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAA TGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAG CAGAGCTCTCTGGCTAACTAGAGAACCCACTGCTTACTGGCTTATCGAAATTAATACGACTCACTATA GGGAGACCCAAGCTAGCTTGGTACCGAGCTCGGATCCACCATGGGATGGAGCTGTATCATCCTCTTCT TGGTAGCAACAGCTACCGGAGTCCACTCCGATGTGTTGATGACCCAATCTCCACTCTCCCTGCCTGTC ACTCCTGGGGAGCCAGCCTCGATCTCTTGCTGGAACAGGCAGCTGTATCCAGAGTGGACAGAAGCCCA GAGACTTGACTGGTATCTGCAGAAACCAGGCCAGTCTCCACAGCTCCTGATCTACAAAGTTTCCAACC GATTTTCTGGGGTCCCAGACAGATTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGC AGAGTGGAGGCTGAGGATACCGGAGTGTATTACTGCGGGACAGGCAGGGCAATGCTGGGCACACACAC CATGGAAGTGACTGTCTACCATTTCGGTGGAGGCACCAAGGTGGAAATCAAGCGTACGGTAGCGGCCC CATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTG CTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAA CTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCACCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTGACTCGAGCATGCATCTAGAGGGCCCTATTCTAT AGTGTCACCTAAATGCTAGAGCTCGCTGATCAGCCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTT GTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAA TGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACA GCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGCTTCTGAG GCGGAAAGAACCAGGCTAGCGTTCGATGTACGGGCCAGATATACGCGTTGACATTGATTATTGACTAG TTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAAC TTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTAT GTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGC CCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAAT GGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTA TTAGTCATCGCTATTACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGA CTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAAC GGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGG GAGGTCTATATAAGCAGAGCTCTCTGGCTAACTAGAGAACCCACTGCTTACTGGCTTATCGAAATTAA TACGACTCACTATAGGGAGACCCAAGCTGGCTAGCGTTTAAACTTAAGCTTACCATGGGATGGAGCTG TATCATCCTCTTCTTGGTAGCAACAGCTACCGGAGTCCACTCCCAGGTGCAGCTGGTGGAGACTGGGG GAGGCTTAATCCAGCCTGGAGGGTCCCTGAGAATGTCCTGTGGGACAGGCAGGGCAATGCTGGGCACA CACACCATGGAAGTAACTGTCTACCATTGGGTTCGCCAGGCTCCGGGGAAGGGGCTGGAGTGGATCGC ATACATTGGTAGTGGTGGTAGTGTTTATGATTTTTTTGTGTGGCTCCGATTCACCATTTCCAGAGACA ATAGCAAGAACACCCTGTATTTGCAATTGAACAGTCTGAGGGCTGAGGACACAGCCGTGTATTACTGC GCCCGATGGAACAGGCAGCTGTATCCAGAGTGGACAGAAGCCCAGAGACTTGACTGGGGCCAAGGAAC CACGGTCACCGTCTCCAGCGCTTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGA GCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTG TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACG TGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCAC ACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACC CAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG ACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGG GAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAA TGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCA AAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAG AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCC TCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATG CATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGATCTAAAGG GCGAATTCGCCCTTAAGGGCGAATTCTGCAGATTCGAGCATGCATCTAGAGGGCCCGTTTAAACCCGC TGATCAGCCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTT GACCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGA GTAGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAAT AGCAGGCATGCTGGGGATGCGGTGGGCTCTATGGCTTCTACTGGGCGGTTTTATGGACAGCAAGCGAA CCGGAATTGCCAGCTGGGGCGCCCTCTGGTAAGGTTGGGAAGCCCTGCAAAGTAAACTGGATGGCTTT CTTGCCGCCAAGGATCTGATGGCGCAGGGGATCAAGCTCTGATCAAGAGACAGGATGAGGATCGTTTC GCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTAT GACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCC GGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAAGACGAGGCAGCGCGGCTAT CGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGAC TGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGT ATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACC AAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTG GACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGAGCATGCCCGACGG CGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTT CTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGT GATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCC CGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAATTATTAACGCTTACAATT TCCTGATGCGGTATTTTCTCCTTACGCATCTGTGCGGTATTTCACACCGCATCAGGTGGCACTTTTCG GGGAAATGTGCGCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCAAATATGTATCCGCTCATGA GACAATAACCCTGATAAATGCTTCAATAATAGCACGTGCTAAAACTTCATTTTTAATTTAAAAGGATC TAGGTGAAGATCCTTTTTGATAATCTCATGACCAAAATCCCTTAACGTGAGTTTTCGTTCCACTGAGC GTCAGACCCCGTAGAAAAGATCAAAGGATCTTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCT TGCAAACAAAAAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTT CCGAAGGTAACTGGCTTCAGCAGAGCGCAGATACCAAATACTGTTCTTCTAGTGTAGCCGTAGTTAGG CCACCACTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTG CTGCCAGTGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAG CGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACACCGAACTGAG ATACCTACAGCGTGAGCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCCGG TAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGAAACGCCTGGTATCTTTAT AGTCCTGTCGGGTTTCGCCACCTCTGACTTGAGCGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAG CCTATGGAAAAACGCCAGCAACGCGGCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCACA TGTTCTT Entire iSCIB1+ DNA plasmid sequence (SEQ ID NO: 18 – see also Example 2): GCTGCTTCGCGATGTACGGGCCAGATATACGCGTTGACATTGATTATTGACTAGTTATTAATAGTAAT CAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGC CCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAAC GCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTAC ATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCAT TATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTAT TACCATGGTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTC CAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAA TGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAG CAGAGCTCTCTGGCTAACTAGAGAACCCACTGCTTACTGGCTTATCGAAATTAATACGACTCACTATA GGGAGACCCAAGCTAGCTTGGTACCGAGCTCGGATCCACCATGGGATGGAGCTGTATCATCCTCTTCT TGGTAGCAACAGCTACCGGAGTCCACTCCGATGTGTTGATGACCCAATCTCCACTCTCCCTGCCTGTC ACTCCTGGGGAGCCAGCCTCGATCTCTTGCTGGAACAGGCAGCTGTATCCAGAGTGGACAGAAGCCCA GAGACTTGACTGGTATCTGCAGAAACCAGGCCAGTCTCCACAGCTCCTGATCTACGCCAACTGCAGTG TTTATGATTTTTTTGTGTGGCTCCATTATTATTCTGTTAGAGATACATTATTAGGACCAGGACGCCCC TACAGGGGGGTCCCAGACAGATTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAG AGTGGAGGCTGAGGATACCGGAGTGTATTACTGCCAGTGCACAGAGGTGCGAGCCGACACAAGGCCCT GGAGTGGTCCCTACATCCTACGAAACCAGGATGACCGTGAGCTGTGGCCAAGAAAATTCTTCTTCGGT GGAGGCACCAAGGTGGAAATCAAGCGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGA TGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCA AAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGAC AGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAA AGTCTACGCCTGCGAAGTCACCCACCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAG AGTGTTGACTCGAGCATGCATCTAGAGGGCCCTATTCTATAGTGTCACCTAAATGCTAGAGCTCGCTG ATCAGCCTCGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGA CCCTGGAAGGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGT AGGTGTCATTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAG CAGGCATGCTGGGGATGCGGTGGGCTCTATGGCTTCTGAGGCGGAAAGAACCAGGCTAGCGTTCGATG TACGGGCCAGATATACGCGTTGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCA TTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACC GCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTT TCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCAT ATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACAT GACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTGATGC GGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCC ATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTC CGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCTCTGGC TAACTAGAGAACCCACTGCTTACTGGCTTATCGAAATTAATACGACTCACTATAGGGAGACCCAAGCT GGCTAGCGTTTAAACTTAAGCTTACCATGGGATGGAGCTGTATCATCCTCTTCTTGGTAGCAACAGCT ACCGGAGTCCACTCCCAGGTGCAGCTGGTGGAGACTGGGGGAGGCTTAATCCAGCCTGGAGGGTCCCT GAGAATGTCCTGCGGGACAGGCAGGGCAATGCTGGGCACACACACCATGGAAGTGACTGTCTACCATT GGGTTCGGCAGGCTCCGGGGAAGGGGCTGGAGTGGATCGCATACATTGGTAGTGGTGGTAGTGTTTAT GATTTTTTTGTGTGGCTCCGATTCACCATTTCCAGAGACAATAGCAAGAACACCCTGTATTTGCAATT GAACAGTCTGAGGGCTGAGGACACAGCCGTGTATTACTGTGCCCGAGTCCCCCTGGATTGTGTTCTGT ATCGATATGGTTCCTTTTCCGTCACCCTGGACATTGTCCAGGGTTGGGGCCAAGGAACCACGGTCACC GTCTCCAGCGCTTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGG GGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACT CAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAA GCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCAC CGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACC CTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATACAGCCTGGACACAGCCGCGGGAGGAGCAGT ACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAG TACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAACCCAAAGG GAGAGCCCAGACACCACAGGTGTACACCATACCCCCACCTCGGGAACAAATGTCCAAGAAGAAGGTCA GCCTGACCTGCCTGGTCACCAACTTCTTCTCTGAAGCCATCAGTGTGGAGTGGGAGAGCAATGGGCAG CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAA GCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTC TGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGATCTAAAGGGCGATATCGC CCTTAAGGGCGAATTCTGCAGATTCGAGCATGCATCTAGAGGGCCCGTTTAAACCCGCTGATCAGCCT CGACTGTGCCTTCTAGTTGCCAGCCATCTGTTGTTTGCCCCTCCCCCGTGCCTTCCTTGACCCTGGAA GGTGCCACTCCCACTGTCCTTTCCTAATAAAATGAGGAAATTGCATCGCATTGTCTGAGTAGGTGTCA TTCTATTCTGGGGGGTGGGGTGGGGCAGGACAGCAAGGGGGAGGATTGGGAAGACAATAGCAGGCATG CTGGGGATGCGGTGGGCTCTATGGCTTCTACTGGGCGGTTTTATGGACAGCAAGCGAACCGGAATTGC CAGCTGGGGCGCCCTCTGGTAAGGTTGGGAAGCCCTGCAAAGTAAACTGGATGGCTTTCTTGCCGCCA AGGATCTGATGGCGCAGGGGATCAAGCTCTGATCAAGAGACAGGATGAGGATCGTTTCGCATGATTGA ACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCAC AACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTT GTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAAGACGAGGCAGCGCGGCTATCGTGGCTGGC CACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTAT TGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATG GCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACA TCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGC ATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGAGCATGCCCGACGGCGAGGATCTC GTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCAT CGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTG AAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAG CGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAATTATTAACGCTTACAATTTCCTGATGCG GTATTTTCTCCTTACGCATCTGTGCGGTATTTCACACCGCATCAGGTGGCACTTTTCGGGGAAATGTG CGCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCAAATATGTATCCGCTCATGAGACAATAACC CTGATAAATGCTTCAATAATAGCACGTGCTAAAACTTCATTTTTAATTTAAAAGGATCTAGGTGAAGA TCCTTTTTGATAATCTCATGACCAAAATCCCTTAACGTGAGTTTTCGTTCCACTGAGCGTCAGACCCC GTAGAAAAGATCAAAGGATCTTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAA AAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAAGGTAA CTGGCTTCAGCAGAGCGCAGATACCAAATACTGTTCTTCTAGTGTAGCCGTAGTTAGGCCACCACTTC AAGAACTCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCAGTGG CGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAGCGGTCGGGCT GAACGGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACACCGAACTGAGATACCTACAG CGTGAGCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCCGGTAAGCGGCAG GGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGAAACGCCTGGTATCTTTATAGTCCTGTCG GGTTTCGCCACCTCTGACTTGAGCGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAA AACGCCAGCAACGCGGCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTTCTT SEQ ID NO: 21 – gp100178-186:MLGTHTMEV SEQ ID NO: 22 – gp100174-190: TGRAMLGTHT MEVTVYH SEQ ID NO: 23 – gp100175-189: GRAMLGTHTMEVTVY SEQ ID NO: 24 – gp100476-490: VLYRYGSFSVTLDIV SEQ ID NO: 25 – TRP2178-192: NCSVYDFFVWLHYYS SEQ ID NO: 26 – TRP260-81:QCTEVRADTRPWSGPYILRNQD SEQ ID NO: 27 – TRP271-91: WSGPYILRNQDDRELWPRKFF SEQ ID NO: 28 – TRP267-83:DTRPWSGPYILRNQDDR SEQ ID NO: 29 – TRP269-77: RPWSGPYIL SEQ ID NO: 30 - pSCIB1 Amino Acid sequence - light chain with leader: MGWSCIILFLVATATGVHSDVLMTQSPLSLPVTPGEPASISCWNRQLYPEWTEAQRLDWYLQKPGQSP QLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDTGVYYCGTGRAMLGTHTMEVTVYHFGGGTK VEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 31 – pSCIB1 Amino acid sequence – heavy chain with leader: MGWSCIILFLVATATGVHSQVQLVETGGGLIQPGGSLRMSCGTGRAMLGTHTMEVTVYHWVRQAPGKG LEWIAYIGSGGSVYDFFVWLRFTISRDNSKNTLYLQLNSLRAEDTAVYYCARWNRQLYPEWTEAQRLD WGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K Examples The present invention will now be described further with reference to the following examples and the accompanying drawings. Figure legends Figure 1: The plasmid map for SCIB1 Figure 2: A schematic diagram of the engineered IgG encoded by SCIB1. Figure 3: The plasmid map for iSCIB1+ Figure 4: A schematic diagram of the engineered IgG encoded by SCIB1 and iSCIB1+ Figure 5: Study Schema for Simon Stage 1 and Simon Stage 2 of SCIB1 in patients with advanced unresectable melanoma receiving either nivolumab with ipilimumab or pembrolizumab. Figure 6: Waterfall plot showing maximum change from baseline in the sum of the reference diameters of the target lesion in patients receiving SCIB1 with nivolumab plus ipilimumab. Data are shown for all the patients who had target lesions evaluated at baseline and who reached the first imaging timepoint of week 13. A bar in the negative quadrant denotes tumour shrinkage whilst a bar in the positive quadrant indicates increase in tumour size. The horizontal lines indicate a 30% reduction in the tumour burden in the target lesion or a 20% increase, as these are the thresholds for a response or progression. The change in tumour burden was defined as the percentage decrease in the sum of the reference diameters of the target lesion from baseline to nadir, observed up until September 2023. Figure 7: Spider plot showing durability of tumour responses in patients over time. Data are shown for all the patients who had target lesions evaluated at baseline and who reached the first imaging timepoint of week 13. The change in tumour burden was defined as the percentage decrease in the sum of the reference diameters of the target lesion from baseline to nadir, observed up until September 2023. Figure 8: C57Bl / 6 mice implanted with B16F1 tumour cells and then dosed with checkpoint inhibitor antibodies and monitored for tumour growth and survival (n≥5). Figure 9: (A) HLA-DR4 transgenic mice implanted with B16 DR4 tumour cells or (B) transgenic HLA- DP4 mice implanted with B16F1 HHDII / DP4 tumour cells and then treated with checkpoint inhibitor antibodies and monitored for tumour growth and survival (n≥5). Figure 10: Ex vivo immune responses measured by IFNƴ ELISpot assay in C57Bl / 6 mice (A), HLA- DR4 transgenic mice (B) or HHDII / DR1 transgenic mice (C), following immunisation with iSCIB1+ (epitope CDR locations indicated). Data represents average of at least 2 independent experiments in which n=3. Error bars shown of standard deviation. Figure 11: (A) C57Bl / 6 mice implanted with B16F1 tumour cells or (B) transgenic HHDII / DP4 mice implanted with B16 F1 HHDII / DP4 tumour cells and then immunised with iSCIB1+ and monitored for tumour growth and survival (n=10). Figure 12: Splenocytes from C57Bl / 6 mice immunised with iSCIb1+ alone or with iSCIB1+ plus doublet checkpoint (anti-PD1 and anti-CTLA4 antibody) therapy were expanded in vitro and analysed for peptide-specific responses against the sequences inserted into (A) CDR L3 (TRP-2 aa60-91) and (B) CDR H3 (gp100 aa471-192). Data is an average of n=3 and error bars shown of standard deviation. Figure 13: C57Bl / 6 mice implanted with b16F1 tumour cells and then immunised with iSCIB1+ alone, iSCIB1+ in combination with double checkpoint (CPI therapy (anti-PD1 and anti-CTLA4 antibodies) or double checkpoint therapy alone and monitored for tumour growth and survival (n=10). Methods and materials (pre-clinical studies) Peptides Peptides were selected based on published sequences, IEDB database (http: / / www.iedb.org / ) binding predictions and SYFPEITHI (http: / / www.syfpeithi.de) binding predictions. Peptides (Table below) were synthesized at >90% purity (Genscript), aliquoted to single use vials and stored lyophilized at −80°C then reconstituted in PBS on day of use. Antigen coordinates sequence TRP-2 180-188 SVYDFFVWL (SEQ ID NO: 2) 178-192 NCSVYDFFVWLHYYS (SEQ ID NO: 25) 60-81 QCTEVRADTRPWSGPYILRNQD (SEQ ID NO: 26) 71-91 WSGPYILRNQDDRELWPRKFF (SEQ ID NO: 27) 67-83 DTRPWSGPYILRNQDDR (SEQ ID NO: 28) 69-77 RPWSGPYIL (SEQ ID NO: 29) Gp100 44-59 WNRQLYPEWTEAQRLD (SEQ ID NO: 3) 174-190 TGRAMLGTHTMEVTVYH (SEQ ID NO: 22) 178-186 MLGTHTMEV (SEQ ID NO: 21) 476-490 VLYRYGSFSVTLDIV (SEQ ID NO: 24) Animals and cell lines C57Bl / 6J (Charles River), HLA-DR4 mice (Model # 4149, Taconic), HHDII / DP4 mice (EM:02221, European Mouse Mutant Archive) or HHDII / DR1 mice (Pasteur Institute) aged between 8 and 16 weeks old, were used. All work was carried out with ethical approval under a Home Office approved project licence. For all the studies mice were randomised into different groups and not blinded to the investigators. Cells, including B16 melanoma expressing relevant MHCI and II alleles (described previously [Pudney et al 2010; Brentville et al 2016; Brentville et al 2019]), were cultured in RPMI medium 1640 with L- glutamine (2mmol / l) with 10% FCS and appropriate antibiotics to maintain plasmids. Murine splenocytes were cultured in RPMI-1640 with 10% FBS (Sigma), 2 mM glutamine, 20 mM HEPES buffer, 100 units / ml penicillin, 100mg / ml streptomycin and 10-5M 2-mercaptoethanol. Cell lines utilised were mycoplasma free, authenticated by suppliers (STR profiling), and used within ten passages. Immunisation protocol Animal experiments were carried out with ethical approval under a Home Office approved project license. C57Bl / 6 (Charles River, UK), HLA-DR4 transgenic (model #4149 Taconic, USA), HHDII / DP4 (HLA-A2.1+ / + HLADP4+ / + hCD4+ / +, EM:02221, European Mouse Mutant Archive) and HLA-A2 / DR1 transgenic (HHDII / DR1, Pasteur Institute) mice aged 8-16 weeks were used. For all studies the mice were randomized into different groups and not blinded to the investigators. DNA (1µg / mouse) was coated onto 1.0µm gold particles (BioRad, Hemel Hempstead, UK) using the manufacturer’s instructions and administered intradermally by gene gun (BioRad, USA). Mice were immunized at day 1, 8 and 15, spleens removed and splenocytes harvested for analysis at day 21 (unless stated otherwise). For tumour challenge experiments mice were challenged with 2.5x104B16F1, 2.5x104B16 DR4 or 1x105B16 HHDII / DP4 tumour cells subcutaneously on the right flank on day 1 and then were immunized with DNA bullets via genegun i.d. on days 4, 11 and 18. Combination studies with anti-PD- 1 antibody clone RMPI-14 (250µg / dose) and anti-CTLA-4 clone 9D9 (100µg dose) were performed with DNA and antibody administered via gene gun or i.p. in saline respectively at days 8, 15 and 22. Tumour growth was monitored at 3-4 days intervals by measuring the tumour size with callipers. Mice were humanely euthanized once tumour approached 15 mm in diameter. Splenocyte culture Splenocytes harvested ex vivo were set up at 5x106 / well in 2ml complete medium with 10-5M 2- mercaptoethanol and 20IU recombinant mouse IL-2 (Miltenyi Biotech). Peptides were added in pools at final concentration of 10µg / ml of each peptide. Cultures were incubated at 37˚C / 5% CO2 for up to 8 days. Elispot assay Elispot assays were performed using murine IFNγ capture and detection reagents according to the manufacturer’s instructions (Mabtech). In brief, the IFNγ specific antibody were coated onto wells of 96-well Immobilin-P plate. Synthetic peptides (Genescript) at 10 µg / ml diluted in culture media (RPMI medium 1640 (GIBCO / BRL) supplemented with 10% FCS (Sigma), 2mM L-glutamine (Sigma) and sodium bicarbonate buffered with additional 20mM HEPES (Sigma) and 50µM 2-mercaptoethanol (Thermofisher)) and 5x105splenocytes per well were added directly ex vivo to the wells of the plate in quadruplicate and plates incubated for 40 hrs at 37˚C / 5% CO2. Cells with culture media only were added as negative control and 5µg / ml Lipopolysaccharide (LPS, Sigma) was used as a positive control. For the assay on in vitro cultured splenocytes, cells were counted and plated out at between 3x104 / well and 1x105 / well. Peptide was added as described above and anti-mouse CD3 antibody (clone 145- 2C11) at 5µg / ml was used as a positive control. Plates were incubated for 20 hrs. After incubation, captured IFNγ was detected by biotinylated specific IFNγ antibody and developed with a streptavidin alkaline phosphatase and chromogenic substrate. Spots were analyzed and counted using an automated plate reader (Cellular Technologies Ltd). Statistics Comparative analysis of the ELISpot results was performed by applying paired or unpaired ANOVA or Student t test as appropriate with P values calculated accordingly. Comparison of survival analysis was by applying the Log-rank test using Graphpad Prism software. References: Pudney, V.A., et al., DNA vaccination with T-cell epitopes encoded within Ab molecules induces high- avidity anti-tumor CD8+ T cells. Eur J Immunol, 2010.40(3): p.899-910 Brentville, V.A., et al., Citrullinated Vimentin Presented on MHC-II in Tumor Cells Is a Target for CD4+ T-Cell-Mediated Antitumor Immunity. Cancer Res, 2016.76(3): p.548-60 Brentville, V.A., et al., T cell repertoire to citrullinated self-peptides in healthy humans is not confined to the HLA-DR SE alleles; Targeting of citrullinated self-peptides presented by HLA-DP4 for tumour therapy. Oncoimmunology, 2019.8(5): p. e1576490. Example 1 – SCIB1 An exemplary nucleic acid for use in the present invention is SCIB1. The DNA sequence of SCIB1 (SEQ ID NO: 17) is shown below (the amino acid sequences of the encoded light and heavy chains of the expression product are included): 1 GCTGCTTCGC GATGTACGGG CCAGATATAC GCGTTGACAT TGATTATTGA 51 CTAGTTATTA ATAGTAATCA ATTACGGGGT CATTAGTTCA TAGCCCATAT 101 ATGGAGTTCC GCGTTACATA ACTTACGGTA AATGGCCCGC CTGGCTGACC 151 GCCCAACGAC CCCCGCCCAT TGACGTCAAT AATGACGTAT GTTCCCATAG 201 TAACGCCAAT AGGGACTTTC CATTGACGTC AATGGGTGGA GTATTTACGG 251 TAAACTGCCC ACTTGGCAGT ACATCAAGTG TATCATATGC CAAGTACGCC 301 CCCTATTGAC GTCAATGACG GTAAATGGCC CGCCTGGCAT TATGCCCAGT 351 ACATGACCTT ATGGGACTTT CCTACTTGGC AGTACATCTA CGTATTAGTC 401 ATCGCTATTA CCATGGTGAT GCGGTTTTGG CAGTACATCA ATGGGCGTGG 451 ATAGCGGTTT GACTCACGGG GATTTCCAAG TCTCCACCCC ATTGACGTCA 501 ATGGGAGTTT GTTTTGGCAC CAAAATCAAC GGGACTTTCC AAAATGTCGT 551 AACAACTCCG CCCCATTGAC GCAAATGGGC GGTAGGCGTG TACGGTGGGA 601 GGTCTATATA AGCAGAGCTC TCTGGCTAAC TAGAGAACCC ACTGCTTACT 651 GGCTTATCGA AATTAATACG ACTCACTATA GGGAGACCCA AGCTAGCTTG M G W 701 GTACCGAGCT CGGATCCACC ATGGGATGGA GCTGTATCAT CCTCTTCTTG A T A T G V H S D V L M T Q S P 751 GTAGCAACAG CTACCGGAGT CCACTCCGAT GTGTTGATGA CCCAATCTCC L S L P V T P G E P A S I S C W 801 ACTCTCCCTG CCTGTCACTC CTGGGGAGCC AGCCTCGATC TCTTGCTGGA 851 ACAGGCAGCT GTATCCAGAG TGGACAGAAG CCCAGAGACT TGACTGGTAT Q K P G Q S P Q L L I Y K V S N 901 CTGCAGAAAC CAGGCCAGTC TCCACAGCTC CTGATCTACA AAGTTTCCAA 951 CCGATTTTCT GGGGTCCCAG ACAGATTCAG TGGCAGTGGA TCAGGGACAG D F T L K I S R V E A E D G V Y 1001 ATTTCACACT CAAGATCAGC AGAGTGGAGG CTGAGGATAC CGGAGTGTAT Y C G T G R M L G T H T M E V T 1051 TACTGCGGGA CAGGCAGGGC AATGCTGGGC ACACACACCA TGGAAGTGAC 1101 TGTCTACCAT TTCGGTGGAG GCACCAAGGT GGAAATCAAG CGTACGGTAG A A P S V F I F P P S D E Q L K S 1151 CGGCCCCATC TGTCTTCATC TTCCCGCCAT CTGATGAGCA GTTGAAATCT 1201 GGAACTGCCT CTGTTGTGTG CCTGCTGAAT AACTTCTATC CCAGAGAGGC K V Q W K V D N A L Q S G N S Q 1251 CAAAGTACAG TGGAAGGTGG ATAACGCCCT CCAATCGGGT AACTCCCAGG E S V T E Q D S K D S T Y S L S S 1301 AGAGTGTCAC AGAGCAGGAC AGCAAGGACA GCACCTACAG CCTCAGCAGC 1351 ACCCTGACGC TGAGCAAAGC AGACTACGAG AAACACAAAG TCTACGCCTG E V T H Q G L S S P V T K S F N 1401 CGAAGTCACC CACCAGGGCC TGAGCTCGCC CGTCACAAAG AGCTTCAACA R G E * 1451 GGGGAGAGTG TTGACTCGAG CATGCATCTA GAGGGCCCTA TTCTATAGTG 1501 TCACCTAAAT GCTAGAGCTC GCTGATCAGC CTCGACTGTG CCTTCTAGTT 1551 GCCAGCCATC TGTTGTTTGC CCCTCCCCCG TGCCTTCCTT GACCCTGGAA 1601 GGTGCCACTC CCACTGTCCT TTCCTAATAA AATGAGGAAA TTGCATCGCA 1651 TTGTCTGAGT AGGTGTCATT CTATTCTGGG GGGTGGGGTG GGGCAGGACA 1701 GCAAGGGGGA GGATTGGGAA GACAATAGCA GGCATGCTGG GGATGCGGTG 1751 GGCTCTATGG CTTCTGAGGC GGAAAGAACC AGGCTAGCGT TCGATGTACG 1801 GGCCAGATAT ACGCGTTGAC ATTGATTATT GACTAGTTAT TAATAGTAAT 1851 CAATTACGGG GTCATTAGTT CATAGCCCAT ATATGGAGTT CCGCGTTACA 1901 TAACTTACGG TAAATGGCCC GCCTGGCTGA CCGCCCAACG ACCCCCGCCC 1951 ATTGACGTCA ATAATGACGT ATGTTCCCAT AGTAACGCCA ATAGGGACTT 2001 TCCATTGACG TCAATGGGTG GAGTATTTAC GGTAAACTGC CCACTTGGCA 2051 GTACATCAAG TGTATCATAT GCCAAGTACG CCCCCTATTG ACGTCAATGA 2101 CGGTAAATGG CCCGCCTGGC ATTATGCCCA GTACATGACC TTATGGGACT 2151 TTCCTACTTG GCAGTACATC TACGTATTAG TCATCGCTAT TACCATGGTG 2201 ATGCGGTTTT GGCAGTACAT CAATGGGCGT GGATAGCGGT TTGACTCACG 2251 GGGATTTCCA AGTCTCCACC CCATTGACGT CAATGGGAGT TTGTTTTGGC 2301 ACCAAAATCA ACGGGACTTT CCAAAATGTC GTAACAACTC CGCCCCATTG 2351 ACGCAAATGG GCGGTAGGCG TGTACGGTGG GAGGTCTATA TAAGCAGAGC 2401 TCTCTGGCTA ACTAGAGAAC CCACTGCTTA CTGGCTTATC GAAATTAATA 2451 CGACTCACTA TAGGGAGACC CAAGCTGGCT AGCGTTTAAA CTTAAGCTTA S C I I L F L V A T A T G 2501M G WCCATGGGATGGAGCTGTATC ATCCTCTTCT TGGTAGCAAC AGCTACCGGA V H S Q V Q L V E T G G G L I Q P 2551 GTCCACTCCC AGGTGCAGCT GGTGGAGACT GGGGGAGGCT TAATCCAGCC G G S L R M S C G T G R A M L G 2601 TGGAGGGTCC CTGAGAATGT CCTGTGGGAC AGGCAGGGCA ATGCTGGGCA T H T M E V T V Y H W V R Q A P G 2651 CACACACCAT GGAAGTAACT GTCTACCATT GGGTTCGCCA GGCTCCGGGG K G L E W I A Y I G S G G S V Y D 2701 AAGGGGCTGG AGTGGATCGC ATACATTGGT AGTGGTGGTA GTGTTTATGA F F V W L R F T I S R D N S K N 2751 TTTTTTTGTG TGGCTCCGAT TCACCATTTC CAGAGACAAT AGCAAGAACA T L Y L Q L N S L R A E D T A V Y 2801 CCCTGTATTT GCAATTGAAC AGTCTGAGGG CTGAGGACAC AGCCGTGTAT C A R W N R Q L Y P E W T E A Q 2851 TACTGCGCCC GATGGAACAG GCAGCTGTAT CCAGAGTGGA CAGAAGCCCA W G Q G T T V T V S S A S 2901 GAGACTTGAC TGGGGCCAAG GAACCACGGT CACCGTCTCC AGCGCTTCCA T K G P S V F P L A P S S K S T S 2951 CCAAGGGCCC ATCGGTCTTC CCCCTGGCAC CCTCCTCCAA GAGCACCTCT G G T A A L G C L V K D Y F P E P 3001 GGGGGCACAG CGGCCCTGGG CTGCCTGGTC AAGGACTACT TCCCCGAACC V T V S W N S G A L T S G V H T 3051 GGTGACGGTG TCGTGGAACT CAGGCGCCCT GACCAGCGGC GTGCACACCT F P A V L Q S S G L Y S L S S V V 3101 TCCCGGCTGT CCTACAGTCC TCAGGACTCT ACTCCCTCAG CAGCGTGGTG T V P S S S L G T Q T Y I C N V N 3151 ACCGTGCCCT CCAGCAGCTT GGGCACCCAG ACCTACATCT GCAACGTGAA H K P S N T K V D K K V E P K S 3201 TCACAAGCCC AGCAACACCA AGGTGGACAA GAAAGTTGAG CCCAAATCTT C D K T H T C P P C P A P E L L G 3251 GTGACAAAAC TCACACATGC CCACCGTGCC CAGCACCTGA ACTCCTGGGG G P S V F L F P P K P K D T L M I 3301 GGACCGTCAG TCTTCCTCTT CCCCCCAAAA CCCAAGGACA CCCTCATGAT S R T P E V T C V V V D V S H E 3351 CTCCCGGACC CCTGAGGTCA CATGCGTGGT GGTGGACGTG AGCCACGAAG D P E V K F N W Y V D G V E V H N 3401 ACCCTGAGGT CAAGTTCAAC TGGTACGTGG ACGGCGTGGA GGTGCATAAT A K T K P R E E Q Y N S T Y R V V 3451 GCCAAGACAA AGCCGCGGGA GGAGCAGTAC AACAGCACGT ACCGTGTGGT S V L T V L H Q D W L N G K E Y 3501 CAGCGTCCTC ACCGTCCTGC ACCAGGACTG GCTGAATGGC AAGGAGTACA K C K V S N K A L P A P I E K T I 3551 AGTGCAAGGT CTCCAACAAA GCCCTCCCAG CCCCCATCGA GAAAACCATC S K A K G Q P R E P Q V Y T L P P 3601 TCCAAAGCCA AAGGGCAGCC CCGAGAACCA CAGGTGTACA CCCTGCCCCC S R D E L T K N Q V S L T C L V 3651 ATCCCGGGAT GAGCTGACCA AGAACCAGGT CAGCCTGACC TGCCTGGTCA K G F Y P S D I A V E W E S N G Q 3701 AAGGCTTCTA TCCCAGCGAC ATCGCCGTGG AGTGGGAGAG CAATGGGCAG P E N N Y K T T P P V L D S D G S3751CCGGAGAACA ACTACAAGAC CACGCCTCCC GTGCTGGACT CCGACGGCTC F F L Y S K L T V D K S R W Q Q3801CTTCTTCCTC TACAGCAAGC TCACCGTGGA CAAGAGCAGG TGGCAGCAGG G N V F S C S V M H E A L H N H Y3851GGAACGTCTT CTCATGCTCC GTGATGCATG AGGCTCTGCA CAACCACTAC T Q K S L S L S P G K *3901ACGCAGAAGA GCCTCTCCCT GTCTCCGGGT AAATGATCTAAAGGGCGAAT3951 TCGCCCTTAA GGGCGAATTC TGCAGATTCG AGCATGCATC TAGAGGGCCC 4001 GTTTAAACCC GCTGATCAGC CTCGACTGTG CCTTCTAGTT GCCAGCCATC 4051 TGTTGTTTGC CCCTCCCCCG TGCCTTCCTT GACCCTGGAA GGTGCCACTC 4101 CCACTGTCCT TTCCTAATAA AATGAGGAAA TTGCATCGCA TTGTCTGAGT 4151 AGGTGTCATT CTATTCTGGG GGGTGGGGTG GGGCAGGACA GCAAGGGGGA 4201 GGATTGGGAA GACAATAGCA GGCATGCTGG GGATGCGGTG GGCTCTATGG 4251 CTTCTACTGG GCGGTTTTAT GGACAGCAAG CGAACCGGAA TTGCCAGCTG 4301 GGGCGCCCTC TGGTAAGGTT GGGAAGCCCT GCAAAGTAAA CTGGATGGCT 4351 TTCTTGCCGC CAAGGATCTG ATGGCGCAGG GGATCAAGCT CTGATCAAGA 4401 GACAGGATGA GGATCGTTTC GCATGATTGA ACAAGATGGA TTGCACGCAG 4451 GTTCTCCGGC CGCTTGGGTG GAGAGGCTAT TCGGCTATGA CTGGGCACAA 4501 CAGACAATCG GCTGCTCTGA TGCCGCCGTG TTCCGGCTGT CAGCGCAGGG 4551 GCGCCCGGTT CTTTTTGTCA AGACCGACCT GTCCGGTGCC CTGAATGAAC 4601 TGCAAGACGA GGCAGCGCGG CTATCGTGGC TGGCCACGAC GGGCGTTCCT 4651 TGCGCAGCTG TGCTCGACGT TGTCACTGAA GCGGGAAGGG ACTGGCTGCT 4701 ATTGGGCGAA GTGCCGGGGC AGGATCTCCT GTCATCTCAC CTTGCTCCTG 4751 CCGAGAAAGT ATCCATCATG GCTGATGCAA TGCGGCGGCT GCATACGCTT 4801 GATCCGGCTA CCTGCCCATT CGACCACCAA GCGAAACATC GCATCGAGCG 4851 AGCACGTACT CGGATGGAAG CCGGTCTTGT CGATCAGGAT GATCTGGACG 4901 AAGAGCATCA GGGGCTCGCG CCAGCCGAAC TGTTCGCCAG GCTCAAGGCG 4951 AGCATGCCCG ACGGCGAGGA TCTCGTCGTG ACCCATGGCG ATGCCTGCTT 5001 GCCGAATATC ATGGTGGAAA ATGGCCGCTT TTCTGGATTC ATCGACTGTG 5051 GCCGGCTGGG TGTGGCGGAC CGCTATCAGG ACATAGCGTT GGCTACCCGT 5101 GATATTGCTG AAGAGCTTGG CGGCGAATGG GCTGACCGCT TCCTCGTGCT 5151 TTACGGTATC GCCGCTCCCG ATTCGCAGCG CATCGCCTTC TATCGCCTTC 5201 TTGACGAGTT CTTCTGAATT ATTAACGCTT ACAATTTCCT GATGCGGTAT 5251 TTTCTCCTTA CGCATCTGTG CGGTATTTCA CACCGCATCA GGTGGCACTT 5301 TTCGGGGAAA TGTGCGCGGA ACCCCTATTT GTTTATTTTT CTAAATACAT 5351 TCAAATATGT ATCCGCTCAT GAGACAATAA CCCTGATAAA TGCTTCAATA 5401 ATAGCACGTG CTAAAACTTC ATTTTTAATT TAAAAGGATC TAGGTGAAGA 5451 TCCTTTTTGA TAATCTCATG ACCAAAATCC CTTAACGTGA GTTTTCGTTC 5501 CACTGAGCGT CAGACCCCGT AGAAAAGATC AAAGGATCTT CTTGAGATCC 5551 TTTTTTTCTG CGCGTAATCT GCTGCTTGCA AACAAAAAAA CCACCGCTAC 5601 CAGCGGTGGT TTGTTTGCCG GATCAAGAGC TACCAACTCT TTTTCCGAAG 5651 GTAACTGGCT TCAGCAGAGC GCAGATACCA AATACTGTTC TTCTAGTGTA 5701 GCCGTAGTTA GGCCACCACT TCAAGAACTC TGTAGCACCG CCTACATACC 5751 TCGCTCTGCT AATCCTGTTA CCAGTGGCTG CTGCCAGTGG CGATAAGTCG 5801 TGTCTTACCG GGTTGGACTC AAGACGATAG TTACCGGATA AGGCGCAGCG 5851 GTCGGGCTGA ACGGGGGGTT CGTGCACACA GCCCAGCTTG GAGCGAACGA 5901 CCTACACCGA ACTGAGATAC CTACAGCGTG AGCTATGAGA AAGCGCCACG 5951 CTTCCCGAAG GGAGAAAGGC GGACAGGTAT CCGGTAAGCG GCAGGGTCGG 6001 AACAGGAGAG CGCACGAGGG AGCTTCCAGG GGGAAACGCC TGGTATCTTT 6051 ATAGTCCTGT CGGGTTTCGC CACCTCTGAC TTGAGCGTCG ATTTTTGTGA 6101 TGCTCGTCAG GGGGGCGGAG CCTATGGAAA AACGCCAGCA ACGCGGCCTT 6151 TTTACGGTTC CTGGCCTTTT GCTGGCCTTT TGCTCACATG TTCTTXXXXX Figure 1 shows the plasmid map for SCIB1 and Figure 2 shows a schematic diagram of the engineered IgG encoded by SCIB1. The amino acid sequence of the modified IgG1 light chain (SEQ ID NO: 12), with a leader peptide (SEQ ID NO: 16) at the N-terminus, encoded by pSCIB1 is shown below: SEQ ID NO: 30: Melanoma T cell epitopes contained within the light chain sequence are colour-coded as follows: gp100DR4 (CD4) peptide sequence = WNRQLYPEWTEAQRLD (SEQ ID NO: 3) gp100DR7 (CD4) peptide sequence = GTGRAMLGTHTMEVTVYH (SEQ 1) The amino acid sequence of the modified IgG1 heavy chain (SEQ ID NO: 11), with a leader peptide (SEQ ID NO: 16) at the N-terminus, encoded by pSCIB1 is shown below: SEQ ID NO: 31: Melanoma T cell epitopes contained within the heavy chain sequence are colour-coded as follows: gp100DR7 (CD4) peptide sequence = GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1) TRP-2 (CD8) peptide sequence ID NO: 2) gp100DR4 (CD4) peptide sequence = WNRQLYPEWTEAQRLD (SEQ ID NO: 3) Example 2 – iSCIB1+ A further exemplary nucleic acid for use in the present invention is iSCIB1+. The DNA sequence of iSCIB1+ (SEQ ID NO: 18) is shown below (the amino acid sequences of the encoded light and heavy chains of the expression product are included): 1 GCTGCTTCGC GATGTACGGG CCAGATATAC GCGTTGACAT TGATTATTGA CTAGTTATTA 61 ATAGTAATCA ATTACGGGGT CATTAGTTCA TAGCCCATAT ATGGAGTTCC GCGTTACATA 121 ACTTACGGTA AATGGCCCGC CTGGCTGACC GCCCAACGAC CCCCGCCCAT TGACGTCAAT 181 AATGACGTAT GTTCCCATAG TAACGCCAAT AGGGACTTTC CATTGACGTC AATGGGTGGA 241 GTATTTACGG TAAACTGCCC ACTTGGCAGT ACATCAAGTG TATCATATGC CAAGTACGCC 301 CCCTATTGAC GTCAATGACG GTAAATGGCC CGCCTGGCAT TATGCCCAGT ACATGACCTT 361 ATGGGACTTT CCTACTTGGC AGTACATCTA CGTATTAGTC ATCGCTATTA CCATGGTGAT 421 GCGGTTTTGG CAGTACATCA ATGGGCGTGG ATAGCGGTTT GACTCACGGG GATTTCCAAG 481 TCTCCACCCC ATTGACGTCA ATGGGAGTTT GTTTTGGCAC CAAAATCAAC GGGACTTTCC 541 AAAATGTCGT AACAACTCCG CCCCATTGAC GCAAATGGGC GGTAGGCGTG TACGGTGGGA 601 GGTCTATATA AGCAGAGCTC TCTGGCTAAC TAGAGAACCC ACTGCTTACT GGCTTATCGA BamHI ~~~~~~ 661 AATTAATACG ACTCACTATA GGGAGACCCA AGCTAGCTTG GTACCGAGCT CGGATCCACC M G W S C I I L F L V A T A T G V H S D 721 ATGGGATGGA GCTGTATCAT CCTCTTCTTG GTAGCAACAG CTACCGGAGT CCACTCCGAT V L M T Q S P L S L P V T P G E P A S I 781 GTGTTGATGA CCCAATCTCC ACTCTCCCTG CCTGTCACTC CTGGGGAGCC AGCCTCGATC S C W N R Q L Y P E W T E A Q R L D W Y 841 TCTTGCTGGA ACAGGCAGCT GTATCCAGAG TGGACAGAAG CCCAGAGACT TGACTGGTAT L Q K P G Q S P Q L L I Y A N C S V Y D 901 CTGCAGAAAC CAGGCCAGTC TCCACAGCTC CTGATCTACG CCAACTGCAG TGTTTATGAT F F V W L H Y Y S V R D T L L G P G R P 961 TTTTTTGTGT GGCTCCATTA TTATTCTGTT AGAGATACAT TATTAGGACC AGGACGCCCC Y R G V P D R F S G S G S G T D F T L K 1021 TACAGGGGGG TCCCAGACAG ATTCAGTGGC AGTGGATCAG GGACAGATTT CACACTCAAG I S R V E A E D T G V Y Y C Q C T E V R 1081 ATCAGCAGAG TGGAGGCTGA GGATACCGGA GTGTATTACT GCCAGTGCAC AGAGGTGCGA A D T R P W S G P Y I L R N Q D D R E L 1141 GCCGACACAA GGCCCTGGAG TGGTCCCTAC ATCCTACGAA ACCAGGATGA CCGTGAGCTG BsiWI ~~~~~~~ W P R K F F F G G G T K V E I K R T V A 1201 TGGCCAAGAA AATTCTTCTT CGGTGGAGGC ACCAAGGTGG AAATCAAGCG TACGGTAGCG A P S V F I F P P S D E Q L K S G T A S 1261 GCCCCATCTG TCTTCATCTT CCCGCCATCT GATGAGCAGT TGAAATCTGG AACTGCCTCT V V C L L N N F Y P R E A K V Q W K V D 1321 GTTGTGTGCC TGCTGAATAA CTTCTATCCC AGAGAGGCCA AAGTACAGTG GAAGGTGGAT N A L Q S G N S Q E S V T E Q D S K D S 1381 AACGCCCTCC AATCGGGTAA CTCCCAGGAG AGTGTCACAG AGCAGGACAG CAAGGACAGC T Y S L S S T L T L S K A D Y E K H K V 1441 ACCTACAGCC TCAGCAGCAC CCTGACGCTG AGCAAAGCAG ACTACGAGAA ACACAAAGTC Y A C E V T H Q G L S S P V T K S F N R 1501 TACGCCTGCG AAGTCACCCA CCAGGGCCTG AGCTCGCCCG TCACAAAGAG CTTCAACAGG XhoI ~~~~~~ G E C * 1561 GGAGAGTGTT GACTCGAGCA TGCATCTAGA GGGCCCTATT CTATAGTGTC ACCTAAATGC 1621 TAGAGCTCGC TGATCAGCCT CGACTGTGCC TTCTAGTTGC CAGCCATCTG TTGTTTGCCC 1681 CTCCCCCGTG CCTTCCTTGA CCCTGGAAGG TGCCACTCCC ACTGTCCTTT CCTAATAAAA 1741 TGAGGAAATT GCATCGCATT GTCTGAGTAG GTGTCATTCT ATTCTGGGGG GTGGGGTGGG 1801 GCAGGACAGC AAGGGGGAGG ATTGGGAAGA CAATAGCAGG CATGCTGGGG ATGCGGTGGG 1861 CTCTATGGCT TCTGAGGCGG AAAGAACCAG GCTAGCGTTC GATGTACGGG CCAGATATAC 1921 GCGTTGACAT TGATTATTGA CTAGTTATTA ATAGTAATCA ATTACGGGGT CATTAGTTCA 1981 TAGCCCATAT ATGGAGTTCC GCGTTACATA ACTTACGGTA AATGGCCCGC CTGGCTGACC 2041 GCCCAACGAC CCCCGCCCAT TGACGTCAAT AATGACGTAT GTTCCCATAG TAACGCCAAT 2101 AGGGACTTTC CATTGACGTC AATGGGTGGA GTATTTACGG TAAACTGCCC ACTTGGCAGT 2161 ACATCAAGTG TATCATATGC CAAGTACGCC CCCTATTGAC GTCAATGACG GTAAATGGCC 2221 CGCCTGGCAT TATGCCCAGT ACATGACCTT ATGGGACTTT CCTACTTGGC AGTACATCTA 2281 CGTATTAGTC ATCGCTATTA CCATGGTGAT GCGGTTTTGG CAGTACATCA ATGGGCGTGG 2341 ATAGCGGTTT GACTCACGGG GATTTCCAAG TCTCCACCCC ATTGACGTCA ATGGGAGTTT 2401 GTTTTGGCAC CAAAATCAAC GGGACTTTCC AAAATGTCGT AACAACTCCG CCCCATTGAC 2461 GCAAATGGGC GGTAGGCGTG TACGGTGGGA GGTCTATATA AGCAGAGCTC TCTGGCTAAC 2521 TAGAGAACCC ACTGCTTACT GGCTTATCGA AATTAATACG ACTCACTATA GGGAGACCCA HindIII ~~~~~~ M G W S C I I L F L 2581 AGCTGGCTAG CGTTTAAACT TAAGCTTACC ATGGGATGGA GCTGTATCAT CCTCTTCTTG V A T A T G V H S Q V Q L V E T G G G L 2641 GTAGCAACAG CTACCGGAGT CCACTCCCAG GTGCAGCTGG TGGAGACTGG GGGAGGCTTA I Q P G G S L R M S C G T G R A M L G T 2701 ATCCAGCCTG GAGGGTCCCT GAGAATGTCC TGCGGGACAG GCAGGGCAAT GCTGGGCACA H T M E V T V Y H W V R Q A P G K G L E 2761 CACACCATGG AAGTGACTGT CTACCATTGG GTTCGGCAGG CTCCGGGGAA GGGGCTGGAG W I A Y I G S G G S V Y D F F V W L R F 2821 TGGATCGCAT ACATTGGTAG TGGTGGTAGT GTTTATGATT TTTTTGTGTG GCTCCGATTC T I S R D N S K N T L Y L Q L N S L R A 2881 ACCATTTCCA GAGACAATAG CAAGAACACC CTGTATTTGC AATTGAACAG TCTGAGGGCT E D T A V Y Y C A R V P L D C V L Y R Y 2941 GAGGACACAG CCGTGTATTA CTGTGCCCGA GTCCCCCTGG ATTGTGTTCT GTATCGATAT G S F S V T L D I V Q G W G Q G T T V T 3001 GGTTCCTTTT CCGTCACCCT GGACATTGTC CAGGGTTGGG GCCAAGGAAC CACGGTCACC AfeI ~~~~~~~ V S S A S T K G P S V F P L A P S S K S 3061 GTCTCCAGCG CTTCCACCAA GGGCCCATCG GTCTTCCCCC TGGCACCCTC CTCCAAGAGC T S G G T A A L G C L V K D Y F P E P V 3121 ACCTCTGGGG GCACAGCGGC CCTGGGCTGC CTGGTCAAGG ACTACTTCCC CGAACCGGTG T V S W N S G A L T S G V H T F P A V L 3181 ACGGTGTCGT GGAACTCAGG CGCCCTGACC AGCGGCGTGC ACACCTTCCC GGCTGTCCTA Q S S G L Y S L S S V V T V P S S S L G 3241 CAGTCCTCAG GACTCTACTC CCTCAGCAGC GTGGTGACCG TGCCCTCCAG CAGCTTGGGC T Q T Y I C N V N H K P S N T K V D K K 3301 ACCCAGACCT ACATCTGCAA CGTGAATCAC AAGCCCAGCA ACACCAAGGT GGACAAGAAA V E P K S C D K T H T C P P C P A P E L 3361 GTTGAGCCCA AATCTTGTGA CAAAACTCAC ACATGCCCAC CGTGCCCAGC ACCTGAACTC L G G P S V F L F P P K P K D T L M I S 3421 CTGGGGGGAC CGTCAGTCTT CCTCTTCCCC CCAAAACCCA AGGACACCCT CATGATCTCC R T P E V T C V V V D V S H E D P E V K 3481 CGGACCCCTG AGGTCACATG CGTGGTGGTG GACGTGAGCC ACGAAGACCC TGAGGTCAAG F N W Y V D G V E V H T A W T Q P R E E 3541 TTCAACTGGT ACGTGGACGG CGTGGAGGTG CATACAGCCT GGACACAGCC GCGGGAGGAG Q Y N S T Y R V V S V L T V L H Q D W L 3601 CAGTACAACA GCACGTACCG TGTGGTCAGC GTCCTCACCG TCCTGCACCA GGACTGGCTG N G K E Y K C K V S N K A L P A P I E K 3661 AATGGCAAGG AGTACAAGTG CAAGGTCTCC AACAAAGCCC TCCCAGCCCC CATCGAGAAA 3721 ACCATCTCCA AACCCAAAGG GAGAGCCCAG ACACCACAGG TGTACACCAT ACCCCCACCT 3781 CGGGAACAAA TGTCCAAGAA GAAGGTCAGC CTGACCTGCC TGGTCACCAA CTTCTTCTCT E A I S V E W E S N G Q P E N N Y K T T 3841 GAAGCCATCA GTGTGGAGTG GGAGAGCAAT GGGCAGCCGG AGAACAACTA CAAGACCACG P P V L D S D G S F F L Y S K L T V D K 3901 CCTCCCGTGC TGGACTCCGA CGGCTCCTTC TTCCTCTACA GCAAGCTCAC CGTGGACAAG S R W Q Q G N V F S C S V M H E A L H N 3961 AGCAGGTGGC AGCAGGGGAA CGTCTTCTCA TGCTCCGTGA TGCATGAGGC TCTGCACAAC EcoRV ~~~~~~ H Y T Q K S L S L S P G K * 4021 CACTACACGC AGAAGAGCCT CTCCCTGTCT CCGGGTAAAT GATCTAAAGG GCGATATCGC EcoRI ~~~~~~ 4081 CCTTAAGGGC GAATTCTGCA GATTCGAGCA TGCATCTAGA GGGCCCGTTT AAACCCGCTG 4141 ATCAGCCTCG ACTGTGCCTT CTAGTTGCCA GCCATCTGTT GTTTGCCCCT CCCCCGTGCC 4201 TTCCTTGACC CTGGAAGGTG CCACTCCCAC TGTCCTTTCC TAATAAAATG AGGAAATTGC 4261 ATCGCATTGT CTGAGTAGGT GTCATTCTAT TCTGGGGGGT GGGGTGGGGC AGGACAGCAA 4321 GGGGGAGGAT TGGGAAGACA ATAGCAGGCA TGCTGGGGAT GCGGTGGGCT CTATGGCTTC 4381 TACTGGGCGG TTTTATGGAC AGCAAGCGAA CCGGAATTGC CAGCTGGGGC GCCCTCTGGT 4441 AAGGTTGGGA AGCCCTGCAA AGTAAACTGG ATGGCTTTCT TGCCGCCAAG GATCTGATGG 4501 CGCAGGGGAT CAAGCTCTGA TCAAGAGACA GGATGAGGAT CGTTTCGCAT GATTGAACAA 4561 GATGGATTGC ACGCAGGTTC TCCGGCCGCT TGGGTGGAGA GGCTATTCGG CTATGACTGG 4621 GCACAACAGA CAATCGGCTG CTCTGATGCC GCCGTGTTCC GGCTGTCAGC GCAGGGGCGC 4681 CCGGTTCTTT TTGTCAAGAC CGACCTGTCC GGTGCCCTGA ATGAACTGCA AGACGAGGCA 4741 GCGCGGCTAT CGTGGCTGGC CACGACGGGC GTTCCTTGCG CAGCTGTGCT CGACGTTGTC 4801 ACTGAAGCGG GAAGGGACTG GCTGCTATTG GGCGAAGTGC CGGGGCAGGA TCTCCTGTCA 4861 TCTCACCTTG CTCCTGCCGA GAAAGTATCC ATCATGGCTG ATGCAATGCG GCGGCTGCAT 4921 ACGCTTGATC CGGCTACCTG CCCATTCGAC CACCAAGCGA AACATCGCAT CGAGCGAGCA 4981 CGTACTCGGA TGGAAGCCGG TCTTGTCGAT CAGGATGATC TGGACGAAGA GCATCAGGGG 5041 CTCGCGCCAG CCGAACTGTT CGCCAGGCTC AAGGCGAGCA TGCCCGACGG CGAGGATCTC 5101 GTCGTGACCC ATGGCGATGC CTGCTTGCCG AATATCATGG TGGAAAATGG CCGCTTTTCT 5161 GGATTCATCG ACTGTGGCCG GCTGGGTGTG GCGGACCGCT ATCAGGACAT AGCGTTGGCT 5221 ACCCGTGATA TTGCTGAAGA GCTTGGCGGC GAATGGGCTG ACCGCTTCCT CGTGCTTTAC 5281 GGTATCGCCG CTCCCGATTC GCAGCGCATC GCCTTCTATC GCCTTCTTGA CGAGTTCTTC 5341 TGAATTATTA ACGCTTACAA TTTCCTGATG CGGTATTTTC TCCTTACGCA TCTGTGCGGT 5401 ATTTCACACC GCATCAGGTG GCACTTTTCG GGGAAATGTG CGCGGAACCC CTATTTGTTT 5461 ATTTTTCTAA ATACATTCAA ATATGTATCC GCTCATGAGA CAATAACCCT GATAAATGCT 5521 TCAATAATAG CACGTGCTAA AACTTCATTT TTAATTTAAA AGGATCTAGG TGAAGATCCT 5581 TTTTGATAAT CTCATGACCA AAATCCCTTA ACGTGAGTTT TCGTTCCACT GAGCGTCAGA 5641 CCCCGTAGAA AAGATCAAAG GATCTTCTTG AGATCCTTTT TTTCTGCGCG TAATCTGCTG 5701 CTTGCAAACA AAAAAACCAC CGCTACCAGC GGTGGTTTGT TTGCCGGATC AAGAGCTACC 5761 AACTCTTTTT CCGAAGGTAA CTGGCTTCAG CAGAGCGCAG ATACCAAATA CTGTTCTTCT 5821 AGTGTAGCCG TAGTTAGGCC ACCACTTCAA GAACTCTGTA GCACCGCCTA CATACCTCGC 5881 TCTGCTAATC CTGTTACCAG TGGCTGCTGC CAGTGGCGAT AAGTCGTGTC TTACCGGGTT 5941 GGACTCAAGA CGATAGTTAC CGGATAAGGC GCAGCGGTCG GGCTGAACGG GGGGTTCGTG 6001 CACACAGCCC AGCTTGGAGC GAACGACCTA CACCGAACTG AGATACCTAC AGCGTGAGCT 6061 ATGAGAAAGC GCCACGCTTC CCGAAGGGAG AAAGGCGGAC AGGTATCCGG TAAGCGGCAG 6121 GGTCGGAACA GGAGAGCGCA CGAGGGAGCT TCCAGGGGGA AACGCCTGGT ATCTTTATAG 6181 TCCTGTCGGG TTTCGCCACC TCTGACTTGA GCGTCGATTT TTGTGATGCT CGTCAGGGGG 6241 GCGGAGCCTA TGGAAAAACG CCAGCAACGC GGCCTTTTTA CGGTTCCTGG CCTTTTGCTG 6301 GCCTTTTGCT CACATGTTCT T Figure 3 shows the plasmid map for iSCIB1+ and Figure 4 shows a schematic diagram of the engineered IgG encoded by SCIB1 and iSCIB1+. Table 1 below shows the amino acid sequence of the heavy and light chains within iSCIB+

