WO2024077601A1 - Peptide vaccines against glioma and uses thereof - Google Patents

Peptide vaccines against glioma and uses thereof Download PDF

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Publication number
WO2024077601A1
WO2024077601A1 PCT/CN2022/125413 CN2022125413W WO2024077601A1 WO 2024077601 A1 WO2024077601 A1 WO 2024077601A1 CN 2022125413 W CN2022125413 W CN 2022125413W WO 2024077601 A1 WO2024077601 A1 WO 2024077601A1
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peptide
seq
cell
pharmaceutical composition
subject
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English (en)
French (fr)
Inventor
Lifeng Zhang
Haiyang WU
Wei Xu
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Chongqing Tcrcure Science And Technology Co Ltd
Guangdong TCRCure Biopharma Technology Co Ltd
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Chongqing Tcrcure Science And Technology Co Ltd
Guangdong TCRCure Biopharma Technology Co Ltd
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Priority to CN202280102256.6A priority Critical patent/CN120712104A/zh
Priority to PCT/CN2022/125413 priority patent/WO2024077601A1/en
Priority to TW112139242A priority patent/TW202430541A/zh
Publication of WO2024077601A1 publication Critical patent/WO2024077601A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/80—Vaccine for a specifically defined cancer

Definitions

  • DIPG Diffuse intrinsic pontine glioma
  • H3K27M The point mutation of replacing the lysine 27 (K27) on the tail of histone H3 with a methionine residue (M) , or H3K27M, has been identified as the driver mutation of DIPG (Schwartzentruber J, et al., 2012; Wu G et al., 2012) . It is estimated that 60-70%DIPG tumors carry heterozygous mutations of H3K27M. All H3K27M occurs among two histone H3 variants (H3.1 and H3.3) , with the H3.3 mutation being found to occur more frequently ( ⁇ 70%) (Argersinger DP, et al. 2021; Zhang X et al., 2019) .
  • the H3K27M mutations have also been identified to be associated with other pediatric brain tumors (e.g., pediatric high-grade glioma) , and with several other adult cancers, including glioma, acute myeloid leukaemia (AML) , and melanoma, etc. (Lowe BR, et al. 2019)
  • the peptide vaccine substantially contains a 10 amino acid (10-AA) long peptide, (R/A) MSAP (S/A) TGGV (SEQ ID NO: ) , which is an epitope restricted to HLA-A*02, and thus the peptide vaccine is designed to specifically trigger CD8 T cell responses or cytotoxic T cell responses.
  • CD4 + T cell responses or the T-helper cell mediated immune responses which have profound impacts on the antitumor immunity
  • the peptide is as short as 10 amino acids which is only able to trigger HLA class I restricted responses.
  • the CD8 + T cell epitopes bound by MHC class I range from 8 to 11 residues (Rosa DS, et al. 2010; Hemmer B et al., 2000)
  • the CD4 + T lymphocyte usually recognize peptides of 12-16 amino acids (Rosa DS, et al. 2010; Hemmer B et al., 2000) or 13-17 amino acids (Chicz RM, et al. 1992; Sercarz EE, et al. 2003) .
  • a pharmaceutical composition in the present disclosure, which is substantially a peptide vaccine composition.
  • the pharmaceutical composition comprises a peptide (i.e. peptide vaccine) , which has a length of at least 12 amino acid residues and comprises a 4-AA peptide segment RMSA (SEQ ID NO: 26) .
  • the pharmaceutical composition is, after administration to a subject according to a therapeutically effective regimen thereof, capable of stimulating CD4 T cell response against histone 3 (H3) K27M mutation (H3K27M) in the subject.
  • the peptide vaccine provided in this present disclosure can stimulate the CD4 T cell response against H3K27M mutation.
  • the 4-AA peptide segment RMSA (SEQ ID NO: 26) in the peptide vaccine substantially corresponds to the "K27M" mutant form (as cited in the literature) of the 4-AA region RKSA (SEQ ID NO: 30) , which corresponds to position 27-30 of both the human histone 3.1 (i.e., H3.1) variant (SEQ ID NO: 22) and the human histone 3.3 (i.e., H3.3) variant (SEQ ID NO: 24) .
  • the peptide vaccine provided herein is able to stimulate the CD4 T cell response against both the H3.1 K27M mutation and the H3.3 K27M mutation in the subject, depending on the sequence of the peptide vaccine.
  • the pharmaceutical composition is further capable of stimulating CD8 T cell response against the H3K27M mutation in the subject after its administration.
  • some embodiments of the peptide vaccine can stimulate both CD4 T cell response and CD8 T cell response after administration.
  • the peptide comprises a 10-AA segment of RMSAP (S/A) TGGV (SEQ ID NO: 25) .
  • the peptide vaccine may comprise a 10-AA segment of RMSAPSTGGV (SEQ ID NO: 5) to thereby be able to stimulate the CD4, and optionally CD8, T cell responses against the H3.3K27M mutation in the subject, or comprise a 10-AA segment of RMSAPATGGV (SEQ ID NO: 29) to thereby be able to stimulate the CD4, and optionally CD8, T cell responses against the H3.1K27M mutation in the subject.
  • the peptide comprises a 18-AA segment of KQLATKAARMSAP (S/A) TGGV (SEQ ID NO: 1) .
  • the peptide vaccine may comprise an 18-AA segment of KQLATKAARMSAPSTGGV (SEQ ID NO: 2) to thereby be able to stimulate the CD4, and optionally CD8, T cell responses against the H3.3K27M mutation in the subject, or comprise an 18-AA segment of KQLATKAARMSAPATGGV (SEQ ID NO: 27) to thereby be able to stimulate the CD4, and optionally CD8, T cell responses against the H3.1K27M mutation in the subject.
  • the peptide in the pharmaceutical composition consists of the 18-AA KQLATKAARMSAPSTGGV (SEQ ID NO: 2) .
  • this 18-AA peptide vaccine when formulated in a pharmaceutical composition comprising the poly ICLC adjuvant and administered to the patients, both the CD4 and CD8 T cell responses against the H3.3K27M mutation can be stimulated. will be provided in the Examples set forth below.
  • the peptide in the pharmaceutical composition consists of the 18-AA KQLATKAARMSAPATGGV (SEQ ID NO: 27) , which is designed to stimulate similar T cell responses against the H3.1K27M mutation.
  • the pharmaceutical composition can further comprise an adjuvant.
  • the adjuvant comprises a toll-like receptor (TLR) agonist, which can optionally include ligands for any of TLR3, TLR4, TLR7/TLR8, and TLR9.
  • TLR3 ligand is used as an adjuvant for the pharmaceutical composition comprising the peptide vaccine, such as poly I: C (polyriboinosinic: polyribocytidylic acid) .
  • poly I polyriboinosinic: polyribocytidylic acid
  • certain derivatives of poly I C with improved stability, safety and/or adjuvanticity, such as Poly ICLC and Poly I: C12U.
  • TLR ligands can also be used, and non-limiting examples can include monophosphoryl lipid A (MPL, as TLR4 ligand) or its derivatives, imiquimod and resiquimod (both as TLR7/8 ligand) , cpG ODN (TLR9 ligand) . More examples and relevant information for such adjuvant can reference to US patent application No.: US20110038888A1, Toussi DN and Massari P, 2014, whose disclosure is incorporated by reference in its entirety.
  • the adjuvant comprises an exogenous substance other than the TLR agonist, which can include Bacillus Calmette-Guerin (BCG) vaccine, but can also include a substance with diverse nature and material property.
  • BCG Bacillus Calmette-Guerin
  • poly ICLC is used as the adjuvant, and in the pharmaceutical composition, poly ICLC and the peptide can have a ratio of approximately 1: 0.5-1: 5 (e.g., 1: 1, 1: 2, 1: 3, 1: 4) by weight.
  • the pharmaceutical composition can be configured to have a dosage form that comprises approximately 0.5 mg poly ICLC and approximately 0.5-2 mg of the peptide.