[0002] FEATURE AMINO ACID SEQUENCE IB LeaderMGWSCIILFLVATATGVHS (SEQ ID NO: 16) Light Variable DVLMTQSPLSLPVTPGEPASISCWNRQLYPEWTEAQRLDWYLQKPGQSPQLLIYANCSVYD FFVWLHYYSVRDTLLGPGRPYRGVPDRFSGSGSGTDFTLKISRVEAEDTGVYYCQCTEVRA (gp100 and TRP2 AA in bold) DTRPWSGPYILRNQDDRELWPRKFFFGGGTKVEIK (SEQ ID NO: 10) Human Kappa Constant RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS region Acc No : P01834 KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 19) (Amino Acids, 1-107) Heavy Variable QVQLVETGGGLIQPGGSLRMSCGTGRAMLGTHTMEVTVYHWVRQAPGKGLEWIAYIGSGGS VYDFFVWLRFTISRDNSKNTLYLQLNSLRAEDTAVYYCARVPLDCVLYRYGSFSVTLDIVQ (gp100 and TRP2 AA in bold) GWGQGTTVTVSS (SEQ ID NO: 9) HuIgG1 CH1-Hinge-CH2- ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG CH3 LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHTAWTQPREEQYNSTY iV1 (murine IgG323 AA RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKPKGRAQTPQVYTIPPPREQMSKK substitutions in bold) KVSLTCLVTNFFSEAISVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 20) Acc No : P01857 (Amino Acids, 1-330) Example 3 – details of clinical study TABLE OF CONTENTS LIST OF ABBREVIATIONS DEFINITION OF TERMS 1. PROTOCOL SYNOPSIS 2. INTRODUCTION AND BACKGROUND INFORMATION 2.1. Introduction 2.2. Findings from Nonclinical and Clinical Studies 2.2.1. Nonclinical Studies 2.2.2. Clinical Studies 2.3. Dose Selection Rationale 2.4. Known and Potential Benefits and Risks to Patients 3. STUDY OBJECTIVES AND ENDPOINTS 3.1. Primary Objectives and Endpoints 3.1.1. Run-In Sub-Cohorts 3.1.2. Main Study 3.2. Secondary Objectives and Endpoints 3.2.1. Main Study 3.3. Exploratory Objectives and Endpoints 4. STUDY DESIGN 4.1. General Study Design 4.2. Planned Number of Patients and Countries 4.3. Study Duration 4.4. Assignment of Patient Numbers 4.5. Blinding and Randomisation 4.6. Justification for Study Design and Selection of Patient Population 4.7. Periodic Review of Safety and Efficacy 4.8. Criteria for Study Completion 4.9. Schedule of Procedures and Assessments 4.10. Post-Treatment Follow-up 5. SELECTION AND WITHDRAWAL OF PATIENTS 5.1. Inclusion Criteria 5.2. Exclusion Criteria 5.3. Treatment Discontinuation 5.4. Withdrawal Criteria 5.4.1. Replacement Patients 5.4.2. Rescreening 5.5. Study Termination 6. TREATMENTS 6.1. Investigational Medicinal Product 6.1.1. Non-Investigational Medicinal Product: Nivolumab with Ipilimumab 6.1.2. Non-Investigational Medicinal Product: Pembrolizumab 6.2. Preparation, Handling, Storage, Accountability and Destruction of Investigational Medicinal Product 6.2.1. SCIB1 6.2.2. Checkpoint Inhibitors 6.2.3. Drug Accountability 6.3. SCIB1 Administration Procedure 6.4. Checkpoint Inhibitors: Use and Precautions 6.5. Treatment Schedule 6.6. Dose Adjustments, Modifications, and Delays 6.6.1. Infusion Reactions 6.6.2. Dose Adjustments and Modifications 6.6.3. Checkpoint Inhibitor Treatment Delays and Discontinuation 6.7. Prior and Concomitant Medication and Therapy 6.7.1. Prohibited Medication and Therapy 6.7.2. Permitted Medication, Pre-Medication, and Supportive Care 6.8. Monitoring of Patient Compliance 7. ASSESSMENT OF EFFICACY 7.1. Tumour Imaging and RECIST Assessment 7.2. Progression-Free and Overall Survival 8. PHARMACODYNAMIC AND BIOMARKER ASSESSMENTS 8.1. Blood Samples 8.1.1. Sample Handling and Shipment 8.1.2. Assessments and Analysis of Study-Specific Blood Samples 8.2. Tumour Samples 8.2.1. Assessments and Analysis of Study-Specific Tumour Samples 9. ASSESSMENT OF SAFETY 9.1. Adverse Events 9.1.1. Definition of an Adverse Event 9.1.2. Recording and Reporting of Adverse Events 9.1.3. Severity of an Adverse Event 9.1.4. Relationship of an Adverse Event to Study Treatment or Device 9.1.5. Protocol Deviations Due to an Adverse Event 9.2. Serious Adverse Events 9.2.1. Definition of a Serious Adverse Event 9.2.2. Expectedness 9.2.3. Reporting of a Serious Adverse Event 9.3. Pregnancy 9.4. Administration and Medication Error Related to Study Treatment 9.5. Clinical and Laboratory Assessments and Tests 9.5.1. Serum Chemistry, Haematology, and Urinalysis 9.5.2. Other Clinical Laboratory Tests 9.5.3. Medical History 9.5.4. Physical Examination 9.5.5. Injection Site Reaction 9.5.6. Vital Signs 9.5.7. Electrocardiography 9.5.8. Ophthalmic Examination 9.5.9. Performance Status Evaluation 10. STATISTICS 10.1. Sample Size and Power Considerations 10.1.1. Run-In Sub-Cohorts 10.1.2. Cohort 1: Nivolumab with Ipilimumab 10.1.3. Cohort 2: Pembrolizumab 10.2. Analysis Sets 10.2.1. Full Analysis Set 10.2.2. Safety Analysis Set 10.2.3. Per Protocol Set 10.3. Data Handling Conventions 10.4. Interim Analyses 10.5. Study Population 10.5.1. Patient Disposition 10.5.2. Demographics and Baseline Characteristics 10.6. Efficacy Analysis 10.6.1. Efficacy Endpoints 10.6.2. Planned Method of Analysis 10.7. Safety Analysis 10.7.1. Adverse Events 10.7.2. Laboratory Parameters 10.7.3. Physical Examination 10.7.4. Vital Signs 10.7.5. 12-Lead Electrocardiogram 10.7.6. Injection Site Reactions 10.7.7. Concomitant Medications 10.8. Pharmacodynamic and Biomarker Analyses 10.9. Reporting Deviations from the Statistical Analysis Plan QUALITY CONTROL AND QUALITY ASSURANCE REGULATORY AND ETHICAL OBLIGATIONS 12.1. Compliance with Good Clinical Practice 12.2. Informed Consent 12.3. Contact with Primary Care Physician 12.4. Research Ethics Committee 12.5. Regulatory Approval 12.6. Periodic Review of Safety and Efficacy 12.7. Registration of the Clinical Study in Trial Registry Websites 12.8. Patient Confidentiality 12.9. Data Protection 12.10. Future Use of Stored Specimens ADMINISTRATIVE AND LEGAL OBLIGATIONS 13.1. Investigator Obligations 13.2. Access to Source Data and Documents 13.3. Insurance 13.4. Protocol and Informed Consent Amendments 13.5. Trial Documentation and Data Storage 13.6. Availability and Retention of Investigational Records 13.7. Data Collection 13.8. Language 13.9. Clinical Monitoring, Source Data Verification, and Audits 13.10. Protocol Deviations and Violations 14. REFERENCES