  • the pharmaceutical composition can be configured to be in a formulation that is suitable for subcutaneous injection to the subject.
  • a method of using the pharmaceutical composition provided in the first aspect to stimulate an immune response in a subject in need thereof is further provided.
  • a "subject” is referred to as a human individual having a cancer, and the cancer is characterized to have a K27M mutation in histone H3 in cancer tissues/cells.
  • a subject can include a human individual with glioma, DIPG, acute myeloid leukaemia (AML) , melanoma (Lowe BR, et al. 2019) , but other examples of the subject can also include other cancers as long as the cancer tissues/cells contain H3K27M.
  • the method substantially comprises a step of: administering, on a therapeutically effective regimen, the pharmaceutical composition according to any one of the embodiments as described above in the first aspect to the subject, thereby inducing the immune response in the subject.
  • the immune response comprises CD4 T cell response against the H3K27M mutation, and optionally, the immune response further comprises CD8 T cell response against the H3K27M mutation.
  • the method prior to the administering step, further comprises a step of: determining the mutated variant type of H3 in the subject.
  • the peptide in the pharmaceutic composition comprises RMSAPSTGGV (SEQ ID NO: 5) . Further optionally, the peptide in the pharmaceutic composition comprises KQLATKAARMSAP S TGGV (SEQ ID NO: 2) . Further optionally, the peptide has a length of 18 AA, and consists of KQLATKAARMSAP S TGGV (SEQ ID NO: 2) .
  • the peptide in the pharmaceutic composition comprises RMSAP A TGGV (SEQ ID NO: 29) . Further optionally, the peptide in the pharmaceutic composition comprises KQLATKAARMSAP A TGGV (SEQ ID NO: 27) . Further optionally, the peptide has a length of 18 AA, and consists of KQLATKAARMSAP A TGGV (SEQ ID NO: 27) .
  • the cancer can comprise at least one of glioma, acute myeloid leukaemia (AML) , or melanoma.
  • AML acute myeloid leukaemia
  • the cancer can comprise glioma, and further optionally, the cancer comprises DIPG.
  • the subject carries HLA-A*02 allele.
  • the subject carries at least one of an HLA-DRB1*07: 01 allele or an HLA-DRB1*01: 01 allele.
  • the therapeutically effective regimen comprises administering the pharmaceutical composition to the subject through subcutaneous injection.
  • the present disclosure further provides a T-cell that expresses a T-cell receptor (TCR) or a functional fragment thereof.
  • TCR T-cell receptor
  • the TCR or its functional fragment is capable of binding to a peptide/MHC II complex, wherein the peptide in the peptide/MHC II complex has a length of at least 12 amino acid residues and comprises RMSA (SEQ ID NO: 26) .
  • the TCR or its functional fragment is further capable of binding to a complex formed between the peptide and MHC I.
  • the peptide comprises RMSAP (S/A) TGGV (SEQ ID NO: 25) . Further optionally, the peptide comprises KQLATKAARMSAP (S/A) TGGV (SEQ ID NO: 1) .
  • the peptide comprises KQLATKAARMSAPSTGGV (SEQ ID NO: 2) , and further optionally, the peptide has a length of 18 AA, and consists of KQLATKAARMSAPSTGGV (SEQ ID NO: 2) .
  • the TCR or the fragment thereof is incapable of bind to a complex between a second peptide and MHC II complex, and the second peptide comprises an amino acid sequence of KQLATKAAR K SAP S TGGV (SEQ ID NO: 6) .
  • the peptide comprises KQLATKAARMSAPATGGV (SEQ ID NO: 27) , and further optionally, the peptide has a length of 18 AA, and consists of KQLATKAARMSAPATGGV (SEQ ID NO: 27) .
  • the TCR or the fragment thereof is incapable of bind to a complex between a second peptide and MHC II complex, and the second peptide comprises an amino acid sequence of KQLATKAARKSAPATGGV (SEQ ID NO: 28) .
  • the TCR is heterologous to the T-cell.
  • the TCR is transduced or transfected into the T-cell via a vector, such as a retroviral vector.
  • the terms “about” or “approximately” when used in conjunction with a number refers to any number within 1, 5 or 10%of the referenced number.
  • neoplasia As used herein, the terms “neoplasia, ” “hyperplasia, ” and “tumor” are often commonly referred to as “cancer, ” which is a general name for more than 100 diseases that are characterized by uncontrolled, abnormal growth of cells. As used herein, a “tumor” also includes a normal, benign, or malignant mass of tissue.
  • peptide refers to a polymer of amino acids linked by amide bonds (or peptide bonds) as is known to those of skill in the art.
  • a peptide can be a polymer of 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more amino acids linked by covalent amide bonds.
  • the peptide is a polymer of 6 to 8, 8 to 10, 10 to 15, 10 to 20, 10 to 25, 10 to 30, 10 to 40, 10 to 50, or 25 to 25 amino acids linked by covalent amide bonds.
  • the peptide is a polymer of 50 to 65, 50 to 75, 50 to 85, 50 to 95, 50 to 100, 75 to 100 amino acids linked by covalent amide bonds.
  • the term can refer to a single peptide chain linked by covalent amide bonds.
  • the term can also refer to multiple peptide chains associated by non-covalent interactions such as ionic contacts, hydrogen bonds, Van der Waals contacts and hydrophobic contacts.
  • the term includes peptides that have been modified, for example by post-translational processing such as signal peptide cleavage, disulfide bond formation, glycosylation (e.g., N-linked glycosylation) , protease cleavage and lipid modification (e.g. S-palmitoylation) .
  • post-translational processing such as signal peptide cleavage, disulfide bond formation, glycosylation (e.g., N-linked glycosylation) , protease cleavage and lipid modification (e.g. S-palmitoylation) .
  • conservative substitution refers to replacement of an amino acid of one class with another amino acid of the same class.
  • a conservative substitution does not alter the structure or function, or both, of a peptide.
  • Classes of amino acids for the purposes of conservative substitution include hydrophobic (Met, Ala, Val, Leu, Ile) , neutral hydrophilic (Cys, Ser, Thr) , acidic (Asp, Glu) , basic (Asn, Gln, His, Lys, Arg) , conformation disrupters (Gly, Pro) and aromatic (Trp, Tyr, Phe) .
  • immune response means a reaction occurring within a human subject that is purported for fighting cancers.
  • An immune response may include the innate immune response and the adaptive immune response; while the former includes immune cells such as neutrophils, macrophages, and monocytes, and cytokines and complement, the latter includes immune cells such as dendritic cells, T cells, B cells, and antibodies to stimulate antigen-specific immune reactions.
  • T-cell response is referred to as one type of adaptive immune response mediated by T cells, which typically includes the specific proliferation and activation of effector functions induced by a peptide in vitro or in vivo against the specific antigens.
  • T cells There are two major subtypes of T cells: CD8 + T cells (i.e. killer T cells, cytotoxic T cells, or effector T cells) and CD4 + T cells (i.e. helper T cells) , and thus the T cell response include the CD4 T cell response and the CD8 T cell response.
  • CD8 T cell response means one type of the T cell response that is mediated by CD8 + T cells or CD8 + lymphocytes.
  • the CD8 + T cells typically serve to destroy virus-infected cells and tumor cells, and typically recognize their targets by binding to short peptide (8-11 AA in length) associated with MHC class I molecules present on the surface of all nucleated cells.
  • the CD8 + T cells also produce several key cytokines including TNF ⁇ , IL-2 and IFN ⁇ , which can influence the effector functions of other cells, in particular macrophages and NK cells.
  • CD4 T cell response means another type of the T cell response that is mediated by CD4 + T cells or CD4 + lymphocytes.
  • the CD4 + T cells typically assist other lymphocytes, including maturation of B cells and activation of cytotoxic T cells and macrophages.
  • MHC class II molecules which are expressed on the surface of antigen-presenting cells (APCs)
  • APCs antigen-presenting cells
  • the CD4 + T cells become activated such that they divide rapidly and secrete cytokines (e.g. IFN ⁇ , IL-2, etc. ) that regulate or assist the immune response.