[0003] LIST OF ABBREVIATIONS Abbreviation Definition ADL activities of daily living AE adverse event AJCC American Joint Committee on Cancer ALT alanine aminotransferase aPTT activated partial thromboplastin time AST aspartate aminotransferase ATC Anatomical Therapeutic Chemical CFSE carboxyfluorescein diacetate succinimidyl ester CD3+ cluster of differentiation 3 positive CD4+ cluster of differentiation 4 positive CD8+ cluster of differentiation 8 positive CFR Code of Federal Regulations CPI checkpoint inhibitor CR complete response CRF case report form CSR clinical study report CT computed tomography CTCAE Common Terminology Criteria for Adverse Events CTL cytotoxic T lymphocyte CTLA-4 CTL associated protein 4 DLT dose-limiting toxicity DNA deoxyribonucleic acid ECG electrocardiogram ECOG Eastern Cooperative Oncology Group ELISpot enzyme-linked immunospot EOT end of treatment EU European Union EUCAN European Cancer Observatory Cancer Database EudraCT European Union Drug Regulating Authorities Clinical Trials FAS full analysis set FT3 free triiodothyronine FT4 free thyroxine gp100 glycoprotein 100 GCP Good Clinical Practice GLP Good Laboratory Practice HBV hepatitis B virus HCV hepatitis C virus HIV human immunodeficiency virus HLA human leukocyte antigen IB Investigator’s brochure ICF informed consent form ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use iCPD confirmed immune progressive disease iCR immune complete response IFN Interferon IgG1 immunoglobulin-1 i.m. intramuscular IMP investigational medicinal product INR international normalised ratio iPR immune partial response iRECIST modified RECIST 1.1 for immune-based therapeutics iSD immune stable disease IUDs intrauterine devices iUPD unconfirmed immune progressive disease i.v. intravenous LDH lactate dehydrogenase mAb monoclonal antibody MedDRA Medical Dictionary for Regulatory Activities MHC major histocompatibility complex MRI magnetic resonance imaging NHS National Health Service Non-IMP non-investigational medicinal product NSAIDs non-steroidal anti-inflammatory drugs NYHA New York Heart Association ORR objective response rate OS overall survival PD progressive disease PD-1 programmed cell death protein 1 PD-L1 programmed death-ligand 1 PD-L2 programmed death-ligand 2 PFS progression-free survival PPS per protocol set PR partial response QPCR quantitative polymerase chain reaction RBC red blood cell REC research ethics committee RECIST response evaluation criteria in solid tumours SAE serious adverse event SAF safety analysis set SAP statistical analysis plan SD stable disease SJS Stevens-Johnson syndrome SmPC summary of product characteristics SOP standard operating procedure SUSAR suspected, unexpected, serious adverse reaction TDS-IM TriGrid™ delivery system − intramuscular TEAE treatment emergent adverse event TEN toxic epidermal necrolysis TRP-2 tyrosinase-related protein-2 TSH thyroid stimulating hormone ULN upper limit of normal UK United Kingdom US United States WBC white blood cell WHO World Health Organisation DEFINITION OF TERMS Term Definition Study drug SCIB1. Study Day / Study the day of administration of the first dose of SCIB1 is designated as Day 1. assessment visit Subsequent study visits will be conducted on the same day each week (± any time window indicated in Table 2). Pre-Screening Visits will be conducted to test for specific human leukocyte antigens (HLAs). HLA consent must be obtained prior to blood sample collection for HLA testing. Study Screening Visits screening procedures and assessments are those that will be completed in the period between Day −28 to Day 1 (before the first dose administration of study drug). Main study consent must be obtained prior to the conduct of any screening evaluations. Study Treatment Visits will commence after screening and the last visit is the day when the end of treatment visit is completed. End of Treatment Visits will be completed for all patients 30 days (± 10 days) after the final dose of SCIB1, or as soon as possible if the decision to discontinue is made more than 30 days after the last dose. The EOT visit may replace the 12 +3 weeks assessment visit for patients who discontinue SCIB1 at a study assessment visit. Post-treatment Follow-up will be conducted every 12 weeks (± 2 weeks) after the final dose of SCIB1 , Visits and will continue for 97 weeks from the first dose of SCIB1. Study Participation defined as the period from the date of main study consent until the date of the final post-treatment assessment. End of Study is defined as the time when all patients have completed the post-treatment follow-up period or have withdrawn. . PROTOCOL SYNOPSIS Indication Metastatic melanoma Rationale Together with BRAF inhibitors, blockade of checkpoint proteins has transformed the treatment of advanced melanoma. Pembrolizumab, a monoclonal antibody (mAb) targeting the programmed cell death protein 1 (PD-1) checkpoint protein, has been shown to be effective in multiple studies. In a study in ipilimumab- refractory melanoma 26% of patients had an objective response to pembrolizumab (Robert et al. 2014), while in a second study in patients at an earlier stage of treatment the objective response rate (ORR) was 33% (Robert et al.2015a). In a study of patients with previously untreated melanoma the response rate to nivolumab, another PD-1 mAb, was 40% (Robert et al.2015b). Combination therapy with anti-PD-1 and anti-cytotoxic T lymphocyte (CTL)- associated protein 4 (CTLA-4) checkpoint inhibitors has led to an increase in these response rates. In a study of two dosing regimens, nivolumab 3 mg / kg combined with 1 mg / kg ipilimumab resulted in an ORR of 45.6%, whereas 1 mg / kg nivolumab with 3 mg / kg ipilimumab resulted in an ORR of 50.6%. The progression- free survival (PFS) and overall survival (OS) were similar between the two regimens. However, there were more Grade 3 / 4 adverse reactions with nivolumab 1 mg / kg with ipilimumab 3 mg / kg compared with nivolumab 3 mg / kg with ipilimumab 1 mg / kg (48.3% versus 33.9%) (Lebbé 2019). In considering the patients who fail to respond to a checkpoint inhibitor one hypothesis is that the tumour is not adequately recognised by the patient’s immune system. Therefore, in these patients, the blockade of the negative immune regulator is ineffective. Recent studies have reported that the frequencies and types of mutations in a melanoma are predictive of response to checkpoint protein antibodies. Tumours with a low mutation burden are less likely to be immunogenic, and therefore less likely to benefit from checkpoint protein blockade (Gubin et al. 2014, Snyder et al.2014). One means to improve the recognition of tumour cells by the immune system is by administration of a cancer vaccine. There is therefore a strong rationale to treat patients receiving a checkpoint inhibitor with a melanoma-targeted cancer vaccine such as SCIB1. The goal of treating with a therapeutic vaccine is to increase the ORR to the checkpoint inhibitor and / or increase the depth and duration of response. SCIB1 is a deoxyribonucleic acid (DNA) plasmid vaccine encoding two cluster of differentiation 8 (CD8) epitopes from the melanoma antigens tyrosinase-related protein-2 (TRP-2) and glycoprotein 100 (gp100), plus two cluster of differentiation 4 (CD4) epitopes from gp100. In a Phase 1 / 2 study in 35 patients with melanoma, immunisation with SCIB1 was found to induce T cell responses to TRP-2 and gp100 in 88% of evaluable patients. Two of nine patients with measurable disease receiving higher doses of SCIB1 (4─8 mg) had measurable reductions in tumour lesions with one patient meeting the criteria for a Response Evaluation Criteria in Solid Tumours (RECIST) partial response (PR). Sixteen patients received SCIB1 at doses of 2─4 mg in the adjuvant setting, and all 16 were alive with a median observation time of 39 months (range 33 to 52 months). At 2 years, 12 (75%) of these patients remained disease-free without additional treatment beyond continued SCIB1 (SCIB1-001 Clinical Study Report ([CSR); data on file). A further four patients have since been treated in the adjuvant setting at a dose of 8 mg and have completed follow-up. The rationale of adding SCIB1 to checkpoint inhibitor therapy is also supported by studies in a transgenic B16 tumour model in mice with SCIB1 and an antibody to murine PD-1. The studies demonstrated superior survival of the mice with the combination relative to SCIB1 p < 0.01) or the PD-1 antibody alone (p < 0.05) (Xue et al.2016). The purpose of the current study is to determine whether the addition of SCIB1 to standard of care checkpoint inhibitors can improve the ORR of patients with advanced melanoma relative to the checkpoint inhibitors alone. Study Population Adult patients with histologically confirmed, unresectable Stage III or Stage IV melanoma who are candidates for nivolumab with ipilimumab doublet checkpoint inhibitor therapy or for pembrolizumab monotherapy and have received no previous systemic treatment for advanced disease. Number of Patients Cohort 1: Nivolumab with Ipilimumab Planned Forty-three patients will be enrolled using Simon’s Optimal 2-stage design (Simon 1989). Six of these patients will form a Run-in sub-cohort for the formal assessment of SCIB1-related dose-limiting toxicities (DLT)s for the combination. An additional nine patients will be enrolled for the first stage, and if there are eight or fewer clinical responses (RECIST 1.1 objective response [complete response (CR) or PR] within 25 weeks of the first dose of SCIB1), the cohort will be stopped. Otherwise, an additional 28 patients will be enrolled in the second stage for a total of 43 patients. Recruitment will continue until a decision on Stage 1 has been made. Cohort 2: Pembrolizumab Forty-four patients will be enrolled using Simon’s Optimal 2-stage design (Simon 1989). Six of these patients will form a Run-in sub-cohort for the formal assessment of SCIB1-related DLTs for the combination. An additional eight patients will be enrolled for the first stage, and if there are five or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), the cohort will be stopped. Otherwise, an additional 30 patients will be enrolled in the second stage for a total of 44 patients. Recruitment will continue until a decision on Stage 1 has been made. In both cohorts, additional patients will be enrolled to replace patients who are non-evaluable. Enrolment will stop if a cohort is not able to complete recruitment within a reasonable time of the other cohort being fully enrolled. Additionally, as part of the interim analysis a feasibility assessment of further enrolment to the cohort not reaching the first stage quota will be performed upon the other cohort reaching the first stage. Number of Sites Up to 20 (worldwide). Planned Objectives Run-In Sub-Cohorts Primary Objective To assess the safety and tolerability of intramuscular (i.m.) SCIB1, in patients receiving either nivolumab with ipilimumab or pembrolizumab. Full Study Primary Objective To determine whether the addition of SCIB1 to either nivolumab with ipilimumab or pembrolizumab increases the ORR relative to historical data for the combination of nivolumab with ipilimumab or pembrolizumab alone in this patient population, as measured by RECIST 1.1. Secondary Objectives i. To determine whether the addition of SCIB1 to either nivolumab with ipilimumab or pembrolizumab improves the duration of response relative to historical data for the combination of nivolumab with ipilimumab or pembrolizumab alone in this patient population. ii. To determine the ORR as measured by the modified RECIST 1.1 criteria for immune-based therapeutics (iRECIST; Seymour et al.2017). iii. To assess the PFS rate for all patients at Week 49 (Day 344) and Week 97 (Day 680). iv. To assess the overall survival (OS) rate for all patients at Week 49 (Day 344) and Week 97 (Day 680). v. To further assess the safety and tolerability of SCIB1 in patients receiving either nivolumab with ipilimumab or pembrolizumab. Exploratory Objective i. To explore the relationship between immune response and clinical outcome. Endpoints Run-In Sub-Cohorts Primary Endpoint Safety and tolerability of SCIB1 in patients receiving either nivolumab with ipilimumab or pembrolizumab as assessed by the recording of adverse events (AEs) (National Cancer Institute Common Terminology Criteria for Adverse Events; CTCAE v5.0), vital signs, physical examination, serum chemistry and haematology, thyroid function test, injection site assessment, urinalysis, 12-lead electrocardiogram (ECG), performance status, and concomitant medications. The target SCIB1-related DLT rate is 0 or 1 in 6 evaluable patients. Full Study Primary Endpoint ORR, measured using the RECIST 1.1 criteria. Secondary Endpoints i. Duration of response, measured from the point of first response (CR or PR) to the date of disease progression (per RECIST 1.1) or death due to any cause. ii. ORR as determined using iRECIST (Seymour et al.2017). iii. PFS rate is defined as the proportion of patients who have not progressed (per RECIST 1.1 and iRECIST), or started new anticancer therapy, or died at each specified timepoint. iv. OS rate is defined as the proportion of patients who remain alive at each specified timepoint. v. Safety and tolerability, by measurements as defined for the Run-in sub- cohorts above. Exploratory Endpoint i. Immune response (enzyme-linked immunospot [ELISpot] and other assays) performed on peripheral blood samples from patients at a limited number of sites. Inclusion Criteria 1) Patient has histologically confirmed, unresectable Stage III or Stage IV melanoma as defined by the American Joint Committee on Cancer (AJCC) (Gershenwald et al.2017). Patients with a diagnosis of melanoma of unknown primary are eligible. 2) Patient has not received prior systemic treatment for advanced disease. Prior adjuvant treatment, defined as treatment following resection of all detectable disease, is permitted; last dose must be at least 4 weeks before the first dose of SCIB1. 3) Patient has been clinically evaluated and checkpoint inhibition with either nivolumab with ipilimumab or pembrolizumab has been determined to be an appropriate treatment for their advanced disease. 4) Patient’s BRAF status must be known; patients with BRAF mutation positive disease may be enrolled without BRAF-inhibitor treatment at the discretion of the Investigator, provided that they have no evidence of rapidly progressive disease (PD). 5) Patient has at least one measurable lesion per RECIST 1.1 criteria by computed tomography (CT) scan or magnetic resonance imaging (MRI). 6) Patient is human leukocyte antigen (HLA)-A2 positive.* 7) Patient is positive for HLA-DR4, HLA-DR7, HLA-DR53 or HLA-DQ6.* 8) Patient is at least 18 years of age. 9) Patient has a life expectancy of more than 3 months. 10) Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 11) Patient has adequate organ function as determined by the following laboratory values: Absolute neutrophil count ≥ 1.5 x 109 / L Lymphocyte count ≥ 0.5 x 109 / L Platelet count ≥ 100 x 109 / L Haemoglobin > 9 g / dL (> 5.6 mmol / L) Serum creatinine or ≤ 1.5 x upper limit of normal (ULN) creatinine clearance > 50 mL / min ≤ 1.5 x ULN or < 3.0 mg / dL if patient has Serum total bilirubin Gilbert’s syndrome ≤ 2.5 x ULN or ≤ 5.0 x ULN if liver Serum transaminases metastases present Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 12) Patient must be able and willing to provide written REC-approved informed consent prior to any study-related procedure. In the event that the patient is re-screened for study participation or if a protocol amendment alters the care of an ongoing patient, a new REC-approved informed consent form (ICF) must be signed. 13) Women of child-bearing potential (including women ≤ 12 months from last menstrual period) must have a negative serum pregnancy test during Screening (within the 72 hours before planned administration of the first dose of study drug on Day 1) and be neither breastfeeding nor intending to become pregnant during study participation, and shall be warned of potential foetal harm from nivolumab with ipilimumab or pembrolizumab. Women of childbearing potential must agree to use highly effective contraceptive methods prior to study entry, for the whole duration of study treatment, and for 120 days after discontinuation of SCIB1 or nivolumab with ipilimumab or pembrolizumab, whichever is last. 14) Men who are potentially fertile with partners of childbearing potential must agree to use highly effective contraceptive methods for the whole duration of study treatment and for 120 days after discontinuation of SCIB1 or nivolumab with ipilimumab or pembrolizumab, whichever is last. 15) Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. * HLA testing will be conducted at accredited laboratories by molecular (DNA) typing. Exclusion Criteria 1) Patient has a diagnosis of mucosal, or ocular melanoma. 2) Patient has active central nervous system metastases or carcinomatous meningitis. (Patients with a response to previous treatment for brain metastases are eligible provided that they are stable without MRI evidence of progression for at least 4 weeks prior to the first dose of study treatment, and systemic steroids have been withdrawn for at least 1 week prior to the first dose of study drug. Patients who have received recent radiosurgery treatment for brain metastases are eligible provided that the patient is completely recovered from post-surgical sequelae, the screening scan must be at least 4 weeks after radiosurgery and systemic steroids have been withdrawn for at least 1 week prior to the first dose of study drug.) 3) Patient has previously received a treatment to block CTLA-4, PD-1, PD-L1, or programmed death-ligand 2 (PD-L2) with the following exception: patients who have received adjuvant treatment with these treatments are eligible. 4) Patient is expected to require any other form of systemic or localised anticancer therapy while receiving study treatment. ) Patient is taking any systemic steroid therapy within one week of the first dose of study drug or is receiving any other form of immune suppressant medication. Physiological doses of systemic steroids such as those for the management of adrenal insufficiency, as well as topical and inhaled steroids, such as those for the management of asthma, are permitted. ) Patient is receiving treatment with any investigational product within 28 days (or 5 half-lives of the treatment concerned if longer than 28 days) prior to the first dose of study treatment. ) Patient has a previous (within 5 years) or current malignancy with the exception of melanoma, and curatively treated local tumours such as carcinoma-in-situ of the breast, cervix, basal or squamous cell carcinoma of the skin, prostate cancer with Gleason grade < 6 and prostate specific antigen within normal range. ) Patient has a concurrent illness which would preclude study conduct and assessment, including, but not limited to uncontrolled medical conditions, uncontrolled and active infection (considered opportunistic, life threatening, or clinically significant), uncontrolled risk of bleeding, or uncontrolled diabetes mellitus, or pulmonary disease (including obstructive pulmonary disease, pulmonary fibrosis, and history of symptomatic bronchospasm), or alcoholic liver disease, or primary biliary cirrhosis. Caution should be used for patients with suspected or diagnosed epilepsy. ) Patient has New York Heart Association (NYHA) class III or IV heart disease, myocardial infarction within previous 6 months, a heart rate of ≤ 50 beats per minute, a history of significant cardiac abnormality and / or clinically significant abnormal baseline ECG reading, active ischaemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant arrhythmia requiring therapy including anticoagulants, uncontrolled hypertension (> 140 / 90 mm Hg), significant cerebrovascular disease, or congestive heart failure. 0) Patient has a history of severe hypersensitivity reaction to treatment with a mAb. 1) Patient has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents (patients with vitiligo or resolved childhood asthma / atopy are an exception and are not excluded for these conditions). The following patients are not excluded from the study: patients who require intermittent use of bronchodilators or local steroid injections, patients with hypothyroidism stable on hormone replacement, and patients who receive physiological doses of steroids as replacement therapy, such as those for the management of adrenal insufficiency. In such cases the recruiting investigator should discuss the patients’ eligibility with the study Medical Monitor prior to enrolment. 12) Patient has received a vaccine within the 28 days prior to first dose of study treatment. 13) Patient has a known history of human immunodeficiency virus (HIV), or has any positive test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating active acute or chronic infection. 14) Patient has a known current or recent history (within the last year) of substance abuse including illicit drugs or alcohol. Treatment SCIB1 treatment will be permanently discontinued in the event of: Discontinuation ^ any DLT related to the vaccine ^ confirmed disease progression and / or the initiation of a new anticancer treatment ^ pregnancy ^ a Sponsor request to discontinue treatment ^ a patient (or their legal representative) request to discontinue treatment ^ a severe or life-threatening AE that in the opinion of the Investigator necessitates the permanent discontinuation of treatment ^ noncompliance with the treatments, procedures, and assessments of the study in the opinion of the study Investigator; or ^ an illness that would interfere with continued SCIB1 treatment. Study Withdrawal A patient will be withdrawn from the study if: Criteria ^ they (or their legal representative) withdraw consent ^ they request permanent discontinuation of treatment and all subsequent study-related activities, including the collection of follow-up information from the patient / caregiver, relatives, medical records, or healthcare provider; or ^ the Sponsor decides to discontinue the study. At the time of withdrawal, the Investigator will document the reason for discontinuation in the patient’s medical chart and case report form (CRF). Patients may discontinue treatment without withdrawing from the study. Study Design and This is a Phase 2, multicentre, open-label study of SCIB1 in patients with Methodology advanced unresectable melanoma receiving either nivolumab with ipilimumab or pembrolizumab. There will be two cohorts, depending on whether the patient is to receive standard of care doublet therapy (nivolumab with ipilimumab) or monotherapy (pembrolizumab) checkpoint inhibitors. In the sub-cohort of each treatment cohort, six patients will receive both SCIB1 and either nivolumab with ipilimumab or pembrolizumab to ensure that there are no unexpected severe toxicities that would prevent further testing. The first two patients in each of these cohorts will be enrolled sequentially at an interval of no less than 14 days to minimise the risk of unexpected severe toxicities. Provided no more than one patient in six evaluable patients experiences a SCIB1-related DLT by Day 35, the remaining patients will be enrolled in the cohort using Simon’s Optimal 2-stage design (Simon 1989). Cohort 1: Nivolumab with Ipilimumab In the first stage, 15 patients (including the six patients from the Run-in sub-cohort) will be enrolled and if there are eight or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), the cohort will be stopped. Otherwise, an additional 28 patients will be enrolled in the second stage for a total of 43 patients. Recruitment will continue until a decision on Stage 1 has been made. Cohort 2: Pembrolizumab In the first stage, 14 patients (including the six patients from the Run-in sub-cohort) will be enrolled and if there are five or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), the cohort will be stopped. Otherwise, an additional 30 patients will be enrolled in the second stage for a total of 44 patients. Recruitment will continue until a decision on Stage 1 has been made. Enrolment will stop if a cohort is not able to complete recruitment within a reasonable time of the other cohort being fully enrolled. Additionally, as part of the interim analysis a feasibility assessment of further enrolment to the cohort not reaching the first stage quota will also be performed upon the other cohort reaching the first stage. DLTs are defined as follows: ^ Drug-related non-haematologic AEs of CTCAE v5.0 Grade ≥ 3 with the exception of: o Grade ≥ 3 gastrointestinal toxicities (nausea, vomiting, diarrhoea, constipation) that can be managed by anti-emetics and other therapies and that do not exceed a period of 48 hours· asymptomatic laboratory changes (other than renal and hepatic laboratory values, and Grade 4 lipase / amylase) that can be successfully supplemented (e.g., electrolyte replacement) within 72 hours o Grade 3 fatigue lasting less than 72 hours o Grade ≥ 3 elevation of ALT or AST for patients with liver metastases that resolves to Grade ≤ 2 within 7 days. Drug-related haematologic AEs of CTCAE v5.0 Grade ≥ 4, thrombocytopenia Grade 3 (platelet count decrease < 50,000 – 25,000 / mm3) with haemorrhage, and Grade 3 haemolysis (transfusion or medical intervention indicated, e.g., steroids), and Grade 3 febrile neutropenia (absolute neutrophil count < 1000 / mm3with a single temperature of > 38.3 °C [101 °F] or a sustained temperature of ≥ 38 °C [100.4 °F] for more than one hour). Toxicities that meet these criteria and are considered related to the administration of study agents will be considered a DLT. Grade 3 events clearly related to tumour flare (local pain, irritation, localised rash) will not be considered DLTs. DLTs in the Run-in sub-cohorts will be assessed up to Day 35. Patients in the Run- in sub-cohorts who withdraw from the study before study Week 5 (Day 36) for reasons other than a DLT will be replaced. In the event that more than one of six patients in the Run-in sub-cohorts has a SCIB1-related DLT, the available safety data will be reviewed by the Investigators and the Sponsor, and a decision made on whether to enrol further patients into the Run-in sub-cohorts to evaluate the safety of SCIB1 in patients receiving either nivolumab with ipilimumab or pembrolizumab. This step is included since some events that occur with the approved use of checkpoint inhibitors meet the definition of a DLT and the contribution, if any, of SCIB1 will need to be assessed. Related CTCAE Grade ≥ 3 events occurred in 10% of 277 patients with melanoma receiving pembrolizumab alone at the recommended dose and schedule (Robert et al.2015a). In the case of the combination of nivolumab with ipilimumab, Grade 3-4 toxicities occurred in 33.9% of 180 patients receiving 3 mg / kg nivolumab with 1 mg / kg ipilimumab, and 48.3% of 178 patients receiving 1 mg / kg nivolumab with 3 mg / kg ipilimumab (Lebbé 2019). In the SCIB1-001 monotherapy study in melanoma patients (n = 35) only two Grade 3 / 4 events were considered related to SCIB1: a Grade 3 event of injection site haematoma and Grade 3 anxiety in a patient that was related to the electroporation procedure used in that study. In this study, the PharmaJet Stratis® device will be used which, in an ongoing study, has been associated with only mild discomfort. Any patient recruited under previous versions of the protocol who has received SCIB1 using the TriGrid™ delivery system version 2.0 (TDS-IM) electroporation device will be re-consented to continue administration using the PharmaJet Stratis® device. A decision to expand enrolment in these circumstances will require review and approval by the Investigators and the Sponsor after a formal review of data. Careful assessment for excess severe toxicity will continue on an ongoing basis in the remainder of the study. During the screening period of up to 28 days patients will complete procedures and assessments to confirm eligibility (see Table 2 for details). Written informed consent must be obtained prior to performing any protocol-specific procedure. Test results and tumour imaging from routine clinical management (including those conducted before written informed consent) are acceptable for screening if obtained within the specified screening time window. A separate consent form will be used for HLA testing; HLA consent must be obtained prior to the screening. During the treatment phase, patients will be monitored for safety and for tumour response and disease progression, as well as survival and the start of any new anticancer therapy. Stopping Rules Grade ≥ 3 AEs, laboratory values, and serious adverse events (SAEs) will be reviewed at regular intervals by the Investigators and the Sponsor. The study will be stopped if at any point the toxicity of SCIB1 in addition to either nivolumab with ipilimumab or pembrolizumab is such that the risk / benefit ratio no longer supports continued investigation. Duration of After a screening period of up to 28 days, patients will receive trial treatment until Participation disease progression, unacceptable toxicity or until Week 85 (Day 596). Patients will be assessed for a period of 97 weeks from the first dose of SCIB1 for tumour response, disease progression, initiation of new cancer treatment and survival. IMP Treatment SCIB1 Four i.m. injections each of 2 mg SCIB1 (8 mg total dose), administered using the PharmaJet Stratis® needle-free injection device, at Weeks 0, 4, 7, 13, 25 (Days 1, 29, 50, 92 and 176, respectively) and every 12 weeks thereafter up to Week 85 (Day 596). On days when both SCIB1 and either nivolumab with ipilimumab or pembrolizumab are administered, SCIB1 will be administered before nivolumab with ipilimumab or pembrolizumab. Any patient recruited under previous versions of the protocol who has received SCIB1 using the TDS-IM electroporation device will be re-consented to continue administration using the PharmaJet Stratis® device. SCIB1 will be permanently discontinued in the event of any DLT related to the vaccine. Non-IMP Treatments Checkpoint Inhibitors Treatment with either nivolumab with ipilimumab or with pembrolizumab will be at the discretion of the Study Investigator and according to standard of care, as detailed in the relevant Summary of Product Characteristics (SmPC) and clinical guidelines. The first dose of checkpoint inhibitors should be administered at Week 1 following the first SCIB1 dose to ensure an adequate primary immune response following the first SCIB1 dose (Massarelli et al 2019). Checkpoint inhibitor treatment beyond the 85 week study duration will be at the discretion of the study investigator, as part of standard of care. Management of Systemic corticosteroids are only permitted for the management of immune- Immune-Mediated mediated adverse events (with the exception of physiologic replacement therapy). Toxicities Management of specific immune-mediated toxicities should follow guidance in the checkpoint inhibitor’s SmPC. Dose Modifications In the event of adverse events, the investigator should consider withholding, and Treatment Delays discontinuing or resuming checkpoint inhibitors as detailed in the relevant SmPC and clinical guidelines. SCIB1 may be continued in patients when nivolumab with ipilimumab or pembrolizumab has been withheld or discontinued provided that, in the opinion of the Investigator, it is in the patient’s interests to do so. In addition, the patient must have shown no evidence of clinical disease progression and the adverse reaction(s) that resulted in the withholding of nivolumab with ipilimumab or pembrolizumab must have improved by the time of the next SCIB1 dose. Patients with BRAF mutation positive disease must be informed of the available BRAF targeted treatment options and must re-consent in order to continue receiving SCIB1 alone. SCIB1 dosing will be continued as per the schedule in Table 2. If SCIB1 doses are missed, for example due to the occurrence of adverse events resulting from administration of nivolumab with ipilimumab or pembrolizumab, the missed doses may be administered after Week 13, with a minimal interval of at least 15 days but preferably maximising the interval between doses to 6 weeks, as per the schedule in Table 2. Method of Blinding and This is an open-label two-cohort, non-randomised study and as such no Randomisation randomisation or blinding is involved. Safety Assessments Patient safety will be assessed by physical examination, vital signs, 12-lead ECG, serum chemistry, haematology, urinalysis, thyroid function tests, injection site assessment, AE documentation, and recording of concomitant medications. The details and timing of these assessments are shown in the Table 2. An end-of- treatment (EOT) visit will be completed for all patients 30 days (± 10 days) after the final dose of SCIB1, or as soon as possible if the decision to discontinue is made more than 30 days after the last dose. The EOT visit may replace the 12 +3 weeks assessment visit for patients who discontinue SCIB1 at a study assessment visit. Efficacy Assessments Tumour response will be determined by both the RECIST 1.1 criteria and the iRECIST criteria. Tumour imaging (chest, abdomen, pelvis, brain, and any area of known disease) will be performed within 28 days prior to first dose of SCIB1 and at the time points indicated in Table 2: Schedule of Procedures and Assessments either during the treatment or during post-treatment follow-up. CT scans (including spiral CT) are the preferred imaging technique unless the patient has a medical reason such as contrast allergy that would make a CT scan unsafe, or the disease is better documented by MRI. The same technique must be used throughout the study for an individual patient. Repeat imaging of the brain is only required if patient has brain metastases at baseline or new brain metastases are suspected. Patients with either objective tumour response or PD should have a repeat scan no sooner than 4 weeks and for up to 8 weeks later to confirm the response, and exclude the possibility of tumour flare reaction respectively. Response status will be assessed by the Investigator (as per RECIST 1.1 and iRECIST). Anonymised copies of imaging data will be retained for the study database. The imaging visit window is ± 7 days and the timing of imaging visits should follow the calendar and not be adjusted for treatment delays. Skin lesions will be documented by digital photography. Anonymised copies of the digital photographs will be collected for the study database. In addition to tumour response and disease progression, all patients will be assessed for survival and subsequent anticancer treatments will be recorded. The assessment period for each patient will be 97 weeks from their first dose of SCIB1. Pharmacodynamics Immune response will be assessed by ELISpot on peripheral blood samples from and Biomarkers patients at a limited number of sites. Additional analyses may be conducted on a subset of these samples including carboxyfluorescein diacetate succinimidyl ester (CFSE) proliferation assays, CTL lysis assays, major histocompatibility complex (MHC) multimer staining for memory cells, assays to assess epitope spreading, Luminex assays for cytokine secretion and T cell subset analysis, and liquid biomarker analysis. Tumour samples will be assessed for the expression of PD-L1. Statistical Methods A dose escalation component is not included since SCIB1 is unlikely to show a dose response. Rather, SCIB1 is to be administered at the dose of 8 mg identified in the Phase 1 study and either nivolumab with ipilimumab or pembrolizumab is to be given at the recommended dose for melanoma patients. Six patients will be enrolled in each Run-in sub-cohort. In the event that more than one patient in the six patients treated in a Run-in sub-cohort has a SCIB1-related DLT the dose and / or schedule of SCIB1 will be reviewed. The study will only progress if a dose and schedule of SCIB1 can be identified that yields no more than one SCIB1- related DLT in six patients when administered to patients receiving either nivolumab with ipilimumab or pembrolizumab at their standard doses and schedule. Patients in the Run-in sub-cohorts who withdraw from the study before study Week 5 (Day 36) for reasons other than a DLT will be replaced. Cohort 1: Nivolumab with Ipilimumab Forty-three patients will be enrolled using Simon’s Optimal 2-stage design (Simon 1989). Patients will be considered evaluable for the primary endpoint provided that they have received at least one dose of SCIB1 and have completed at least one post-baseline tumour assessment by Week 25 (Day 176) or have withdrawn from the study due to disease progression or SCIB1 treatment-related toxicity or have died from complications related to melanoma or due to SCIB1-related toxicity. Non-evaluable patients will be replaced. This sample size has been determined based on the Simon 2-stage design (Simon 1989). The sample size calculation assumes that an ORR of 50% would be of no interest since it approximates to the historical observations of ORR to nivolumab with ipilimumab for this group of patients (Lebbé 2019). Conversely, an ORR of 70% would be considered to be a positive signal for further development of SCIB1 administered in addition to nivolumab with ipilimumab. The trial is designed with a null hypothesis that the ORR is 50%. In the first stage, 15 patients will be enrolled and if there are eight or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), further recruitment to this cohort will be stopped. Recruitment will continue until a decision on Stage 1 has been made. The null hypothesis will be rejected if 27 or more responses are observed in 43 patients. This design yields a type I error rate of 5% and a power of 80% when the true response rate is 70%. Cohort 2: Pembrolizumab The full cohort will enrol a total of 44 evaluable patients (including the six from the Run-In sub-cohort) using Simon’s Optimal 2-stage design (Simon 1989). Patients will be considered evaluable for the primary endpoint provided that they have received at least one dose of SCIB1 and have completed at least one post- baseline tumour assessment by Week 25 (Day 176) or have withdrawn from the study due to disease progression or SCIB1 treatment-related toxicity or have died from complications related to melanoma or due to SCIB1-related toxicity. Non- evaluable patients will be replaced. This sample size has been determined based on the Simon 2-stage design (Simon 1989). The sample size calculation assumes that an ORR of 30% would be of no interest since it approximates to the historical observations of ORR to pembrolizumab alone for this group of patients (Robert et al. 2015a). Conversely, an ORR of 55% would be considered to be a positive signal for further development of SCIB1 administered in addition to pembrolizumab. The trial is designed with a null hypothesis that the ORR is 35%. In the first stage, 14 patients will be enrolled and if there are five or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), further recruitment to this cohort will be stopped. Recruitment will continue until a decision on Stage 1 has been made. The null hypothesis will be rejected if 21 or more responses are observed in 44 patients. This design yields a type I error rate of 5% and a power of 80% when the true response rate is 55%. Efficacy reporting will be carried out for patients enrolled in the study based on both the full analysis set (FAS) and per protocol set (PPS) (where applicable). Safety reporting will be carried out for both the Run-in sub-cohorts of patients and also for the full set of patients enrolled in the study, based on the safety analysis set (SAF). The primary efficacy endpoint is based on the ORR as measured using the RECIST 1.1 criteria. It corresponds to whether or not a patient achieved a PR or CR at any time post start of treatment. If a patient is evaluable for the primary endpoint but has not completed at least one post-baseline tumour assessment by Week 25 (Day 176) then they are counted as a non-responder. AEs will be coded using the current version of the Medical Dictionary for Regulatory Activities (MedDRA). Summary presentations for the number and percentage of patients reporting treatment emergent AEs (TEAEs), severity of TEAEs, TEAEs by relationship (separately presented for relationship to IMP, non- IMP and PharmaJet Stratis® injection procedure), and treatment-emergent SAEs will be produced. In addition, a summary of TEAEs of Grade ≥ 3 will also be presented. Separate presentations will be produced for (i) patients enrolled during the run-in sub-cohorts and (ii) all patients, for the SAF. SAEs and TEAEs directly resulting in withdrawal from the study will be listed. 2. INTRODUCTION AND BACKGROUND INFORMATION 2.1 Introduction Malignant melanoma is an aggressive tumour of the skin. Surgery alone is curative in a high proportion of patients when melanoma is diagnosed early (Stage I and II). However, once the tumour has begun to spread the disease is difficult to treat and patient mortality is high. In the United States (US), it was estimated that in 2016, more than 76,000 people would be diagnosed with melanoma, and that approximately 10,000 patients would die from their disease (Siegel et al. 2016). The corresponding numbers for the European Union (EU) are 82,000 new diagnoses and approximately 15,700 deaths (European Cancer Observatory Cancer Database [EUCAN] Database, 2012). Until relatively recently treatment for patients with unresectable Stage IV melanoma consisted of chemotherapy, commonly dacarbazine, or cytokine therapy (interferon [IFN] alpha or interleukin-2). The ORR to such treatment was low and the 2-year OS was less than 20% (Keilholz et al.2005). Two new classes of therapy have markedly improved the treatment and outcome for patients with Stage IV disease. For patients with mutations of the BRAF gene, combined treatment with BRAF and MEK kinase inhibitors has resulted in ORRs in excess of 60% and a 2-year OS of 50% (Long et al.2015, Ascierto et al.2016). The other class of new therapy for advanced melanoma is checkpoint inhibition. By blocking the immune checkpoints, such as PD-1 and CTLA-4, which have been co-opted by melanoma cells to evade the immune system, these treatments have significantly improved clinical outcome. The anti-PD-1 antibody, nivolumab was compared to dacarbazine in a randomised trial of patients with previously untreated, BRAF V600 wild-type, melanoma (Robert et al. 2015a). The results for nivolumab and dacarbazine respectively were an ORR of 40% versus 13.9%, a median PFS of 5.1 versus 2.2 months and a significant improvement in OS (hazard ratio for death, 0.42; p < 0.001). The anti-PD-1 antibody pembrolizumab was compared to the CTLA-4 checkpoint protein antibody, ipilimumab, in a randomised trial of patients with advanced melanoma (Robert et al. 2015b). The results for pembrolizumab and ipilimumab respectively were an ORR of 33% versus 12%, a median PFS of 4.1 versus 2.8 months and a significant improvement in OS (hazard ratio for death, 0.69; p = 0.004). Anti-PD-1 and anti-CTLA-4 antibodies have been combined to give greater efficacy. The results for nivolumab combined with ipilimumab compared to nivolumab alone were an ORR of 50% versus 40%, a median PFS of 11.5 versus 6.9 months, and a 2-year OS rate of 64% versus 59% respectively (Larkin et al. 2017). Although the response rate and PFS were improved for the combination compared to nivolumab alone, the combination was associated with a higher incidence of CTCAE Grade 3 or 4 treatment-related toxicity (55% versus 16%). The majority of these toxicities resolved within 3─4 weeks; however, approximately one third of patients permanently discontinued the combination due to AEs (Larkin et al.2015). In a separate study, nivolumab 3 mg / kg combined with 1 mg / kg ipilimumab resulted in an ORR of 45.6% whereas 1 mg / kg nivolumab with 3 mg / kg ipilimumab resulted in an ORR of 50.6%. The PFS and OS were similar between the two regimens. However, there were more Grade 3 / 4 adverse reactions with nivolumab 1 mg / kg with 3 mg / kg ipilimumab compared with nivolumab 3 mg / kg with ipilimumab 1 mg / kg (48.3% versus 33.9%) (Lebbé 2019). Despite the success of immune checkpoint blockade in the treatment of melanoma, a substantial proportion of patients do not respond. One of the reasons for lack of response is likely to be due to an inadequate initial immune response to the developing tumour. Therefore, treatments to enhance anti- tumour immune activity are of interest as companion therapies to the checkpoint inhibitors. SCIB1 is a plasmid DNA that is designed to express an engineered human immunoglobulin-1 (IgG1) antibody molecule containing a CTL epitope derived from the TRP-2 melanoma antigen plus two helper T cell sequences derived from the melanoma gp100 protein. One of the gp100 sequences also incorporates a nested CTL epitope. SCIB1 is administered by needle-free injection and is designed to be taken up by antigen presenting cells which synthesise the antibody construct, process the antigens and present epitopes on either MHC class I or MHC class II molecules. T cells recognizing these complexes then act as amplifiers of the immune response (cluster of differentiation 4 positive [CD4+] helper T cells) or direct effectors of tumour cell attack (cluster of differentiation 8 positive [CD8+] CTLs) (Metheringham et al. 2009). In addition to this process of direct presentation, there is evidence that SCIB1 antibody is secreted and that this secreted product binds to the CD64 Fc-gamma receptor (FcgR) on dendritic cells via the heavy chain Fc region, resulting in uptake and cross-presentation of the epitopes to CD8+ and CD4+ cells (Pudney et al.2010; Durrant et al.2010). The result of these dual processes is the production of high frequency and high avidity immune responses to melanoma- associated antigens. 2.2 Findings from Nonclinical and Clinical Studies 2.2.1 Nonclinical Studies Primary Pharmacodynamics The TRP-2 CD8+ CTL epitope encoded by SCIB1 is recognised in certain mouse strains, thereby enabling the immune response elicited following administration of SCIB1 to be evaluated in an animal model. Preliminary studies using a gene gun to administer the SCIB1 plasmid intradermally demonstrated that high frequency and high avidity responses were induced in mice, and that these responses correlated with successful tumour growth inhibition and regression. Recognition of the melanoma-derived gp100 DR4 helper T cell epitope was also confirmed in transgenic HLA-DR4 mice, demonstrating that the sequence was processed and presented correctly. Intramuscular delivery of SCIB1 using the TDS-IM electroporation device also induces high frequency and high avidity T cell immune responses in mice, and it has been demonstrated that a good memory response can be elicited. Assessment of the dose response in mice indicates that, on either a dose per body mass basis or a calculated human equivalent dose, the doses selected for the first clinical study fell within one log of efficacious doses in mice; in addition, the 3-week interval selected for the clinical administration of SCIB1 using the TDS-IM device gave positive responses in the animal studies. In murine studies repeated doses at 2 or 3 weeks were shown to result in a greater immune response, as measured by IFNg ELISpot assay, than a single dose, and the avidity of the response was higher with repeated administration of SCIB1. Assessment after 3 weekly doses and an interval of 10 weeks suggested the presence of a memory response. Fluorescence-activated cell sorting analysis of the phenotype of TRP-2-specific CD8+ cells revealed that they were double positive for CF62L and CD127 suggesting a central memory. In a dose response study with SCIB1 administered to C57BL / 6 mice at 3 weekly intervals, a dose of 10 µg / mouse was shown to give an immune response that was greater in both frequency and avidity relative to doses of 3 and 1 µg / mouse. A dose of 10 µg / mouse approximates to a human dose of 2.5 mg. SCIB1 treatment of HLA-DR4 transgenic mice injected subcutaneously with B16 murine melanoma cells resulted in a significant delay in tumour growth relative to treatment with a control plasmid (p = 0.0027). Treatments were given by i.m. injection with electroporation using the TDS-IM device on Days 0, 6, and 13 relative to tumour cell injection. In experiments designed to support the combination treatment used in this study, SCIB1 was administered intradermally at a dose of 1 µg / mouse using a gene gun device on Days 4, 8 and 11 in combination with an anti-PD-1 blocking mAb injected intraperitoneally at a dose of 250 µg / mouse on Days 4 and 11. The HLA-DR4 transgenic mice had been injected with B16F1 DR4 murine melanoma tumour cells (2.5 x 104) on Day 0. Results indicated that SCIB1 alone and anti-PD-1 alone were effective in this murine cancer model but the effectiveness of the combination was significantly greater than that of either agent alone. Forty percent of mice dosed with SCIB1 alone showed long term survival compared to less than 20% of the control mice (p = 0.022). A similar anti-tumour response was induced by PD-1 blockade, which resulted in long-term survival in 50% of mice (p = 0.0047). This anti-tumour response could be significantly enhanced by combining PD 1 blockade with SCIB1, with treated animals showing enhanced survival of 80% compared to control (p < 0.0001) or when compared to SCIB1 (p = 0.0066) or PD-1 blockade alone (p = 0.0234). At a six-fold higher dose of B16F1 DR4 tumour cells (1.5 x 105cells) only the combined therapy demonstrated a significant survival advantage over the control (p = 0.0126). An examination of the infiltrating lymphocytes in these experimental tumours revealed a significant increase in proportion of cluster of differentiation 3 positive (CD3+)CD8+cells in the SCIB1 treated animals with a more modest increase in animals treated with PD-1 blockade alone. However, CD3+CD8+T cell infiltration was greater for the combination than for either SCIB1 (p = 0.0004) or PD-1 blockade alone (p = 0.0026). T cell proliferation measured by Ki67 was also increased by both SCIB1 and PD-1 blockade alone and was further increased by the combination relative to each agent alone (p = 0.0373 and p = 0.0167, respectively). In these studies, the proportion of CD4+T cells infiltrating the tumour site was also increased by treatment with SCIB1, either alone (p = 0.0086) or in combination with PD-1 blockade (p = 0.0321). The treatments induced no significant differences in the number of infiltrating forkhead box P3-expressing regulatory CD4+T cells in the tumours. Finally, SCIB1 but not PD-1 blockade was shown to upregulate PD-L1 expression (Xue et al.2016). Toxicology Studies A single dose toxicology study of SCIB1 administered by i.m. injection with electroporation was performed in C57BL / 6 mice (Report LHP0002). Tissue samples collected through Day 90 were analysed for SCIB1 plasmid using a validated quantitative polymerase chain reaction (QPCR) assay (Report LHP0005). The single 40 μg / mouse dose produced no apparent adverse effects related to treatment. QPCR analysis revealed high copy numbers of the DNA plasmid in the injection sites of all mice on day 3, with male and female mice having averages of 653,000 and 18,700,000 copies per µg of genomic DNA, respectively. By Day 90, the copy number at the injection site was less than 100 per μg of genomic DNA in male mice and averaged 207 in female mice, indicating effective clearance of the DNA plasmid from the injection sites. One ovary sample had a copy number of 21,773 on Day 3. However, all other gonadal tissues were below the level of quantification on Days 3, 35, and 90 with the exception of a single testes sample showing a very low but positive signal (greater than 11 copies per µg of genomic DNA) on Day 90. Pilot (Report LHP0003) and Good Laboratory Practice (GLP)-compliant repeat-dose studies (Report LHP0001) have been performed with SCIB1 in C57BL / 6 mice. No adverse findings were noted during the pilot study in which a dose of 40 µg / mouse was administered on Days 1, 8 and 15. An increase in IFNg response was observed in four of five of the SCIB1-treated female mice but no IFNg response was observed in control female mice. In the GLP-compliant study mice were administered SCIB1 at a dose of 40 µg / mouse by i.m. injection with electroporation on Days 1, 22, 43, 64, and 85. A control group was included and control group mice were administered phosphate buffered saline. One control female mouse and one control male mouse died shortly after the fourth and fifth dose, respectively. No treatment-related clinical signs were observed and no effects on body weight, food consumption, ophthalmoscopy, haematology, blood chemistry, or organ weights were noted. In both control and SCIB1-treated mice, dark areas, myofibrillar necrosis, haemorrhages, inflammatory reactions, and muscular regeneration were observed in both the right and left tibialis muscles of the injection sites. These observed local tolerance effects were greater in SCIB1-treated mice compared to control mice and had almost complete reversibility after the 4-week recovery period. No significant histopathological findings were observed in the testes of male mice or the uteri of female mice, suggesting that these organs were not adversely affected by SCIB1 administration. Ovaries from female mice were not evaluated histopathologically; therefore, the biodistribution study (Report LHP0002) finding that SCIB1 might be delivered to and incorporated into the ovary could not be confirmed from the histopathology results from this repeat-dose toxicology study. The study conclusion was that SCIB1 did not cause any sign of systemic toxicity based on the results from the various parameters evaluated when administered by i.m. injection with electroporation at a dose of 40 µg / mouse at 3-week intervals for five doses. Injection site findings were of greater incidence and severity in SCIB1-treated mice compared to control mice; these changes were almost completely reversible during the 4-week recovery period. In addition, SCIB1-treated mice had an increase in IFNg response as measured by ELISpot assay, indicating that SCIB1 produced the desired immune system response. 2.2.2 Clinical Studies SCIB1 has been investigated in a single, open-label, non-randomised, Phase 1 / 2 study (SCIB1-001) conducted in the UK in patients with melanoma. The study was designed to determine the safety and tolerability of four dose levels of SCIB1 administered by the i.m. route using the TDS-IM electroporation device, and to assess the immune effects and anti-tumour activity. In Part One of the study patients were enrolled in dose cohorts with a minimum of three patients per cohort. The SCIB1 dose was escalated from 0.4 mg to 2 mg, to 4 mg, and finally, by protocol amendment, to 8 mg. The treatment schedule consisted of doses on Weeks 0, 3, 6, 12, and 24. Part Two of the study was an expansion phase with patients treated at a dose of 4 mg. After a protocol amendment, additional patients were enrolled in Part Two at a dose of 8 mg. Further details on the study design and assessments are available in the SCIB1 IB. Patient Population For Part One Cohorts 1 to 3, patients were required to have a histological confirmation of AJCC Stage III or IV melanoma, either with or without tumour present at screening; patients with tumour present had to have measurable disease according to RECIST. Patients in Part One Cohort 4 (8 mg dose) and patients in Part Two Cohort 2a (8 mg dose) had to have measurable disease at screening. Patients in Part Two Cohorts 1 (4 mg dose) and 2b (8 mg dose) were required to have resected disease. Patients had to be HLA-A2 positive, and also positive for HLA-DR4, HLA-DR7, HLA-DR53, or HLA-DQ6. In total, 35 patients (18 male, 17 female) were enrolled in the study with a median age of 60 years (range 25 to 75 years). Fifteen patients had tumour present at baseline and 20 patients had resected disease at baseline. Five of the patients with tumour present at screening had received prior chemotherapy, one had received prior chemotherapy and ipilimumab, one had previously been treated with a vaccine and one had undergone located limb perfusion. One of the 20 patients with resected disease had received prior therapy (vaccine). No DLTs were observed in the dose escalation phase (n = 11) of Part One of the study and a dose of 4 mg was selected for expansion in Part Two (n = 14). A dose of 8 mg was also subsequently studied in Part One (n = 5) and then Part Two (n = 5). Safety Overall, 23 patients completed all planned injections for the main part of the study (up to and including Week 24). Twelve patients received one or more doses of SCIB1 in the continuation phase of treatment, including nine patients with resected disease. The median exposure for main and continued treatment combined was 170 days with a maximum of 1107 days (16 doses). The most common AEs during the main study (> 10%) were injection site haematoma (77%), injection site pain (37%), fatigue (26%), headache (20%), procedural pain (17%), arthralgia, blurred vision, constipation, pain in extremity (14%), depressed mood, dizziness, dyspnoea, nausea, and rash (11%). Overall, 28 patients had AEs reported as related to study drug. The most common events considered related to study drug were injection site haematoma (37%), injection site pain (20%), fatigue (14%), blurred vision, headache, and procedural pain (11%). In total, 32 patients (91%) experienced AEs related to the electroporation device and procedure. SAEs were most commonly related to progression of malignant melanoma and none were considered likely to be related to study drug or the process of its administration. Severe and life-threatening (Grade 3 and 4) AEs were infrequent with 14 events in five patients meeting these criteria in the main study. Two Grade 3 / 4 events were considered related to SCIB1: a Grade 3 event of injection site haematoma in one patient and Grade 3 anxiety in a different patient, each of whom was treated with 4 mg SCIB1. Five Grade 3 / 4 events in two patients were considered related to the electroporation device or the electroporation procedure; a Grade 3 event of injection site haematoma, and Grade 3 events of anxiety (two events), injection site pain, and anticipatory anxiety. The events of injection site pain and anticipatory anxiety led to the patient discontinuing SCIB1 treatment. A second patient declined continuation treatment due to pain and discomfort from the electroporation procedure. Three deaths were databased under the main study phase, although they occurred after the patients had withdrawn from the main study and were recorded as follow-up information; two were disease- related (one patient 0.4 mg; one patient 4 mg) and one was due to community-acquired pneumonia (8 mg). A further two deaths were recorded after the patients had withdrawn from continued administration, both of which were disease-related: one patient treated at 4 mg and one patient treated at 8 mg. All of these patients had tumour present at screening. Efficacy In the immune response assays, 88% of patients responded in the ELISpot assay and 82% in the proliferation assay during the main study period plus continuation phase. The number of responders to individual melanoma-specific peptides in the ELISpot assay increased with continued administration of SCIB1. Comparison of ELISpot responses between dose groups indicated a stronger response at 8 mg than 4 mg. The number of responders to individual peptides in the proliferation assay also increased with continued administration of SCIB1. There was a significantly stronger proliferation response to one peptide in patients with no tumour present at screening and receiving 8 mg doses compared with patients receiving 2 / 4 mg doses. There was also a significantly stronger proliferation response to any peptide in patients with no tumour present at screening when compared with patients with tumour present at screening. Of the 15 patients with tumour present at study entry, one patient, treated at a dose of 8 mg, met the RECIST criteria for a PR, which had a duration of 204 days (29 weeks). A second patient, treated at a dose of 4 mg, had a greater than 30% reduction in the size of their target lesions but progression of a non-target lesion. Patients who entered the study without detectable tumour present, and were treated with SCIB1 in the adjuvant setting, were followed for disease-free survival. The longest follow-up is available for the 16 patients treated with 2 and 4 mg of SCIB1. At the cut-off date of 29 October 2016, all 16 patients were alive with a median observation time of 39 months (range 33 to 52 months). At 2 years, 12 (75%) of these patients remained disease-free without additional treatment beyond continued SCIB1. 2.3 Dose Selection Rationale On the basis of the safety findings from Study SCIB1-001 and the observations of a stronger immune response at a dose of 8 mg compared to 4 mg, the 8 mg dose has been selected for this study. The dose of SCIB1 will be administered by the i.m. route using the PharmaJet Stratis® needle-free injection device. The 8 mg dose in patients equates to a dose of approximately 0.114 mg / kg, or 4.44 mg / m2. This compares to the dose in mice in the toxicology studies of 40 µg / mouse, equivalent to 2.0 mg / kg or 6.0 mg / m2. 2.4 Known and Potential Benefits and Risks to Patients AEs most commonly attributed to SCIB1 were fatigue (14%), blurred vision and headache (11%). Injection site haematoma and injection site pain were attributed to the electroporation procedure used in SCIB1-001 and also to SCIB1, with a total incidence of 77% and 37% respectively. SCIB1 has been shown to induce immune responses in patients in melanoma (Patel et al.2018). 3. STUDY OBJECTIVES AND ENDPOINTS 3.1 Primary Objectives and Endpoints 3.1.1 Run-In Sub-Cohorts Objective To assess the safety and tolerability of i.m. SCIB1 in patients receiving either nivolumab with ipilimumab or pembrolizumab. Endpoints As measured by the recording of AEs (CTCAE v5.0), vital signs, physical examination, serum chemistry and haematology, thyroid function test, injection site assessment, urinalysis, 12-lead ECG, performance status, and concomitant medications. The target SCIB1-related DLT rate is 0 or 1 in six evaluable patients. 3.1.2 Main Study Objective To determine whether the addition of SCIB1 to either nivolumab with ipilimumab or pembrolizumab increases the ORR relative to historical data for the combination of nivolumab with ipilimumab or pembrolizumab alone in this patient population. Endpoint Objective response rate as measured by RECIST 1.1 criteria. 3.2 Secondary Objectives and Endpoints 3.2.1 Main Study Objective To determine whether the addition of SCIB1 to either nivolumab with ipilimumab or pembrolizumab improves the duration of response relative to historical data for the combination of nivolumab with ipilimumab or pembrolizumab alone in this patient population. Endpoint Duration of response, measured from the point of first response (CR or PR) to the date of disease progression (per RECIST 1.1) or death due to any cause. Objective To determine the ORR as measured using the iRECIST criteria (Seymour et al.2017). Endpoint ORR as determined by iRECIST. Objective To assess the PFS rate for all patients at Week 49 (Day 344) and Week 97 (Day 680). Endpoint PFS rate is defined as the proportion of patients who have not progressed (per RECIST 1.1 and iRECIST), started new anticancer therapy, or died at each specified timepoint. Objective To assess the OS rate for all patients at Week 49 (Day 344) and Week 97 (Day 680). Endpoint OS rate is defined as the proportion of patients who remain alive at each specified timepoint. Objective To further assess the safety and tolerability of SCIB1 in patients receiving either nivolumab with ipilimumab or pembrolizumab. Endpoint Safety and tolerability, by measurements as defined for the Run-in sub-cohorts above. 3.3 Exploratory Objectives and Endpoints Objective To explore the relationship between immune response and clinical outcome. Endpoint Immune response assessment (ELISpot, and other assays) performed on peripheral blood samples from patients at a limited number of sites. 4. STUDY DESIGN 4.1 General Study Design This is a Phase 2, multicentre, open-label study of SCIB1 in patients with advanced unresectable melanoma receiving either nivolumab with ipilimumab or pembrolizumab. There will be two cohorts, depending on whether the patient is to receive standard of care doublet therapy (nivolumab with ipilimumab) or monotherapy (pembrolizumab) checkpoint inhibitors. In the Run-in sub-cohorts, six patients will receive both SCIB1 and either nivolumab with ipilimumab or pembrolizumab, to ensure that there are no unexpected severe toxicities that would prevent further testing. The first two patients in each of these cohorts will be enrolled sequentially at an interval of no less than 14 days to minimise the risk of unexpected severe toxicities. Provided no more than one patient in six evaluable patients experiences a SCIB1-related DLT by Day 35 the remaining patients will be enrolled in the cohorts using Simon’s Optimal 2-stage design (Simon 1989) (Figure 5). Cohort 1: Nivolumab with Ipilimumab In the first stage, 15 patients (including the six patients from the Run-in sub-cohort) will be enrolled and if there are eight or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), the cohort will be stopped. Otherwise, an additional 28 patients will be enrolled in the second stage for a total of 43 patients. Recruitment will continue until a decision on Stage 1 has been made. Cohort 2: Pembrolizumab In the first stage, 14 patients (including the six patients from the Run-in sub-cohort) will be enrolled and if there are five or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), the cohort will be stopped. Otherwise, an additional 30 patients will be enrolled in the second stage for a total of 44 patients. Recruitment will continue until a decision on Stage 1 has been made. Enrolment will stop if a cohort is not able to complete recruitment within a reasonable time of the other cohort being fully enrolled. Additionally, as part of the interim analysis a feasibility assessment of further enrolment to the cohort not reaching the first stage quota will be performed upon the other cohort reaching the first stage. DLTs are defined as follows: Drug-related non-haematologic AEs of CTCAE v5.0 Grade ≥ 3 with the exception of: ^ Grade ≥ 3 gastrointestinal toxicities (nausea, vomiting, diarrhoea, constipation) that can be managed by anti-emetics and other therapies and that do not exceed a period of 48 hours ^ asymptomatic laboratory changes (other than renal and hepatic laboratory values, and Grade 4 lipase / amylase) that can be successfully supplemented (e.g., electrolyte replacement) within 72 hours ^Grade 3 fatigue lasting less than 72 hours^Grade ≥ 3 elevation of ALT or AST for patients with liver metastases that resolves to Grade ≤ 2within 7 days. Drug-related haematologic AEs of CTCAE v5.0 Grade ≥ 4, thrombocytopenia Grade 3 (platelet count decrease < 50,000–25,000 / mm3) with haemorrhage, and Grade 3 haemolysis (transfusion or medical intervention indicated, e.g., steroids), and Grade 3 febrile neutropenia (absolute neutrophil count < 1000 / mm3 with a single temperature of > 38.3 °C [101 °F] or a sustained temperature of ≥ 38 °C [100.4 °F] for more than one hour). Toxicities that meet these criteria and are considered related to the administration of study agents will be considered a DLT. Grade 3 events clearly related to tumour flare (local pain, irritation, localised rash) will not be considered DLTs. DLTs in the Run-in sub-cohorts will be assessed up to Day 35. Patients in the Run-in sub-cohorts who withdraw from the study before Week 5 (Day 36) for reasons other than a DLT will be replaced. In the event that more than one of six patients in either of the Run-in sub-cohorts has a SCIB1-related DLT, the available safety data will be formally reviewed by the Investigators and the Sponsor, and a decision made on whether to enrol further patients to evaluate the safety of the combination. This step is included since some events that occur with the approved use of checkpoint inhibitors meet the definition of DLT and the contribution, if any, of SCIB1 will need to be assessed. Related CTCAE Grade ≥ 3 events occurred in 10% of 277 patients with melanoma receiving pembrolizumab alone at the recommend dose and schedule (Robert et al.2015b). In the case of the combination of nivolumab with ipilimumab, Grade 3–4 toxicities occurred in 33.9% of 180 patients receiving 3 mg / kg nivolumab with 1 mg / kg ipilimumab, and 48.3% of 178 patients receiving 1 mg / kg nivolumab with 3 mg / kg ipilimumab (Lebbé 2019). In the SCIB1-001 monotherapy study in melanoma patients (n = 35) only two Grade 3 / 4 events were considered related to SCIB1: a Grade 3 event of injection site haematoma and Grade 3 anxiety in a patient that was related to the electroporation procedure used in that study. In this study, the PharmaJet Stratis® device will be used which, in an ongoing study, has been associated with only mild discomfort. Any patient recruited under previous versions of the protocol who has received SCIB1 using the TDS-IM electroporation device will be re-consented to continue administration using the PharmaJet Stratis® device. A decision to expand enrolment in these circumstances will require review and approval by the Investigators and the Sponsor. Careful assessment for excess severe toxicity will continue on an ongoing basis in the remainder of the study. During the screening period of up to 28 days patients will complete procedures and assessments to confirm eligibility. Written informed consent must be obtained prior to performing any protocol-specific procedure (procedures and assessments performed for the purpose of the study rather than as part of routine medical care). Test results and tumour imaging from routine clinical management (including those conducted before written informed consent) are acceptable for screening if obtained within the specified screening time window. A separate consent form will be used for HLA testing; HLA consent must be obtained prior to the screening. During study treatment, patients will be monitored for safety and for tumour response and disease progression, as well as survival and the start of any new anticancer therapy. 4.2 Planned Number of Patients and Countries Eighty-seven patients are planned to be enrolled from up to 20 clinical oncology centres worldwide. Additional patients will be enrolled to replace patients who are non-evaluable for DLTs in the Run-in sub-cohorts or non-evaluable for the primary endpoint of ORR by RECIST 1.1 (Section 5.4.1). 4.3 Study Duration Due to COVID-19 the study was delayed and started recruitment in 2021 and completion is anticipated in 2025. 4.4 Assignment of Patient Numbers Patients will be assigned a unique 3-digit identification number after they sign the HLA informed consent document and agree to participate in the study. Patient identification numbers will serve as the primary method of identifying each patient on the CRFs and on the site’s source documents throughout the study. 4.5 Blinding and Randomisation This is an open label, two-cohort, non-randomised study and as such no blinding or randomisation will be required. 4.6 Justification for Study Design and Selection of Patient Population Pembrolizumab treatment has been shown to be effective in patients with advanced melanoma. However only approximately one third of treated patients respond to this checkpoint protein antibody (Robert et al.2015b). The reason for a lack of clinical response in the remaining patients is unknown but is likely to involve in part a failure of the immune system to recognise the patient’s melanoma. Combination treatment with antibodies to both PD-1 and CTLA-4 has been shown to increase the response rate in previously untreated melanoma patients to approximately 50%, but this combination therapy is associated with a much higher incidence of severe and life-threatening toxicities, and treatment withdrawals due to these toxicities (Larkin et al.2015). Vaccination provides a means to increase the immune recognition of the patient’s tumour and may be associated with an increased response rate without the same rise in severe toxicities. SCIB1 has been shown to cause a cellular immune response in more than 85% of treated melanoma patients, with signs of single-agent clinical activity. The current design of an open-label, non-randomised Phase 2 study in patients with previously untreated, unresectable, melanoma is justified on the basis that these patients will be receiving current standard of care checkpoint inhibitor therapy, either nivolumab with ipilimumab or pembrolizumab. SCIB1 was well tolerated in its Phase 1 / 2 trial and the addition of SCIB1 should not interfere with the activity of either nivolumab with ipilimumab or pembrolizumab in this population. The sample size of 87 patients is sufficient to determine whether SCIB1 has potential to improve the RECIST 1.1 response rate (as compared to the historical rate for the combination of nivolumab with ipilimumab or pembrolizumab alone in this population) to justify a larger randomised study. 4.7 Periodic Review of Safety and Efficacy The safety and efficacy data from the study will be formally reviewed at frequent and regular intervals, including at the end of the run-in period and at the end of the first stage of the Simon 2-stage design. The review committee will include study investigators, the Sponsor’s medical monitor, and the Sponsor’s clinical operations lead or designee. A Run-in Sub-Cohort Review Plan will be established prior to enrolment of the first patient in the study and it will reflect the safety review that will take place during the run-in period. The full Safety and Efficacy Review Charter will be finalised by the completion of the run-in period and prior to further patient enrolment in the study beyond the run-in period. 4.8 Criteria for Study Completion The study treatment period for each patient consists of ten doses of SCIB1. Patients who complete this will have completed study treatment (Week 85 [Day 596]) and will enter post-treatment follow-up for 12 weeks, including an EOT visit (to monitor safety following the last dose of SCIB1). Patients will be assessed for tumour response, disease progression, initiation of new cancer treatment, and survival for 97 weeks from the first dose of SCIB1. The study will be complete when all patients have completed the post-treatment follow-up period or have withdrawn. 4.9 Schedule of Procedures and Assessments The study procedures and assessments to be performed for all patients are summarised in Table 2 below. Details of the procedures and assessments are provided in Sections 7─9. 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dah.nsycolaad et ethtb yamne.daed seir p r e inl o tss irto)2is it toDmmelabereesuo eettinl esp euvwuon 9 e lmi laenoit ssudn:ir ly htdesnamht ees a dnIodmevya in a vi de rdet eseUnn o ooO msaNueb be iTra i a tns abtan hwuTahD(kStrAraeionrspetshAcs) ))q)r)s)t u)vw)x501510252 4.10 Post-Treatment Follow-up Post-treatment follow-up will be completed for all patients who have received at least two doses of SCIB1 (Day 1 and Week 4) and have not withdrawn from the study. Patients will attend clinic visits for tumour assessments (including CT / MRI scans) and skin lesion assessments every 12 weeks (± 2 weeks) following their last dose of SCIB1, including patients who received the final SCIB1 dose on Week 85 (Day 596), unless disease progression occurs or a new anticancer treatment is initiated. If disease progression occurs or a new anticancer treatment is initiated, subsequent follow-up may be conducted by a healthcare professional by telephone / video conference call, during a routine clinic visit or patients’ medical records reviewed. All patients will therefore be evaluated for a period of 97 weeks from the first dose of SCIB1. The following information will be collected: ^Date of clinic visit / follow-up telephone / video conference call^ Date of development of any new cancer, including type and means of diagnosis ^Tumour assessment using RECIST 1.1 and iRECIST criteria and skin lesion assessment for allpatients who have not had documented disease progression or started a new anticancer treatment (tumour assessments should take place at the time points indicated in Table 2: : Schedule of Procedures and Assessments either during the treatment or during post-treatment follow-up). ^ Date of disease progression and means by which established ^ Date of initiation of new cancer treatment and generic name of treatment agent(s) ^ Date of death and primary cause 5 SELECTION AND WITHDRAWAL OF PATIENTS 5.1 Inclusion Criteria 1) Patient has histologically confirmed, unresectable Stage III or Stage IV melanoma as defined by the AJCC (8thEdition; Gershenwald et al. 2017). Patients with a diagnosis of melanoma of unknown primary are eligible. 2)Patient has not received prior systemic treatment for advanced disease. Prior adjuvant treatment,defined as treatment following resection of all detectable disease, is permitted; last dose must be at least 4 weeks before the first dose of SCIB1. 3) Patient has been clinically evaluated and checkpoint inhibition with either nivolumab with ipilimumab or pembrolizumab has been determined to be an appropriate treatment for their advanced disease. 4)Patient’s BRAF status must be known; patients with BRAF mutation positive disease may be enrolledwithout BRAF inhibitor treatment at the discretion of the Investigator, provided that they have no evidence of rapidly progressing disease. 5) Patient has at least one measurable lesion per RECIST 1.1 criteria by CT scan or MRI. 6) Patient is HLA-A2 positive.* 7)Patient is positive for HLA-DR4, HLA-DR7, HLA-DR53 or HLA-DQ6.*8)Patient is at least 18 years of age. 9) Patient has a life expectancy of more than 3 months. 10) Patient has an ECOG performance status of 0 or 1. 11)Patient has adequate organ function as determined by the following laboratory values:Absolute neutrophil count ≥ 1.5 x 109 / L Lymphocyte count ≥ 0.5 x 109 / L Platelet count ≥ 100 x 109 / L Haemoglobin > 9 g / dL (> 5.6 mmol / L) ≤ 1.5 x ULN Serum creatinine or creatinine clearance > 50 mL / min ≤ 1.5 x ULN or < 3.0 mg / dL if patient has Serum total bilirubin Gilbert’s syndrome ≤ 2.5 x ULN or ≤ 5.0 x ULN if liver metastases Serum transaminases (AST / ALT) present 12)Patient must be able and willing to provide written REC-approved informed consent prior to any studyrelated procedure. (In the event that the patient is re-screened for study participation or if a protocol amendment alters the care of an ongoing patient, a new REC-approved ICF must be signed.) 13) Women of child-bearing potential (including women ≤ 12 months from last menstrual period) must have a negative serum pregnancy test during Screening (within the 72 hours before planned administration of the first dose of study drug on Day 1) and be neither breastfeeding nor intending to become pregnant during study participation, and shall be warned of potential foetal harm from either nivolumab with ipilimumab or pembrolizumab. Women of child-bearing potential must agree to use highly effective contraceptive methods (Appendix E) prior to study entry, for the whole duration of study treatment, and for 120 days after discontinuation of SCIB1, nivolumab with ipilimumab, or pembrolizumab, whichever is last. 14) Men who are potentially fertile with partners of childbearing potential must agree to use highly effective contraceptive methods (Appendix E) for the whole duration of study treatment and for 120 days after discontinuation of SCIB1, nivolumab with ipilimumab, or pembrolizumab, whichever is last. 15) Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. * HLA testing will be conducted at accredited laboratories by molecular (DNA) typing. 5.2 Exclusion Criteria 1) Patient has a diagnosis of mucosal or ocular melanoma. Patient has active central nervous system metastases or carcinomatous meningitis. (Patients with a response to previous treatment for brain metastases are eligible provided that they are stable without MRI evidence of progression for at least 4 weeks prior to the first dose of study treatment, and systemic steroids have been withdrawn for at least 1 week prior to the first dose of study drug. Patients who have received recent radiosurgery treatment for brain metastases are eligible provided that the patient is completely recovered from post-surgical sequelae, the screening scan must be at least 4 weeks after radiosurgery and systemic steroids have been withdrawn for at least 1 week prior to the first dose of study drug.) Patient has previously received a treatment to block CTLA-4, PD-1, PD-L1, or PD-L2 with the following exception: patients who have received adjuvant treatment with these treatments are eligible. Patient is expected to require any other form of systemic or localised anticancer therapy while receiving study treatment. Patient is taking any systemic steroid therapy within 1 week of the first dose of study drug or is receiving any other form of immune suppressant medication. Physiological doses of systemic steroids such as those for the management of adrenal insufficiency, as well as topical and inhaled steroids, such as those for the management of asthma, are permitted. Patient is receiving treatment with any investigational product within 28 days (or 5 half-lives of the treatment concerned) prior to the first dose of study treatment. Patient has a previous (within 5 years) or current malignancy with the exception of melanoma, and curatively treated local tumours such as carcinoma-in-situ of the breast, cervix, basal or squamous cell carcinoma of the skin, prostate cancer with Gleason grade < 6 and prostate-specific antigen within normal range. Patient has a concurrent illness which would preclude study conduct and assessment, including, but not limited to uncontrolled medical conditions, uncontrolled and active infection (considered opportunistic, life threatening, or clinically significant), uncontrolled risk of bleeding, or uncontrolled diabetes mellitus, or pulmonary disease (including obstructive pulmonary disease, pulmonary fibrosis, and history of symptomatic bronchospasm), or alcoholic liver disease, or primary biliary cirrhosis. Caution should be used for patients with suspected or diagnosed epilepsy. Patient has NYHA class III or IV heart disease, myocardial infarction within previous 6 months, a heart rate of ≤ 50 beats per minute, a history of significant cardiac abnormality and / or clinically significant abnormal baseline ECG reading, active ischaemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant arrhythmia requiring therapy including anticoagulants, uncontrolled hypertension (> 140 / 90 mm Hg), significant cerebrovascular disease, or congestive heart failure. Patient has a history of severe hypersensitivity reaction to treatment with a mAb. Patient has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents (patients with vitiligo or resolved childhood asthma / atopy are an exception and are not excluded for these conditions). The following patients are not excluded from the study: patients who require intermittent use of bronchodilators or local steroid injections, patients with hypothyroidism stable on hormone replacement, and patients who receive physiological doses of steroids as replacement therapy, such as those for the management of adrenal insufficiency. In such cases the recruiting investigator should discuss the patients’ eligibility with the study Medical Monitor prior to enrolment. Patient has received a vaccine within 28 days of first dose of study treatment. Patient has a known history of HIV, or has any positive test for HBV or HCV indicating active acute or chronic infection. Patient has a known current or recent history (within the last year) of substance abuse including illicit drugs or alcohol. 5.3 Treatment Discontinuation SCIB1 treatment will be permanently discontinued in the event of: 1) any DLT related to the vaccine 2) confirmed disease progression and / or the initiation of a new anticancer treatment 3) pregnancy 4) a Sponsor request to discontinue treatment 5)a patient (or their legal representative) request to discontinue treatment6)a severe or life-threatening AE that in the opinion of the Investigator necessitates the permanentdiscontinuation of treatment 7) noncompliance with the treatments, procedures, and assessments of the study in the opinion of the study Investigator; or 8) an illness that would interfere with continued SCIB1 treatment. At the time of treatment discontinuation, the Investigator will document the reason for discontinuation in the patient’s medical chart and CRF. Patients may elect to discontinue treatment, but continue with follow-up and be monitored for disease progression, initiation of new cancer treatment, and survival. In the event of discontinuation of SCIB1 treatment, patients will complete the end of treatment visit and enter post-treatment follow up. Nivolumab with ipilimumab, or pembrolizumab, will be permanently discontinued in the event of the severe or life-threatening adverse reactions as detailed in the relevant SmPC and clinical guidelines. 5.4 Withdrawal Criteria A patient will be withdrawn from the study if: ^ they (or their legal representative) withdraw consent ^ they request permanent discontinuation of treatment and all subsequent study-related activities including the collection of follow-up information from the patient / caregiver, relatives, medical records or healthcare provider; or ^the Sponsor decides to discontinue the study.Patients who permanently discontinue treatment for any other reason (as defined in Section 5.3) will only be considered withdrawn from the study if no follow-up information can be obtained from the sources previously described. At the time of withdrawal, the Investigator will document the reason for discontinuation in the patient’s medical chart and CRF. Patients may discontinue treatment without withdrawing from the study as outlined in Section 5.3. 5.4.1 Replacement Patients In the Run-in sub-cohorts, patients who withdraw, or do not complete safety assessments to the extent where overall safety of the vaccination cannot be assessed, before Week 5 (Day 36) for reasons other than a DLT will be replaced. Patients who are non-evaluable for the primary endpoint of ORR by RECIST 1.1 will be replaced as required in order to have 43 evaluable patients in cohort 1 and 44 evaluable patients in cohort 2. Patients will be considered evaluable for the primary endpoint provided that they have received at least one dose of SCIB1 and have completed at least one post-baseline tumour assessment by Week 25 (Day 176) or have withdrawn from the study due to disease progression or SCIB1 treatment-related toxicity or have died from complications related to melanoma or due to SCIB1-related toxicity. 5.4.2 Rescreening Rescreening of patients who have previously failed screening is only permitted after consultation with the Sponsor’s medical monitor. Screening procedures outside of the screening time window must be repeated. 5.5 Study Termination Grade ≥ 3 AEs, laboratory values, and SAEs will be reviewed on a frequent basis by the Investigators and the Sponsor. The study will be paused in the event of a death with a causal relationship to SCIB1, or in the event that the cumulative total of Grade 4 events with a causal relationship to SCIB1 exceeds three. The study may be restarted following an evaluation of the cause of the toxicity and the implementation of a plan of correction (if necessary), provided that the Investigators and Sponsor consider it appropriate to do so. The study may be terminated in whole or in part if at any point the toxicity of SCIB1 in addition to either nivolumab with ipilimumab or pembrolizumab is such that the risk / benefit ratio no longer supports continued investigation, and that additional patient recruitment is not justified on medical or ethical grounds. This determination may be made by the Investigators in conjunction with the Sponsor, or by REC or national regulatory authorities. The Sponsor may also elect to terminate the study in the event that enrolment is sufficiently slow to prevent the completion of the study in an acceptable timeframe, or in the event that SCIB1 development is discontinued. The study may also be terminated if five or fewer clinical responses are observed (RECIST 1.1 objective response [CR or PR]) within 25 weeks of the first dose of SCIB1. In the event that the study is terminated prematurely the Sponsor will notify the investigators and national health authorities. The Investigator must promptly notify all enrolled patients and the REC of study termination. 6 TREATMENTS 6.1 Investigational Medicinal Product The IMP for this study is SCIB1, a plasmid DNA (laboratory designation pVaxDCIB68) designed to express an engineered human IgG1 antibody molecule carrying a CTL epitope derived from the TRP-2 melanoma antigen plus two helper T cell sequences derived from the melanoma gp100 protein. One of the gp100 sequences also incorporates a nested CTL epitope. SCIB1 is formulated in phosphate-buffered saline at a concentration of 4 mg / mL. Each glass 2 mL vial is closed with a FluroTec® stopper and a Flip-off overcap and contains an extractable volume of 1.0 mL. 6.1.1 Non-Investigational Medicinal Products 6.1.1 Nivolumab with Ipilimumab The combination of nivolumab with ipilimumab is indicated for the treatment of unresectable or metastatic melanoma in adult patients. The combination has since been adopted and is reimbursed by health care payers internationally including the UK’s National Health Service (NHS). Nivolumab with ipilimumab will be obtained as a standard of care treatment through hospital pharmacies and will be used in accordance with the prescribing information and local guidelines. 6.1.2 Pembrolizumab Pembrolizumab is approved in the EU, US, Australia and UK for the treatment of patients with unresectable or metastatic melanoma. Pembrolizumab will be obtained as a standard of care treatment through hospital pharmacies and will be used in accordance with the prescribing information and local guidelines. 6.2 Preparation, Handling, Storage, Accountability and Destruction of Investigational Medicinal Product 6.2.1 SCIB1 SCIB1 must be stored frozen at −20°C (±5 °C) / −5°F (±10 °F) and thawed before use. Further details are provided in the IMP handling Instructions. 6.2.2 Checkpoint Inhibitors Treatment with either nivolumab with ipilimumab or with pembrolizumab will be at the discretion of the Study Investigator and according to standard of care, as detailed in the relevant SmPC and clinical guidelines. The first dose of checkpoint inhibitors should be administered at Week 1 following the first SCIB1 dose to ensure an adequate primary immune response following the first SCIB1 dose (Massarelli et al 2019). Checkpoint inhibitor treatment beyond the 85 week study duration will be at the discretion of the study investigator, as part of standard of care. Storage, packaging, and handling of checkpoint inhibitors will be in accordance with the SmPC, as appropriate. 6.2.3 Drug Accountability Drug accountability records will include receipt of quantities of SCIB1 will be maintained for all occasions on which SCIB1 is dispensed. These records will include the patient’s study identification number; date, time, and number of vials of drug dispensed; date and quantity administered; date and number of vials of any drug returned to the pharmacy for destruction or disposal according to local standard operating procedure (SOP). These records must be available for regular inspection by the study monitor. The Investigator is responsible for ensuring all used and unused trial supplies are accounted for. No unused vials of SCIB1 will be destroyed or returned to the central depot until study drug accountability has been performed. The IMP, SCIB1, is for use only in patients who have provided informed consent and have enrolled in this study. 6.3 SCIB1 Administration Procedure SCIB1 will be administered to the patients using the i.m. PharmaJet Stratis® needle-free injection device. The administration procedure will be performed by site personnel qualified for the administration of i.m. injections and who have completed the device training seminar. Each administration will comprise four injections performed at separate sites. Eligible injection sites include the outer aspect of the upper left and right arm (medial deltoid muscle) or the left and right outer thigh (lateralis muscle). The set-up of the device and administration of SCIB1 to the patient will be performed as described in the PharmaJet Stratis® needle- free injection Instructions for Use document. Standard technique and precautions for i.m. administration will be utilised in site preparation, SCIB1 administration, and medical waste disposal to ensure safety of patients and study personnel. Any patient recruited under previous versions of the protocol who has already received SCIB1 using the TDS-IM electroporation device will be re-consented to continue administration using the PharmaJet Stratis® device. 6.4 Checkpoint Inhibitors: Use and Precautions Directions in the SmPC on the reconstitution, preparation, and administration of checkpoint inhibitors should be followed. The management of adverse reactions and modifications to the treatment schedules are described in Section 6.6. 6.5 Treatment Schedule Patients will receive four i.m. injections each of 2 mg SCIB1, administered using the PharmaJet Stratis® needle-free injection device, at Weeks 0, 4, 7, 13, 25 (Days 1, 29, 50, 92 and 176, respectively) and every 12 weeks thereafter until Week 85 (Day 596). On Day 1, patient eligibility must be confirmed before administering the first dose of SCIB1. On days when both SCIB1 and either nivolumab with ipilimumab or pembrolizumab are administered, SCIB1 will be administered before nivolumab with ipilimumab or pembrolizumab. 6.6 Dose Adjustments, Modifications, and Delays 6.6.1 Infusion Reactions The management of infusion reactions associated with the administration of a checkpoint inhibitor should follow standard of care, as detailed in the relevant SmPC and clinical guidelines. Patients should be monitored for infusion reactions for at least 1 hour after the last dose of checkpoint inhibitor on that day. 6.6.2 Dose Adjustments and Modifications Dose reduction of SCIB1 is not anticipated to be of value for this study. The management of toxicities will be by treatment delays as described in the following section. 6.6.3 Treatment Delays and Checkpoint Inhibitor Discontinuation In the event of adverse events, the investigator should consider withholding, discontinuing, or resuming checkpoint inhibitors as detailed in the relevant SmPC and national or local clinical treatment guidelines. SCIB1 may be continued in patients when either nivolumab with ipilimumab or pembrolizumab has been withheld or discontinued provided that in the opinion of the Investigator it is in the patient’s interests to do so. In addition, the patient must have shown no evidence of clinical disease progression and the adverse reaction(s) that resulted in the withholding of checkpoint inhibitor(s) must have improved by the time of the next SCIB1 dose. Patients with BRAF mutation positive disease must be informed of the available BRAF targeted treatment options and must re-consent in order to continue receiving SCIB1 alone. SCIB1 dosing will be continued as per the schedule in Table 2. If SCIB1 doses are missed, for example due to the occurrence of adverse events, the missed doses may be administered after Week 13, with a minimal interval of at least 15 days but preferably maximising the interval between doses to 6 weeks, as per the schedule in Table 2. Specific Recommendations for Immune-Mediated Adverse Events Immune-mediated toxicities may be managed by corticosteroid immunosuppression. Management of specific immune-mediated toxicities should follow guidance in the checkpoint inhibitor’s SmPC. 6.7 Prior and Concomitant Medication and Therapy Details of the prior medications that the patient has received in the 30 days prior to Day 1 will be collected. All concomitant medications administered while a patient is receiving study treatment and through a period of 30 days post last dose of SCIB1 treatment must be recorded in the CRF. Concomitant medication records must include generic name, indication, dose, start and end date(s) and route of administration. 6.7.1 Prohibited Medication and Therapy Other forms of systemic treatment for melanoma are not permitted while the patient is receiving treatment under this protocol. This includes chemotherapy, biologic therapy, other forms of immunotherapy, and gene therapy. Surgery and local radiotherapy for skin lesions is not permitted and should be discussed in advance with the study Medical Monitor. Systemic corticosteroids and other immunosuppressive agents are not permitted except as described in Section 6.7.2. 6.7.2 Permitted Medication, Pre-Medication, and Supportive Care Systemic corticosteroids are only permitted for the management of immune-mediated AEs as described in Section 6.6 (with the exception of physiologic replacement therapy). For patients whose immune-related adverse reactions cannot be controlled with corticosteroids, administration of other systemic immunosuppressants can be considered. Physiological doses of systemic steroids such as those used for the management of adrenal insufficiency, and topical and inhaled steroids, such as those used for the management of chronic medical conditions such as asthma, are permitted. Vaccines are permitted (including influenza and COVID-19 vaccines, as long as they are not live vaccines), but they should be scheduled between doses of SCIB1 after Week 7 (Day 50) to allow 28 days prior to the next dose of SCIB1. Live vaccines, including the nasal influenza vaccine, are not permitted. 6.8 Monitoring of Patient Compliance The Investigator and clinical site personnel will be responsible for monitoring patient compliance. A check of study drug compliance will be performed during each visit after the initial dispensation of study drug, and study drug accountability records will be completed. A patient who is noncompliant with the treatments, procedures and assessments of the study should be withdrawn following a discussion between the Investigator and Sponsor and the REC notified. 7 ASSESSMENT OF EFFICACY 7.1 Tumour Imaging and RECIST Assessment The primary efficacy measure for the study is tumour response measured according to the RECIST 1.1 criteria (Eisenhauer et al.2009, Appendix A). Response according to the iRECIST (Seymour et al.2017, Appendix B) will also be determined as a secondary efficacy measure. Tumour imaging (chest, abdomen, pelvis, brain, and any area of known disease) will be performed within 28 days prior to first dose of SCIB1. CT scans are the preferred imaging technique unless the patient has a medical reason such as contrast allergy that would make a CT scan unsafe, or the disease is better documented by MRI. The same technique must be used throughout the study for an individual patient. A brain MRI (preferred) or CT scan at baseline is required to establish the presence or absence of brain metastases. Repeat imaging of the brain is only required if patient has brain metastases at baseline or new brain metastases are suspected. Patients with either objective tumour response or PD should have a repeat scan no sooner than 4 weeks and up to 8 weeks later to confirm the response, and exclude the possibility of tumour flare reaction respectively. Response status will be assessed by the Investigator (as per RECIST 1.1 and iRECIST). Anonymised copies of the imaging data will be collected for the study database. The imaging visit window is ± 7 days and the timing of imaging visits should follow the calendar and not be adjusted for treatment delays. Tumour assessments should take place at the time points indicated in Table 2: Schedule of Procedures and Assessments either during the treatment or during post-treatment follow- up. At least one measurable lesion according to RECIST 1.1 criteria must be present at baseline. A measurable lesion is defined as measuring at least 10 mm in longest diameter by CT scan or a lymph node that measures at least 15 mm in short axis (with a CT scan slice thickness of 5 mm). Skin lesions will be documented by digital photography. Copies of the digital photographs will be collected for the study database. Assessments by iRECIST will be used to determine the management of patients in the study and the decision making for discontinuation. If a patient is determined to have iRECIST PD, then confirmation of this will be required in a second study treatment scan. The second scan should be no sooner than 4 weeks and up to 8 weeks later. The patient may continue to receive study treatment during this period at the discretion of the Investigator provided that the patient has no worsening of performance status, no clinically relevant increase in disease-related symptoms, no requirement for intensified management of disease- related symptoms, and is still tolerating the study treatment adequately. Details of the criteria for determining and confirming disease progression by iRECIST are provided in Appendix B. 7.2 Progression-Free and Overall Survival Patients will be assessed for progression and survival for a period of 97 weeks from their first dose of SCIB1. The following will be recorded: ^disease status and the date of evaluation^ date of disease progression by RECIST 1.1 and iRECIST ^ date of start of any new cancer treatment and generic name of treatment agent(s) ^ date of death from any cause, with primary cause 8 PHARMACODYNAMIC AND BIOMARKER ASSESSMENTS 8.1 Blood Samples At a limited number of sites, blood samples (60 mL) will be taken for the analysis of cellular immune response and liquid biomarkers. 8.1.1 Sample Handling and Shipment Blood samples will be couriered at ambient temperature to arrive at the Scancell laboratories within 8 hours of the blood sample being taken. Lymphocytes and plasma will be prepared and either tested immediately or stored frozen in a cryofreezer until analysis. 8.1.2 Assessments and Analysis of Study-Specific Blood Samples Samples will be assessed for cellular immunity to TRP-2 and gp100 peptides by antigen-specific T cell activation of lymphocytes measured by IFNγ ELISpot assay. The immunological response data, including frequency and avidity, if applicable, will be tabulated and plotted to assess descriptively the response patterns throughout the study. The T cell frequencies against each antigen, before and after treatment, will be assessed by ELISpot assay. The designation of a patient as an immunological responder will be defined in the SAP. Additional analyses may be conducted on a subset of samples as follows: CFSE proliferation assays, CTL lysis assays, MHC multimer staining for memory cells, assays to assess epitope spreading, Luminex assays for cytokine secretion and T cell subset analysis, and liquid biomarker analysis. Assays will be conducted depending on the responses seen in the ELISpot assays and if sufficient cells and plasma are recovered from the blood samples. 8.2 Tumour Samples A formalin-fixed, paraffin-embedded (FFPE) archival (< 5 years of age) or fresh tumour biopsy is required at baseline for the analysis of PD-L1 expression. PD-L1 analysis may be performed at accredited laboratories. 8.2.1 Assessments and Analysis of Study-Specific Tumour Samples An FFPE tumour tissue sample will be submitted for PD-L1 expression analysis using an appropriate quantitative immunohistochemical assay. 9 ASSESSMENT OF SAFETY 9.1 Adverse Events 9.1.1 Definition of an Adverse Event An AE is any undesirable medical experience or change in an existing condition that occurs during or after the administration of SCIB1, nivolumab with ipilimumab, or pembrolizumab, whether or not it is considered related to these products or other trial procedures (21 Code of Federal Regulation [CFR] 312.32a and consistent with ICH E2A guidance). Abnormal laboratory findings and other abnormal investigational findings (e.g., on an ECG trace) should be reported as AEs if they are considered medically important by the Investigator. In this study disease progression is expected and will not be recorded as an AE. However, medical events and conditions associated with disease progression (e.g., respiratory failure, weight loss) will be recorded as AEs. 9.1.2 Recording and Reporting of Adverse Events AEs will be collected from the time of the first study related-procedure (including study-specific screening procedures) until up to 30 days after the last dose of SCIB1 or until the next dose of checkpoint inhibitor, whichever is longer. All AEs for patients who signed the main study consent must be recorded on the patient’s CRF and must include details on the description of the event in concise medical terminology, date of onset, date of resolution or status if not resolved, severity, relationship to SCIB1 (IMP), relationship to needle-free injection procedure, relationship to either nivolumab with ipilimumab or pembrolizumab (non-IMP), action taken, and outcome. The Investigator and clinical site personnel will cooperate with the Sponsor in investigating and following-up any AEs of concern. All AEs are to be assessed to determine if they meet the criteria for reporting as an SAE, as defined in Section 9.2.1. 9.1.3 Severity of an Adverse Event The severity of AEs will be graded according to the CTCAE v5.0. AEs that are not included in the CTCAE will be graded according to the CTCAE general guidelines for grading as follows: Grade 1 Mild, asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated Grade 2 Moderate, minimal, local intervention, or non-invasive intervention indicated; limiting age- appropriate instrumental activities of daily living (ADL), e.g., preparing meals, shopping for groceries or clothes, using the telephone, managing money Grade 3 Severe or medically significant but not immediately life threatening; hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self-care ADL, e.g., bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden Grade 4 Life-threatening consequences; urgent intervention indicated Grade 5 Death related to AE 9.1.4 Relationship of an Adverse Event to Study Treatment or Device AEs will be determined by the Investigator to be either related or not related to each of the following: the IMP, the non-IMP, or the PharmaJet Stratis® needle-free injection procedure. For an event to be considered related there should be evidence of exposure to the product or procedure with a reasonable temporal relationship. The AE should be considered more likely explained by the product or procedure than by another cause; this includes events considered possibly related to the product or procedure. Events not meeting these conditions should be reported as non-related. 9.1.5 Protocol Deviations Due to an Adverse Event Deviations from the protocol may be permitted on a case-by-case basis only for patients having an AE or medical emergency. The Investigator or other physician in attendance must contact the Sponsor’s medical expert as soon as possible to discuss the deviation and whether or not the patient should continue to participate in the study. 9.2 Serious Adverse Events 9.2.1 Definition of a Serious Adverse Event An SAE is any untoward medical occurrence that meets one or more of the following criteria: ^results in death, unless death is solely the result of disease progressionis life-threatening* ^ requires hospitalisation or prolongs existing hospitalisation** ^results in significant disability / incapacity (substantial disruption of ability to conduct normal lifefunctions) ^ is a congenital anomaly / birth defect; and / or ^ is an important medical event that may not result in death, be life-threatening, or require hospitalisation, but may jeopardise the patient and may require medical intervention to prevent one of the outcomes listed in these criteria. * This refers to the risk to the patient at the time of the event and does not include events that might have been life-threatening had they been more severe. ** Hospitalisation for elective surgery, for rehabilitation, for social reasons, or other procedure planned prior to the signing of informed consent is not classified as an SAE. 9.2.2 Expectedness An SAE that is not included in the Reference Safety Information in the current Investigator’s Brochure (IB) for the IMP or SmPC for the non-IMP, by specificity, severity, outcome, or frequency, is considered to be unexpected. 9.2.3 Reporting of a Serious Adverse Event SAEs will be collected from the time of the first study-related procedure (including study-specific screening procedures) until up to 30 days after the last dose of SCIB1 or until the next dose of checkpoint inhibitor, whichever is longer. In addition, any SAE that the Investigator or clinical site personnel become aware of, and assessed as related to study participation (SCIB1 treatments or procedures), must be recorded up to and including any follow-up contact until resolution or improvement. SAEs that occur whilst the patient is in the study, must be reported to the Safety Desk within 24 hours of the site becoming aware of the event, even if the SAE does not appear to be trial related. This should be done by emailing or faxing a copy of the SAE report form to the Safety Desk. Completion and submission of the SAE report form must not be delayed, even if not all the information is available. Details of contacts for the reporting of SAEs will be provided prior to the enrolment of the first patient. Patients with SAEs should be monitored carefully until the event resolves, or is considered stable by the Investigator, and the Investigator and clinical site personnel should work with the Sponsor’s safety representative to understand the underlying cause of the event. Additional follow-up information relating to the event must be reported to the Safety Desk as soon as possible after it is available. The Sponsor will ensure that all ICH GCP guidelines, and relevant local and national regulatory requirements, are met with regard to reporting timelines for suspected, unexpected, serious adverse reactions (SUSARs), and the preparation of periodic summary reports. Investigators will be notified by the Sponsor of all SUSARs and are required to comply with local reporting requirements for the notification of RECs. 9.3 Pregnancy Following the administration of study treatment, pregnancy in any female patient, or the female partner of any male patient, will be followed until completion of the pregnancy. The pregnancy will be reported immediately by phone and by emailing or faxing a completed Pregnancy Report to the Safety Desk within 24 hours of knowledge of the event. The Investigator will follow the patient until completion of the pregnancy and must assess the outcome in the shortest possible time but not more than 30 days after delivery or termination. The Investigator should notify the Safety Desk of the outcome of the pregnancy by submitting a follow-up Pregnancy Report. The continuation of one or both study treatments by a female patient who has become pregnant will be reviewed by the Investigator and Sponsor on a case-by-case basis. If the outcome of the pregnancy meets the criteria for immediate classification of an SAE (spontaneous or therapeutic abortion, stillbirth, neonatal death, or congenital anomaly), the Investigator will also report the event by phone, and by emailing or faxing a completed SAE report within 24 hours of knowledge of the event. Any congenital anomaly detected in an aborted foetus is to be documented. 9.4 Administration and Medication Error Related to Study Treatment Administration of SCIB1 in error (outside of the protocol specified dosages and time points) should be recorded, as should any malfunction of the PharmaJet Stratis® needle-free injection device. Any overdose (overdose on a single day or frequency of dosing shorter than specified in the protocol) should be reported immediately to the Sponsor. Dosing errors in relation to the administration of nivolumab with ipilimumab or pembrolizumab during the SCIB1 treatment phase (until EOT) should be recorded and reported to the Sponsor. Any AE or SAE that occurs in relation to a study medication error should be reported as described in the preceding sections. 9.5 Clinical and Laboratory Assessments and Tests No study-specific procedures may be carried out until the patient has given written informed consent. Clinical data from procedures performed in the routine care of the patient may be used for screening purposes provided that they are within the specified screening time window. Laboratory values and test results following an AE may be captured. 9.5.1 Serum Chemistry, Haematology, and Urinalysis Serum chemistry, haematology, and urine samples will be taken according to the schedule detailed in Table 2. These samples should be taken prior to dosing and will be analysed by local laboratories. Serum chemistry will consist of albumin, ALT, alkaline phosphatase, AST, bicarbonate or carbon dioxide, urea, calcium, chloride, creatinine, total bilirubin (and direct if clinically indicated), gamma glutamyl transferase, LDH, non-fasting glucose, phosphorus (measured as phosphate), potassium, sodium, uric acid (urate), and total protein. Haematology will consist of haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelet count, RBC count, WBC count, and WBC differential (basophils, eosinophils, lymphocytes, monocytes, neutrophils). Urinalysis (dipstick) will record protein, glucose, ketones, blood, nitrites, leucocytes, bilirubin, pH, and specific gravity. Microscopic if clinically indicated only: bacteria, RBCs, WBCs, casts, and crystals. Serum chemistry, haematology and urinalysis performed as part of the screening procedure within 48 hours of the first dose of study treatment do not need to be repeated on Day 1. 9.5.2 Other Clinical Laboratory Tests HLA Tissue Typing HLA testing will be conducted at accredited laboratories by molecular (DNA) typing. A separate consent form will be used for HLA typing to limit the number of invasive screening tests for patients who are ineligible for the study based on the HLA type. Eligible patients must be HLA-A2 positive and positive for HLA-DR4, HLA-DR7, HLA-DR53 or HLA-DQ6. Pregnancy Test and Verification of Post-Menopausal Status For women of reproductive potential (including women ≤ 12 months from last menstrual period), a urine pregnancy test will be performed within 72 hours before the first dose of study drug on Day 1. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required. The pregnancy test (serum and / or urine) will be performed at the intervals shown in Table 2. A serum or urine pregnancy test will also be performed at the EOT visit for these patients. Sites may elect to use a serum pregnancy test from the start. Hepatitis Tests Blood samples will be obtained at screening for HBV and HCV testing. Coagulation Tests International normalised ratio (INR) and activated partial thromboplastin time (aPTT) will be determined at screening and at the EOT visit. Thyroid Function Tests Samples for the measurement of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH), will be taken according to the schedule detailed in Table 2. Samples should be taken prior to dosing. Thyroid function tests performed as part of the screening procedure within 48 hours of the first dose of study treatment do not need to be repeated on Day 1. Thyroid function tests may be performed at accredited laboratories affiliated with the study sites if their local laboratory is unable to perform these tests. 9.5.3 Medical History The patient’s medical history will be recorded at screening and will include details of chronic diseases, significant previous illness, all current illness and current concomitant medication. 9.5.4 Physical Examination Complete physical examination will include assessments of eyes, neurological and cardiovascular systems, lungs, abdomen, head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, extremities, skin and other areas with signs and symptoms of disease, to be performed at the time points detailed in Table 2. Height and weight will be recorded at screening and weight only will be recorded at the other time points. A ‘limited’ physical examination may be performed (cardiovascular system, lungs, abdomen, skin, weight, and areas with signs and symptoms of disease) at checkpoint inhibitor only visits as required, as specified in Table 2. Physical examination should be performed prior to dosing. A skin lesion assessment will be performed according to the schedule in Table 2.. Photographs should be taken to document change in existing and new skin lesions. 9.5.5 Injection Site Reaction An assessment of each injection site will be performed approximately 1 hour after the completion of SCIB1 administration. An assessment of each injection site will also be performed at some study visits where no study drug is administered, as outlined in Table 2. Pain, tenderness, erythema, and swelling will be assessed on a scale of 0 to 3 where 0 is absent, 1 is mild, 2 is moderate, 3 is severe (Appendix C). In the case of any moderate or severe injection site reactions being observed, digital photography of the injection sites should be performed at the specified time points in Table 2 or as needed outside of these time points. Anonymised copies of digital photographs will be transmitted via secure file transfer to a dedicated database. 9.5.6 Vital Signs Vital signs will be measured approximately 10 to 15 minutes prior to dosing and then again at 5 minutes, 30 minutes, and 1 hour after SCIB1 dose administration and the patient should be observed for at least 1 hour after receiving either nivolumab with ipilimumab or pembrolizumab for at least the first two doses. Vital signs will also be measured at the EOT visit. Vital signs are to include temperature, pulse, respiratory rate and blood pressure. 9.5.7 Electrocardiography A 12-lead ECG will be performed at the time points detailed in Table 2. The ECG findings will be interpreted by a qualified physician. Any clinically significant findings from the screening ECG will be recorded in medical history. Clinically significant findings from the on-study ECGs will be recorded as AEs. 9.5.8 Ophthalmic Examination Patients are required to have a fundoscopic examination, performed by a healthcare professional trained in performing fundoscopic examination, for example an ophthalmologist, optometrist or other medical professional, during screening and as clinically warranted if the patient experiences any visual disturbance during the study. 9.5.9 Performance Status Evaluation ECOG performance status will be assessed at the time points detailed in Table 2. The ECOG performance criteria is in Appendix D. ECOG performance status should be assessed prior to dosing. 10 STATISTICS The following is a summary of the statistical analysis planned for the study. Further details will be provided in the Statistical Analysis Plan (SAP). 10.1 Sample Size and Power Considerations 10.1.1 Run-In Sub-Cohorts The Run-in sub-cohorts are included to establish the safety and tolerability of SCIB1 treatment of patients receiving either nivolumab with ipilimumab or pembrolizumab to an extent sufficient to support additional recruitment in the full study. For each cohort, a Run-in sub-cohort of six patients is planned with the objective of identifying DLTs. Each cohort will only progress if no more than one patient in the Run-in sub-cohort of six has a SCIB1-related DLT. Patients in the Run-in sub-cohorts who withdraw from the study before Week 5 (Day 36) for reasons other than a DLT will be replaced. In the event that more than one patient in the Run-in sub-cohorts has a SCIB1-related DLT the data will be formally reviewed by the Investigators and the Sponsor and a decision will be made on whether it would be appropriate to recruit an additional Run-in sub-cohort of six patients at a reduced dose of SCIB1. 10.1.2 Cohort 1: Nivolumab with Ipilimumab Forty-three patients will be enrolled using Simon’s Optimal 2-stage design (Simon 1989). Six of these patients will form a Run-in sub-cohort for the formal assessment of DLTs for the combination. Patients will be considered evaluable for the primary endpoint provided that they have received at least one dose of SCIB1 and have completed at least one post-baseline tumour assessment by Week 25 (Day 176) or have withdrawn from the study due to disease progression or SCIB1 treatment-related toxicity or have died from complications related to melanoma or due to SCIB1-related toxicity. Non-evaluable patients will be replaced. This sample size has been determined based on the Simon 2-stage design. The sample size calculation assumes that an ORR of 50% would be of no interest since it approximates to the historical observations of ORR to nivolumab with ipilimumab for this group of patients (Lebbé 2019). Conversely, an ORR of 70% would be considered to be a positive signal for further development of SCIB1 administered in addition to nivolumab with ipilimumab. The trial is designed with a null hypothesis that the ORR is 50%. In the first stage, 15 patients will be enrolled and if there are eight or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), further recruitment to this cohort will be stopped. Recruitment will continue until a decision on Stage 1 has been made. The null hypothesis will be rejected if 27 or more responses are observed in 43 patients. This design yields a type I error rate of 5% and a power of 80% when the true response rate is 70%. 10.1.3 Cohort 2: Pembrolizumab The full cohort will enrol a total of 44 evaluable patients (including the six from the Run-in sub-cohort) using Simon’s Optimal 2-stage design (Simon 1989). Patients will be considered evaluable for the primary endpoint provided that they have received at least one dose of SCIB1 and have completed at least one post-baseline tumour assessment on Week 25 (Day 176) or have withdrawn from the study due to disease progression or SCIB1 treatment-related toxicity or have died from complications related to melanoma or due to SCIB1-related toxicity. Non-evaluable patients will be replaced. This sample size has been determined based on the Simon 2-stage design. The sample size calculation assumes that an ORR of 30% would be of no interest since it approximates to the historical observations of ORR to pembrolizumab alone for this group of patients (Robert et al.2015b). Conversely, an ORR of 55% would be considered to be a positive signal for further development of the combination. The trial is designed with a null hypothesis that the ORR is 35%. In the first stage, 14 patients will be enrolled and if there are five or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), further recruitment to this cohort will be stopped. Recruitment will continue until a decision on Stage 1 has been made. The null hypothesis will be rejected if 21 or more responses are observed in 44 patients at the end of the study. This design yields a type I error rate of 5% and a power of 80% when the true response rate is 55%. In the event that a higher than expected proportion of patients have received a PD-1 inhibitor in the adjuvant setting, these assumptions will be adjusted to reflect the lower response rate expected in these patients from pembrolizumab alone (ORR estimated to be less than 10%). 10.2 Analysis Sets 10.2.1 Full Analysis Set The FAS will consist of all enrolled patients who receive at least one dose of either SCIB1, nivolumab with ipilimumab, or pembrolizumab. 10.2.2 Safety Analysis Set The SAF will consist of all enrolled patients who receive at least one dose of either SCIB1, nivolumab with ipilimumab, or pembrolizumab. 10.2.3 Per Protocol Set The PPS will consist of all enrolled patients who are evaluable for the primary endpoint of tumour response by the RECIST 1.1 criteria. Patients will be included in the PPS if they have: ^ received at least one dose of SCIB1 and have completed at least one post-baseline tumour assessment by Week 25 (Day 176) ^ died from complications related to melanoma or due to SCIB1--related toxicity; or ^ withdrawn from the study due to disease progression or SCIB1 treatment-related toxicity. ^ do not have important protocol deviations considered as having a serious impact on the safety or efficacy results. 10.3 Data Handling Conventions For all variables, only the observed data from the patients will be used in the statistical analyses. There is no plan to impute missing data, unless otherwise specified in the SAP. 10.4 Interim Analyses Safety review of the data will be performed when the Run-in sub-cohorts of six patients have been enrolled and assessed up to Day 35. An interim analysis will be performed at the end of Stage 1 when 15 (nivolumab with ipilimumab cohort) or 14 (pembrolizumab cohort) evaluable patients have been enrolled and followed up for response – if there are eight or fewer responders in the 15 patients in the nivolumab with ipilimumab cohort or five or fewer responders in the 14 patients in the pembrolizumab cohort, the trial will stop. Otherwise, the trial will continue to stage 2 where a further 28 (nivolumab with ipilimumab cohort) or 30 (pembrolizumab) patients will be recruited. As part of the interim analysis, a feasibility assessment of further enrolment to the cohort not reaching the first stage quota will be performed upon the other cohort reaching the first stage. A CSR will be compiled when all the patients have completed study treatment. A CSR addendum will be created when all the patients have completed post-treatment follow-up. 10.5 Study Population The FAS will be used for the presentation of baseline and efficacy parameters. In addition, the PPS will be used for the evaluation of the efficacy parameters. The SAF will be used for the presentation of safety parameters. 10.5.1 Patient Disposition For each of the run-in, and full (i.e., all patients) parts of the study the number of patients screened, enrolled and within each analysis population will be summarised. In addition, the number of patients completing / not completing the study will be presented along with the primary reason for withdrawal. Withdrawal will be identified as withdrawal from treatment only or withdrawal from treatment and study (e.g., post-treatment follow-up). The number of patients who complete study treatment (ten doses of SCIB1) will be summarised. 10.5.2 Demographics and Baseline Characteristics Demographic variables at screening and baseline characteristics will be summarised, for each of the run- in set of patients, and separately for all patients in the FAS. Medical history information collected at screening will be included within a patient listing. 10.6 Efficacy Analysis The efficacy analysis will be performed for patients enrolled in the study based on both the FAS and PPS. An efficacy analysis will not be performed at the end of the Run-in sub-cohorts. 10.6.1 Efficacy Endpoints Objective Response Rate as Measured by RECIST 1.1 Criteria The primary efficacy endpoint is based on the ORR as measured using the RECIST 1.1 criteria. It corresponds to whether or not a patient achieved a PR or CR at any time post start of treatment. The ORR will be summarised for all patients within the FAS and the PPS. Each patient will be summarised by his or her best response. If a patient is evaluable for the primary endpoint but has not completed at least one post-baseline tumour assessment by Week 25 (Day 176) then they are counted as a non-responder. Duration of Response The duration of response will be measured from the time when the measurement criteria are met for CR or PR (ORR definition) until the first date that PD (per RECIST 1.1) is documented or death due to any cause, whichever occurs first. Patients who neither progress nor die will be censored on the date of their last assessment. Duration of overall response will be estimated using Kaplan−Meier methodology and summarised for all patients within the FAS and the PPS. The Kaplan−Meier estimate of the survivor function will be plotted. Immune-Related ORR Measured by iRECIST Criteria This endpoint will be reported in a similar way to the primary endpoint (see above) except the determination of the ORR will be based on using the iRECIST criteria (Seymour et al.2017). Progression-Free Survival The PFS rate at Week 49 (Day 344) and Week 97 (Day 680) is defined as the proportion of patients who have not progressed (per RECIST 1.1 and iRECIST) or started new anticancer therapy or died at each timepoint. PFS will be summarised for all patients within the FAS and the PPS. Patients who neither progress nor die will be censored on the date of their last disease assessment. Patients who start new anticancer treatment without a report of disease progression will be censored on the date of their last disease assessment before the new treatment is initiated. Patients who do not complete any tumour assessments and do not die will be censored on the date of first dose of SCIB1. PFS will be estimated using Kaplan−Meier methodology. Anticancer treatment is defined as any systemic treatment for malignancy including melanoma. Overall Survival Rate The OS rate at Week 49 (Day 344) and Week 97 (Day 680) is defined as the proportion of patients who remain alive at each timepoint. OS will be summarised for all patients, for both the FAS and the PPS, and will be estimated using Kaplan−Meier methodology. 10.6.2 Planned Method of Analysis No statistical testing is planned to be performed as there is only one treatment group and there is no hypothesis testing set in this study. Ninety-five percent confidence intervals will be presented alongside summary statistics where it is deemed appropriate. Additional details will be provided within the SAP. Descriptive statistics for all endpoints that are continuous data will have the following summary statistics presented: number of non-missing observations, mean, standard deviation, median, lower quartile, upper quartile, minimum, and maximum. Categorical variables will be summarised using proportions (counts and percentages). Time to event variables will have the following presented: number of events, number of censored observations, and Kaplan−Meier estimates for the median (50th), 25th, and 75thpercentiles, and the estimated event rates at defined time-points. 10.7 Safety Analysis Safety reporting will be carried out for both the run-in subset of patients and also for the full set of patients enrolled in the study, based on the SAF. 10.7.1 Adverse Events AEs will be coded using the current version of the MedDRA at the time of study start. An AE is treatment emergent if the onset date is on or after the date of first dosing with study treatment (SCIB1). Any AE with an onset date earlier than the first dosing with study treatment will be classified as a pre-treatment AE. If a patient experiences more than one AE with the same preferred term, that preferred term will be counted only once. It will be assigned the greatest observed severity and the strongest relationship to study treatment. Summary presentations for the number and percentage of patients reporting treatment emergent AEs (TEAEs), severity of TEAEs, TEAEs by relationship (separately presented for relationship to SCIB1, nivolumab with ipilimumab, pembrolizumab, or PharmaJet Stratis® needle-free injection procedure), and treatment-emergent SAEs will be produced. In addition, a summary of TEAEs of Grade ≥ 3 will also be presented. Separate presentations will be produced for (i) patients enrolled during the run-in and (ii) all patients, for the SAF. SAEs and AEs directly resulting in withdrawal from study will be listed. 10.7.2 Laboratory Parameters Laboratory parameters (haematology, chemistry, urinalysis, and other laboratory parameters [Section 9.5.2]) will be summarised by scheduled visit. Where appropriate, corresponding CTCAE grades will be calculated according to the values reported. The baseline grades and the worst grade post-baseline will be summarised. Laboratory values outside the reference range will be identified within patient listings. 10.7.3 Physical Examination Physical examination data will be included within a patient listing. 10.7.4 Vital Signs Vital signs measurements will be summarised for actual values and changes from baseline over the scheduled visits (and for time point assessments within each visit). 10.7.5 12-Lead Electrocardiogram Twelve-lead ECG data will be included within a patient listing. 10.7.6 Injection Site Reactions Injection site reactions will be summarised by scheduled visit. As injection site reactions are to be recorded at the four injection sites, the most severe reaction observed across the four sites will be summarised. 10.7.7 Concomitant Medications Concomitant therapies will be coded to their generic name and Anatomical Therapeutic Chemical (ATC) Class using the current version of the World Health Organisation (WHO) Drugs Dictionary at the time of study start. Medications will be assigned as being prior to, or concomitant with study treatment. If the medication stop date is before the study treatment start date (SCIB1), the medication will be assigned as being prior to study treatment. In all other situations, the medication will be assigned as being concomitant with study treatment. Concomitant medications will be separately summarised by ATC Class and generic (preferred) name. Prior medications will be identified in a patient listing. If a patient has separate periods of taking specific medications, then that medication is only counted once within the specific period of observation (i.e., prior or concomitant) where it is taken. 10.8 Pharmacodynamic and Biomarker Analyses Immune response will be assessed by ELISpot assays on peripheral blood samples from patients at a limited number of sites. Additional analyses may be conducted on a subset of these samples including CFSE proliferation assays, CTL lysis assays, MHC multimer staining for memory cells, assays to assess epitope spreading, Luminex assays for cytokine secretion and T cell subset analysis, and liquid biomarker analysis. Tumour samples will be assessed for the expression of PD-L1. 10.9 Reporting Deviations from the Statistical Analysis Plan The handling of deviations from the SAP, will be described in the final CSR. 11 QUALITY CONTROL AND QUALITY ASSURANCE The study will be conducted in accordance with SOPs that meet ICH and national guidelines for clinical trials. 12 REGULATORY AND ETHICAL OBLIGATIONS 12.1 Compliance with Good Clinical Practice This study will be performed in accordance with ICH GCP guidelines. 12.2 Informed Consent It is the Investigator’s responsibility to obtain written informed consent from the patient after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study. The Investigator will also explain to the patient that the patient is free to refuse participation in the study and free to withdraw from the study at any time without prejudice to future treatment. Signed informed consent must be obtained before the patient receives any study treatment or has any study-specific procedures or assessments (procedures and assessments performed for the purpose of the study rather than as part of routine medical care). The ICF signed must be current and include any relevant information from protocol amendments. Patients on study should be re-consented when the revisions to the ICF are substantive and include changes that indicate an altered benefit / risk relationship resulting from study treatments or study participation. A separate ICF will be signed to allow a blood sample to be drawn for HLA tissue typing prior to other screening procedures being performed. The HLA ICF can be obtained by a trained healthcare professional designated by the investigator. The ICF signed must be current and include any relevant information from protocol amendments. Original copies of the signed and dated ICFs must be retained in the Investigator Site File, and be available for inspection by the study monitor, Sponsor representative or representatives from the relevant national regulatory authority. 12.3 Contact with Primary Care Physician ICH GCP guidelines recommend that the Investigator inform the patient’s primary care physician about the patient’s participation in the trial if the patient has a primary care physician and if the patient agrees to the primary care physician being informed. 12.4 Research Ethics Committee A copy of the protocol and the proposed patient information sheets and ICFs will be submitted to the REC. Written approval of the protocol and the ICFs must be obtained prior to recruitment of patients into the study and the shipment of study treatments to the clinical site. The Investigator must inform, and obtain approval from, the REC for all protocol amendments, and all amendments to the patient information sheets and ICFs. All SUSARs likely to affect the safety of the patients or the conduct of the study will be sent to the REC. Copies of the REC notification and acknowledgment must be provided to the Sponsor. 12.5 Regulatory Approval The study will not commence until regulatory approval has been obtained from the relevant national regulatory authorities. 12.6 Periodic Review of Safety and Efficacy Safety and efficacy data will be formally reviewed on a frequent and regular basis by the Investigators and the Sponsor. The review committee will include study investigators, the Sponsor’s medical monitor, and the Sponsor’s clinical operations lead or designee. 12.7 Registration of the Clinical Study in Trial Registry Websites Study information on study objectives and design, as well as patient eligibility criteria, will be posted on public clinical trial registers before enrolment begins. 12.8 Patient Confidentiality In compliance with ICH GCP guidelines, it is a requirement that the Investigator and institution permit authorised representatives of the Sponsor, regulatory authorities, and REC direct access to review the patient’s original medical records at the site for verification of trial-related procedures and data. Measures to protect confidentiality include: only the study number, patient number, and date of birth will identify the patient on the CRF or other documents submitted to the Sponsor. This information will be used in the database for patient identification. Patient names or addresses will not be entered on the CRF or in the database. No material bearing a patient’s name will be kept on file by the Sponsor. Patients will be informed of their rights within the ICF. 12.9 Data Protection All personnel involved in the study will comply with national guidelines on data protection. 12.10 Future Use of Stored Specimens All biological specimens are taken solely for the research purposes of this clinical study. Blood samples will be destroyed 12 months after the completion of the CSR. Tumour tissue blocks will be returned from analytical laboratories to the originating sites using local procedures. In the event the patient withdraws consent after obtaining the samples, they will be tested and the results used as detailed in the protocol. At the point the consent is withdrawn no further samples will be obtained. 13 ADMINISTRATIVE AND LEGAL OBLIGATIONS 13.1 Investigator Obligations All Investigators will ensure that they comply with ICH GCP and will provide training documentation from study initiation. 13.2 Access to Source Data and Documents The Investigator shall permit authorised representatives of the Sponsor and national regulatory authorities to have direct access to portions of the patient’s medical records related to the study. As part of the required content of informed consent, the patient must be informed that his or her medical records will be reviewed for this purpose. 13.3 Insurance Prior to the start of the trial, the Sponsor will ensure that adequate insurance is in place for the conduct of the trial. 13.4 Protocol and Informed Consent Amendments No changes from the final approved (signed) protocol may be implemented without the prior written approval or favourable opinion of a written amendment by the REC and national regulatory authorities, as applicable, except when necessary to address immediate safety concerns to the patients or when the change involves only non-substantial logistics or administrative changes. The Principal Investigator at each clinical site and the Sponsor will sign the protocol amendment. 13.5 Trial Documentation and Data Storage The Investigator must retain a comprehensive and centralised filing system of all trial-related documentation that is needed for inspection by representatives of the Sponsor and national regulatory authorities. 13.6 Availability and Retention of Investigational Records The Investigator must retain essential documents according to the applicable regulations and depending on the future development of the investigational product as follows: ^ for at least 15 years after the completion or discontinuation of the trial ^ for at least 2 years after the last approval of a marketing authorisation in the US or European Community; or ^ for at least 2 years after the formal discontinuation of the clinical development of the investigational product. The Sponsor will determine the minimum retention period and notify the Investigator when documents may be destroyed. Patient files and other source data (including copies of protocols, CRFs, original reports of test results, agent dispensing logs, correspondence, records of informed consent, and other documents pertaining to the conduct of the trial) must be kept for the maximum period permitted by the clinical institution. No trial document will be destroyed without the prior written agreement of the Sponsor and the Investigator. Should the Investigator wish to assign the trial records to another party or move them to another location, written agreement must be obtained from the Sponsor. 13.7 Data Collection Data will be collected using study-specific electronic CRFs. The data collected on the CRFs will be captured in a clinical data management system that meets the technical requirements described in 21 CFR Part 11 (USA) and requirements of other concerned competent authorities. Data will be collected at the clinical site by designated and trained personnel. CRFs must be completed for each patient who provided main study informed consent. Patient identity should not be discernible from the data provided on the CRF. Data processed from other sources (e.g., central laboratory, bioanalytical laboratory) will be sent to the clinical site, where they will be retained but not transcribed to the CRF, unless otherwise noted in the protocol. These data may also be sent electronically to the Sponsor (or data management contract research organisation). All patient data must have supportive original source documentation in the medical records, or equivalent, before they are transcribed to the CRF. Source documentation will also be needed for post-treatment follow- up data. Data may not be recorded directly on the CRF and considered as source data. 13.8 Language CRFs will be completed in English. Generic names of concomitant medications should be recorded in the CRF wherever possible. All written materials to be used by the patients must be in a language that the patient can read and understand. 13.9 Clinical Monitoring, Source Data Verification, and Audits Study monitor responsibilities will be undertaken by experienced clinical study monitors. The clinical study monitor will be responsible for ensuring that patients have signed the ICF and that the study is conducted according to applicable SOPs, the protocol, and other written instructions and regulatory guidelines, in compliance with GCP guidelines. The main responsibilities of the study monitors are to visit the Investigator and clinical site personnel involved in the study before, during, and after the study, in compliance with the Clinical Monitoring Plan. This is to ensure adherence to the protocol and that all data are correctly and completely recorded and reported. Study monitors are also required to confirm that signed informed consent has been obtained prior to the patient undergoing any study-specific procedures or receiving study treatment. The monitors should also confirm that the ICF that has been signed, is current and in accordance with any protocol amendments and REC approvals. Study monitoring, source data verification and auditing of the clinical sites will be carried out as described in the Clinical Monitoring Plan. 13.10 Protocol Deviations and Violations Protocol Deviations A protocol deviation is any non-adherence to procedures, assessments or schedules specified in the protocol . Protocol Violations A protocol violation is any non-adherence to the protocol inclusion / exclusion criteria, or other significant non-adherence to procedures, assessments or schedules specified in the protocol that impact the main objectives of the study or patient safety. For the purposes of this study protocol violations will be considered to be important protocol deviations. Protocol deviations will be defined in the study monitoring plan and will be recorded by clinical site personnel in the source documents. When a protocol violation is reported, the Sponsor will determine whether to discontinue the patient from the study or permit the patient to continue in the study, with documented approval from the medical expert. The decision will be based on ensuring the safety of the patient and preserving the integrity of the study. Requests to deviate from the inclusion and exclusion criteria of the protocol, or any protocol schedules, mandated procedures or assessments, will not be granted by the Sponsor. If clinical site personnel learn that a patient who did not meet protocol inclusion and exclusion criteria was entered in a study, they must immediately inform the Sponsor or a Sponsor representative and REC, as required, of the protocol violation. 14 REFERENCES Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol.2016 Sep;17(9):1248–60. Durrant LG, Pudney V, Spendlove I, et al. Vaccines as early therapeutic interventions for cancer therapy: neutralising the immunosuppressive tumour environment and increasing T cell avidity may lead to improved responses. Expert Opin Biol Ther.2010 May;10(5):735–48. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer.2009;45:228–47. EUCAN. Cancer factsheets. 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Xue W, Brentville VA, Symonds P, et al. SCIB1, a huIgG1 antibody DNA vaccination, combined with PD-1 blockade induced efficient therapy of poorly immunogenic tumors. Oncotarget.2016 Dec 13;7(50):83088– 83100. Example 4 – Results of clinical study This example sets out the results of a clinical study substantially in accordance with Example 3. Introduction Immunotherapy with checkpoint inhibitors (CPI), including programmed death 1 (PD-1) inhibitors given alone and in combination with cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors, has transformed first- line treatment outcomes in patients with unresectable or metastatic advanced melanoma1,2However, at 5 years, the overall survival is 52%1which means approximately half of patients do not derive a meaningful benefit from treatment. Furthermore, in the pivotal trial Checkmate-067, the surrogate endpoints for survival such overall response rate (ORR) and PFS at 3 years are 58% and 34% respectively3. In the real-world setting, the ORR that is achieved with the combination is nearer to 50%4and some skilled in the art have reporting 28% in the real-world setting5. Recently, nucleic acid therapeutic vaccine in melanoma showed efficacy in the unresectable stage of the disease in combination with pembrolizumab in delaying time to recurrence6. However, in the unresectable stage of the disease, nucleic acid vaccines have not shown a meaningful effect in reducing tumour burden. Methods Patients In the SCOPE clinical trial testing the addition of SCIB1 to standard of checkpoint inhibitor regimens, eligible patients had histologically confirmed stage III (unresectable) or stage IV melanoma and had received no prior systemic treatment for advanced disease, however, prior treatment in the adjuvant melanoma setting was permitted. Other eligibility criteria included an age of at least 18 years; an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0, indicating no symptoms, or 1, indicating mild symptoms); measurable disease as assessed by means of computed tomography or magnetic resonance imaging according to Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1; availability of tissue collected from metastatic or unresectable tumours (archival or recently biopsied samples) for the assessment of PD-L1 status; and known BRAF V600 mutation status. Patients must also be positive for the Class I HLA type HLA-A2 and at least one of the following class 2 HLA type: HLA-DR4, HLA-DR7, HLA- DR53 or HLA-DQ6. Key exclusion criteria were the presence of active brain metastases, ocular melanoma, mucosal melanoma or autoimmune disease. Patients receiving a higher than a physiological dose of steroids 1 week prior to the first dose of SCIB1 were excluded from study entry. Patients with BRAF mutation positive disease with evidence of rapidly progressing disease were also excluded from being vaccinated with SCIB1. Trial Design and Treatment Cohort 1: Nivolumab with Ipilimumab In the first stage (see figure 5), 15 patients (including the six patients from the Run-in sub-cohort) will be enrolled and if there are eight or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), the cohort will be stopped. Otherwise, an additional 28 patients will be enrolled in the second stage for a total of 43 patients. Recruitment will continue until a decision on Stage 1 has been made. In this cohort, patients were treated as follows: 8mg total dose per dosing occasion of SCIB1 given in four intramuscular injections of 2mg SCIB1 administered using Pharmajet Stratis needle-free injection device at weeks Weeks 0, 4, 7, 13, 25 and every 12 weeks thereafter up to week 85. 1 mg / kg nivolumab given intravenously over 30 minutes in combination with 3 mg / kg ipilimumab administered intravenously over 30 minutes every 3 weeks for the first 4 doses. This is then followed by a second phase in which nivolumab monotherapy is administered intravenously at either 240 mg over 30 minutes every 2 weeks or at 480 mg over 60 minutes every 4 weeks. For the monotherapy phase, the first dose of nivolumab should be administered: ^ 3 weeks after the last dose of the combination of nivolumab and ipilimumab if using 240 mg every 2 weeks; or ^ 6 weeks after the last dose of the combination of nivolumab and ipilimumab if using 480 mg every 4 weeks The first dose of checkpoint inhibitors was given 1 week after the first dose of SCIB1 and the total treatment duration was 97 weeks or until progression of disease or dose limiting toxicity. Cohort 2: Pembrolizumab In the first stage, 14 patients (including the six patients from the Run-in sub-cohort) will be enrolled and if there are five or fewer clinical responses (RECIST 1.1 objective response [CR or PR] within 25 weeks of the first dose of SCIB1), the cohort will be stopped. Otherwise, an additional 30 patients will be enrolled in the second stage for a total of 44 patients. Recruitment will continue until a decision on Stage 1 has been made. In this cohort the patient was treated as follows: 8mg total dose per dosing occasion of SCIB1 given in four intramuscular injections of 2mg SCIB1 administered using Pharmajet Stratis needle-free injection device at weeks Weeks 0, 4, 7, 13, 25 and every 12 weeks thereafter up to week 85. Either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes The total treatment duration was 97 weeks or until progression of disease or dose limiting toxicity and the first dose of checkpoint inhibitors was given 1 week after the first dose of SCIB1. The study was designed using Simon’s two stage methodology with 80% power when the true response rate is 70% (Cohort 1) and 55% (Cohort 2) with an overall type I error of 5%. The trial was designed with a null hypothesis that the ORR is 50% (cohort 1) and 30% (cohort 2). The null hypothesis values are commensurate with outcomes in the real-world setting in patients treated with unresectable melanoma. The primary endpoint of the study is to measure the objective response rate according to the RECIST 1.1 criteria and this will be compared to the historical data for the combination of nivolumab with ipilimumab or pembrolizumab alone in these separate patient populations. The secondary endpoints are to determine whether the addition of SCIB1 to either nivolumab with ipilimumab or pembrolizumab improves the duration of response relative to historical data for the combination of nivolumab with ipilimumab or pembrolizumab alone in this patient population. The progression-free survival defined as the proportion of patients who have not progressed (per RECIST 1.1 and iRECIST), started new anticancer therapy, or died at each specified timepoint will be analysed with the overall survival rate defined as the proportion of patients who remain alive at each specified timepoint. The safety and tolerability data of patients will also be summarised in these 2 cohorts. Additionally, exploratory endpoints will assess the relationship between the immune response and clinical outcome using ELISpot, and other assays performed on peripheral blood samples from patients. Results Patients and Treatment From October 2019 through September 2024, a total of 17 patients were enrolled in cohort 1 and 3 were enrolled in cohort 2. In cohort 1 the baseline characteristics of patients was such that 12 were male and 5 were female, all 17 patients had metastatic disease to the lung, liver and or brain.8 of the patients had a Braf mutation whilst 9 were wild type.8 patients had a lactate dehydrogenase (LDH) level greater than the upper limit of normal and 9 patients were below the limit. LDH is an important prognostic factor, an elevated LDH is an indicative of poor prognosis.12 patients were below the age of 65, 2 were between 65 and 74 years of age and only 3 patients were 75 years or older. In cohort 2, 1 patient was male and 2 were female. All 3 patients had metastatic disease to the lung or the liver. Only one patient had a Braf mutation and 1 patient had an elevation in the LDH beyond the upper limit of normal. All three patients in cohort 2 were beyond the age of 75. All patients across both cohorts presented with total tumour burden greater than 20 cm. See table 3: Cohort 1 Cohort 2 Number of patients (n) Gender Male 12 1 Female 5 2 Age <65 12 0 ≥65- <75 2 0 ≥75 3 3 Stage of disease at study entry III 0 0 IV 17 3 Braf Mutation 8 1 Wildtype 9 2 Lactate Dehydrogenase Cohort 1 Cohort 2 Number of patients (n) >Upper limit of normal 8 1 ≤ULN 9 0 Total Tumour Burden ≥20 cm 17 3 <20 cm 0 0 Prior treatment in the adjuvant setting Yes 6 1 No 11 2 Table 3: Baseline Characteristics of the Patients The data was cut in September 2023 and in cohort 1, 11 patients had reached the first computerised tomography or magnetic resonance diagnostic imaging time point of 13 weeks post-vaccination with SCIB1. The other 6 patients had recently entered the study, therefore, had not reached the first imaging time point. For the purposes of efficacy, only patients in cohort 1 will be summarised herein. Of the 11 patients, 9 patients (81.8%) had shown an overall response rate (ORR) as measured by RECIST 1.1 at week 13. Of those, 5 patients had reached week 19, 4 reached week 25 and 2 had reached week 37. The response in these patients was sustained and showed an overall decrease in total burden. In patients who had reached the week 25 diagnostic imaging timepoint, demonstrated the biggest overall decrease (-69 to -94%) in total tumour burden, See figures 6 and 7: The waterfall plot (Figure 6) shows the maximum change from baseline in the sum of the reference diameters of the target lesion in patients receiving SCIB1 with nivolumab plus ipilimumab. Data are shown for all the patients who had target lesions evaluated at baseline and who reached the first imaging timepoint of week 13. A bar in the negative quadrant denotes tumour shrinkage whilst a bar in the positive quadrant indicates increase in tumour size. The horizontal lines indicate a 30% reduction in the tumour burden in the target lesion or a 20% increase, as these are the thresholds for a response or progression. The change in tumour burden was defined as the percentage decrease in the sum of the reference diameters of the target lesion from baseline to nadir, observed up until September 2023. As can be seen from Figure 6, just a single patient experienced a progression of disease, whilst all other 10 patients experienced a shrinkage in their total tumour burden. Of the 10 patients showing a response, only one patient at the time of the data cut hadn’t reached the threshold of a partial response. However it is expected that at their next scan should the tumour continue to reduce the patient will also be a responder and therefore contributing to SCIB1’s remarkable treatment effect when combined with the checkpoint inhibitors. Adverse Events Treatment-related adverse events of any grade occurred in all patients treated with SCIB1 with ipilimumab and nivolumab (see table 4) . The most common adverse event reported to date are injection site reactions related to the SCIB1. These reactions are mild in severity and resolve with time. The patients who experienced the biggest overall decrease in tumour burden (-94%) also experienced vitiligo characterised as hyperpigmentation / depigmentation covering >10% body surface area. At the last assessment the adverse was ongoing and was reported to have a causal relationship with SCIB1. Incidence of treatment-related adverse events of CTCAE grade 3 or 4 severity was reported in 16 patients, and on 8 occasions the combination of checkpoint inhibitors had a causal relationship, whilst in only one occasion was SCIB1 thought to be related. One patient died whilst on study due to pneumonia and this was not thought to be related to the metastatic melanoma or the treatment regimen consisting of SCIB1 with Ipilimumab plus nivolumab. There were no serious adverse events reported with a causal relationship with SCIB1 (see table 4). The serious adverse events reported with a causal relationship to the checkpoint inhibitors were in keeping with the summary of product characteristics. The addition of SCIB1 to the checkpoint inhibitors has not shown to potentiate the toxicity of the checkpoint inhibitors. Total Related Related to Related to Related to to ipi / nivo nivo Needle SCIB1 mono free procedure All AEs 116 19 24 0 7 SAEs 12 0 7 0 1 AEs > G3 16 1 8 0 0 Lab abnormalities reported as 12 0 5 0 0 AE AE leading to Rx 3 0 3 0 0 discontinuation AE leading to Deaths 1 0 0 0 0 Table 4: Summary of Adverse Events (Cohort1) Patient ID SAE Term Grade Related Related to Outcome to ipi / nivo SCIB1 1 Transaminitis 4 N Y Unknown Campylobacter 3 N Y Recovered Infection Pneumonia (initially 5 N N Fatal General Deterioration 2 Transaminitis 4 N Y Not recovered Transaminitis 3 N Y Not recovered 3 Diarrhea 3 N Y Recovered 4 Adrenal 2 N N Not recovered Haemorrhage COVID 3 N N Recovered 5 Fever 1 N Y Recovered Fall Recovered Fever of Unknown Not recovered Origin Table 4: Summary of Serious Adverse Events (Cohort 1) Discussion In this open-label, Phase II study involving patients in the first-line treatment setting of advanced / metastatic melanoma, the addition of SCIB1 to ipilimumab with nivolumab resulted in a remarkable overall response rate of 81.8%. The characteristics of the study participants at baseline were typical of patients with advanced / metastatic melanoma and is reflective of the real-world setting, although patients were selected based on their HLA type. Pivotal clinical trials have reported an ORR of 54-58%1,2,3and studies conducted in the real-world setting have reported an ORR of 28%-48%4,5. The magnitude of tumour shrinkage as shown in the ORR data presented in the waterfall plot figure 6 and the spider plot figure 7 has not been shown previously in this treatment setting in any of the approved combination immunotherapies or those currently in development. Those experienced in the art use RECIST ORR as a surrogate marker for survival as by reducing tumours and arresting their growth it is expected that life is extended in these patients. Figure 7 demonstrates durability in tumour response, and this is significant in the field as durability of response correlates to survival as is seen on long-term outcome studies 2,3. SCIB1 when given with ipilimumab and nivolumab has a meaningful impact on tumour shrinkage and the prolongation of life in a treatment setting where 50% of patients succumb to melanoma despite treatment with checkpoint inhibitors. It is also hypothesised that SCIB1 can be added to any combination of checkpoint inhibitor therapy, including but not limited to relatlimab with nivolumab for a similar treatment effect as has been shown when combined with ipilimumab plus nivolumab. In conclusion, SCIB1 when added to ipilimumab and nivolumab and continued when ipilimumab is withdrawn or when nivolumab is withdrawn has a profound impact on the overall response rate in tumours to the extent where the overall survival rate can be improved beyond 52% as had been shown in the long-term outcomes studies of ipilimumab plus nivolumab1. References: 1. J.Larkin et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma N Engl J Med 2019; 381:1535-1546 2. Jedd D. Wolchok et al. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma Journal of Clinical Oncology 202240:2, 127-137 3. Errico, A. CheckMate 067—frontline nivolumab improves PFS alone or in combination with ipilimumab. Nat Rev Clin Oncol 12, 435 (2015). 4. P. Serra-Bellver et al. Real-world outcomes with ipilimumab and nivolumab in advanced melanoma: a multicentre retrospective study European Journal of Cancer 176 (2022) 121e132 5. Parakh S, Randhawa M, Nguyen B, Warburton L, Hussain MA, Cebon J, Millward M, Yip D, Ali S. Real-world efficacy and toxicity of combined nivolumab and ipilimumab in patients with metastatic melanoma. Asia Pac J Clin Oncol.2019 Feb;15(1):26-30 6. L.J Albrecht et al., The Latest Option: Nivolumab and Relatlimab in Advanced Melanoma the Latest Option: Nivolumab and Relatlimab in ATdvanced Melanoma. Curr Oncol Rep 25, 647–657 (2023). Example 5 – Evidence of checkpoint inhibition efficacy in pre-clinical mouse melanoma models Murine B16F1 melanoma is known from previous literature to be unresponsive to checkpoint therapies. C57Bl / 6 mice were implanted with 2.5x104B16F1 melanoma cells subcutaneously and then treated with 100µg anti-mouse CTLA4 antibody (clone 9D9) or 250µg anti-mouse PD1 antibody (clone RMP1-14) and anti-CTLA4 antibody i.p on days 8, 15 and 22 post tumour implant. Tumour growth was monitored and mice terminated when tumours reached the 15mm diameter end point. Neither checkpoint antibody therapy showed any significant effect on tumour growth and survival (Figure 8.) Despite this, some tumor models are known to be responsive to checkpoint therapies. The B16F1 melanoma line was engineered to express human HLA alleles (HLA-DR4 or HLA-DP4) to use in human HLA transgenic mouse models (Brentville et al.2016, Cancer Research 76:548-60; Brentville et al.2019, Oncoimmunology 8:e1576490). HLA-DR4 mice (Taconic model 4149) have a C57Bl / 6 background except that murine MHC Class II alleles are replaced with human HLA-DR4. For this model, the B16F1 cell line has been engineered to express human HLA-DR4 (B16 DR4). HHDII / DP4 mice (HLA-A2.1+ / + HLADP4+ / + hCD4+ / +, EM:02221, European Mouse Mutant Archive) also have a C57Bl / 6 background where the murine Class I alleles are replaced with chimeric human HLA-A2 (HHDII) and the Class II alleles are replaced with HLA-DP4. For this model, B16F1 tumour cells have been engineered so that they do not express murine MHC Class I or II, but do express human HLA-A2 and HLA-DP4 (B16 HHDII / DP4). HLA-DR4 or HHDII / DP4 transgenic mice were implanted with B16 DR4 or B16 HHDII / DP4 melanoma cells respectively. HLA-DR4 transgenic mice were implanted with 2.5x104B16 DR4 cells subcutaneously followed by treatment with 250µg anti-PD1 (clone RMP1-14), 250µg anti-PD1 and anti- PDL1 (clone 10F.9G2) or 250µg anti-PD1, anti-PDL1 and 100µg anti-CTLA4 (clone 9D9) antibodies i.p on days 8 and 11 or days 4 and 11. All checkpoint antibody combinations demonstrated significant enhanced su...

Claims

Claims 1. A composition for use in a method of treating cancer in a subject, wherein the composition (i) is a vaccine composition comprising one or more nucleic acids encoding a plurality of tumour antigen T cell epitopes, wherein the T cell epitopes comprise GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), SVYDFFVWL (SEQ ID NO: 2) and WNRQLYPEWTEAQRLD (SEQ ID NO: 3), and wherein the method comprises administering the composition to the subject in combination with (a) a programmed death-1 (PD-1) inhibitor; and (b) a cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor; (ii) comprises a programmed death-1 (PD-1) inhibitor, and wherein the method comprises administering the PD-1 inhibitor to the subject in combination with (a) a vaccine composition comprising one or more nucleic acids encoding a plurality of tumour antigen T cell epitopes, wherein the T cell epitopes comprise GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), SVYDFFVWL (SEQ ID NO: 2) and WNRQLYPEWTEAQRLD (SEQ ID NO: 3); and (b) a cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor; or (iii) comprises a cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor, and wherein the method comprises administering the CTLA-4 inhibitor to the subject in combination with (a) a vaccine composition comprising one or more nucleic acids encoding a plurality of tumour antigen T cell epitopes, wherein the T cell epitopes comprise GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1), SVYDFFVWL (SEQ ID NO: 2) and WNRQLYPEWTEAQRLD (SEQ ID NO: 3); and (b) a programmed death-1 (PD-1) inhibitor.

2. The composition for use according to claim 1, wherein the cancer is melanoma, optionally wherein the melanoma is stage III or stage IV melanoma, is metastatic melanoma and / or is unresectable.

3. The composition for use according to any preceding claim, wherein the subject has received no prior systemic treatment for advanced melanoma, optionally wherein the melanoma is unresectable stage III or stage IV melanoma and the subject had received no prior systemic treatment for advanced disease.

4. The composition for use according to any preceding claim, wherein the one or more nucleic acids encode an antibody, comprising a heavy chain and a light chain, into which the T cell epitopes are inserted or substituted.

5. The composition for use according to claim 4, wherein the T cell epitopes are inserted or substituted into one or more CDRs of the antibody.

6. The composition for use according to claim 4 or claim 5, wherein the antibody comprises: (i) the T cell epitope of GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1) in CDR-H1;(ii) the T cell epitope of SVYDFFVWL (SEQ ID NO: 2) in CDR-H2; and (iii) the T cell epitope of WNRQLYPEWTEAQRLD (SEQ ID NO: 3) in CDR-L1. or (i) the T cell epitope of GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1) in each of CDR-H1 and CDR-L3; (ii) the T cell epitope of SVYDFFVWL (SEQ ID NO: 2) in CDR-H2; and (iii) the T cell epitope of WNRQLYPEWTEAQRLD (SEQ ID NO: 3) in each of CDR-H3 and CDR- L1.

7. The composition for use according to any preceding claim, wherein the T cell epitopes further comprise VPLDCVLYRYGSFSVTLDIVQG (SEQ ID NO: 4), ANCSVYDFFVWLHYYSVRDTLLGPGRPYR (SEQ ID NO: 5) and QCTEVRADTRPWSGPYILRNQDDRELWPRKFF (SEQ ID NO: 6) 8. The composition for use according to claim 7 when appended to any one of claims 4 to 6, wherein the antibody comprises: (i) the T cell epitope of GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1) in CDR-H1; (ii) the T cell epitope of SVYDFFVWL (SEQ ID NO: 2) in CDR-H2; (iii) the T cell epitope of VPLDCVLYRYGSFSVTLDIVQG (SEQ ID NO: 4) in CDR-H3; (iv) the T cell epitope of WNRQLYPEWTEAQRLD (SEQ ID NO: 3) in CDR-L1; (v) the T cell epitope of ANCSVYDFFVWLHYYSVRDTLLGPGRPYR (SEQ ID NO: 5) in CDR-L2; and (vi) the T cell epitope of QCTEVRADTRPWSGPYILRNQDDRELWPRKFF (SEQ ID NO: 6) in CDR-L3.

9. The composition for use according to any one of claims 4 to 8, wherein the antibody comprises (a) a VH comprising the amino acid sequence provided in SEQ ID NO: 7 and a VL comprising the amino acid sequence provided in SEQ ID NO: 8, or (b) a VH comprising the amino acid sequence provided in SEQ ID NO: 9 and a VL comprising the amino acid sequence provided in SEQ ID NO:

10.

10. The composition for use according to any one of claims 4 to 9, wherein the antibody comprises (a) a heavy chain comprising the amino acid sequence provided in SEQ ID NO: 11 and a light chain comprising the amino acid sequence provided in SEQ ID NO: 12, or (b) a heavy chain comprising the amino acid sequence provided in SEQ ID NO: 13 and a light chain comprising the amino acid sequence provided in SEQ ID NO:

14.

11. The composition for use according to any preceding claim, wherein the one or more nucleic acids comprise one or more non-specific promoters for promoting expression of the T cell epitopes, optionally wherein the promoter is a CMV-IE promoter, further optionally wherein the promoter comprises the nucleotide sequence provided in SEQ ID NO: 15.

12. The composition for use according to any preceding claim, wherein the antibody comprises a leader sequence for promoting secretion of the antibody upon expression of the one or more nucleic acids, optionally wherein the leader sequence is at the N-terminus of the heavy chain and / or the N- terminus of the light chain of the antibody, further optionally wherein the leader sequence comprises the amino acid sequence provided in SEQ ID NO:

16.

13. The composition for use according to any preceding claim, wherein the vaccine composition comprises a single nucleic acid encoding the plurality of tumour antigen T cell epitopes, optionally wherein the nucleic acid comprises the nucleotide sequence provided in SEQ ID NO: 17 or SEQ ID NO:

18.

14. The composition for use according to any preceding claim, wherein the PD-1 inhibitor is nivolumab.

15. The composition for use according to any preceding claim, wherein the CTLA-4 inhibitor is ipilimumab.

16. The composition for use according to any preceding claim, wherein the vaccine composition is administered in a total amount of nucleic acid in the range of 6 to 10 mg per dose, preferably about 8 mg per dose.

17. The composition for use according to any preceding claim, wherein a first dose of the vaccine composition is administered to the subject (a) at week 0 and then subsequent doses are administered during weeks 4, 7, 13, 25 and then every 12 weeks thereafter, or (b) on day 1 and then subsequent doses are administered on days 29, 50, 92, 176 and then every 84 days thereafter.

18. The composition for use according to any preceding claim, wherein the PD-1 inhibitor is administered to the subject in a first phase of four doses of about 1 mg / kg every three weeks, followed by a second phase of doses of (i) about 240 mg every two weeks, wherein the first dose of the second phase is administered about three weeks after the fourth dose of the first phase; or (ii) about 480 mg every four weeks, wherein the first dose of the second phase is administered about six weeks after the fourth dose of the first phase.

19. The composition for use according to any preceding claim, wherein the CTLA-4 inhibitor is administered to the subject in four doses of about 3 mg / kg every three weeks, optionally wherein each dose of the CTLA-4 inhibitor is administered on the same day as each dose in the first phase of four doses of the PD-1 inhibitor.

20. The composition for use according to any preceding claim, wherein each dose of the CTLA-4 inhibitor and the PD-1 inhibitor is administered on the same day, wherein the CTLA-4 inhibitor and the PD-1 inhibitor are administered in separate compositions or in a single composition, and / or wherein the first dose of the CTLA-4 inhibitor and the first dose of the PD-1 inhibitor are administered about one week after the first dose of the vaccine composition.

21. A vaccine composition comprising a DNA molecule encoding an antibody, into which a plurality of tumour antigen T cell epitopes are inserted or substituted, for use in a method of treating unresectable stage III melanoma or stage IV melanoma in a subject, wherein the antibody comprises the T cell epitope of GTGRAMLGTHTMEVTVYH (SEQ ID NO: 1) inserted or substituted in CDR-H1, the T cell epitope of SVYDFFVWL (SEQ ID NO: 2) inserted or substituted in CDR-H2, and the T cell epitope of WNRQLYPEWTEAQRLD (SEQ ID NO: 3) inserted or substituted in CDR-L1, wherein a first dose of the vaccine composition is administered to the subject at week 0 and then subsequent doses are administered during weeks 4, 7, 13, 25 and then every 12 weeks thereafter, and wherein the vaccine composition is administered intramuscularly in a total amount of DNA of about 8 mg per dose, wherein the vaccine composition is administered in combination with nivolumab and ipilimumab, wherein nivolumab is administered to the subject in a first phase of four doses of about 1 mg / kg every three weeks, followed by a second phase of doses of (i) about 240 mg every two weeks, wherein the first dose of the second phase is administered about three weeks after the fourth dose of the first phase; or (ii) about 480 mg every four weeks, wherein the first dose of the second phase is administered about six weeks after the fourth dose of the first phase, wherein ipilimumab is administered to the subject in four doses of about 3 mg / kg every three weeks and wherein each dose of ipilimumab is administered on the same day as each dose in the first phase of four doses of nivolumab, and wherein the first dose of nivolumab and the first dose of ipilimumab is administered about one week after the first dose of the vaccine composition.

22. The composition for use according to claim 21, further characterised by one or more of the features defined in any one of claims 1 to 20.

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