  • cytokines e.g. IFN ⁇ , IL-2, etc.
  • antigen-presenting cells refers to dendritic cells (DC) , monocytes/macrophages, B lymphocytes or other cell type (s) expressing the necessary MHC/co-stimulatory molecules, which effectively allow for T cell recognition of the presented peptide.
  • DC dendritic cells
  • monocytes/macrophages monocytes/macrophages
  • B lymphocytes or other cell type (s) expressing the necessary MHC/co-stimulatory molecules, which effectively allow for T cell recognition of the presented peptide.
  • MHC refers to “major histocompatibility antigen” .
  • HLA human leukocyte antigen
  • HLA-A HLA-B
  • HLA-C HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1.
  • MHC class I molecules are made of a single polymorphic chain containing 3 domains (alpha 1, 2 and 3) , which associates with beta 2 microglobulin at cell surface.
  • Class II molecules are made of 2 polymorphic chains, each containing 2 chains (alpha and beta) .
  • Class I MHC molecules are expressed on virtually all nucleated cells. Peptide fragments presented in the context of class I MHC molecules are recognized by CD8 T lymphocytes (cytotoxic T lymphocytes or CTLs) . CD8 + T cells or lymphocytes frequently mature into cytotoxic effectors which can lyse cells bearing the stimulating antigen. Class II MHC molecules are expressed primarily on activated lymphocytes and antigen-presenting cells. CD4 + T lymphocytes (helper T lymphocytes or HTLs) are activated with recognition of a unique peptide fragment presented by a class II MHC molecule, usually found on an antigen presenting cell like a macrophage or dendritic cell. CD4 + T lymphocytes proliferate and secrete cytokines that either support an antibody-mediated response through the production of IL-4 and IL-10 or support a cell-mediated response through the production of IL-2 and IFN ⁇ .
  • CD8 T lymphocytes cytotoxic T lymphocytes or CTLs
  • HLAs are characterized by a deep binding groove to which endogenous as well as foreign, potentially antigenic peptides bind.
  • the groove is further characterized by a well-defined shape and physicochemical properties.
  • HLA class I binding sites are closed, in that the peptide termini are pinned down into the ends of the groove. They are also involved in a network of hydrogen bonds with conserved HLA residues. In view of these restraints, the length of bound peptides is limited to 8-10 residues.
  • class II sites are open at both ends. This allows peptides to extend from the actual region of binding, thereby “hanging out” at both ends. Class II HLAs can therefore bind peptide ligands of variable length, usually more than 12 amino acid residues.
  • the term "adjuvant” is referred to as an exogenous substance that, when simultaneous administered to a subject with a particular vaccine (e.g. the peptide vaccine disclosed herein) can enhance the immune responses in the subject to the vaccine, and is also called “immune adjuvant” .
  • a particular vaccine e.g. the peptide vaccine disclosed herein
  • immuno adjuvant e.g. the peptide vaccine disclosed herein
  • the adjuvant that can be used simultaneously with the peptide vaccine as disclosed herein, which can include exogenous substances that have a wide variety of nature and origin, such as mineral salts, oil and water-based emulsions, polymers, microparticles, liposomes, saponins, microbial products and cytokines.
  • the mechanisms of action of the adjuvant in the present disclosure which can involve non-specific effects (i.e., antigen depot at the immunization site) to specific activation of immune cells leading to improved host innate and adaptive responses.
  • poly I: C is referred to as polyinosinic: polycytidylic acid, and can also be abbreviated as poly (I: C) or alike, which is typically used in the form of a sodium salt to simulate immune response.
  • poly ICLC or poly I: CLC or alike, is referred to as a mixture of poly I: C with stabilizers carboxymethylcellulose and polylysine.
  • the term “therapeutically effective regimen” refers to a regimen for dosing, timing, frequency, manner, and duration of the administration of the pharmaceutical composition comprising the peptide vaccine in a subject in need thereof for the treatment and/or management of his or her cancer that is characterized by having the H3K27M mutation, and the dosing, timing, frequency, and duration of the administration are configured in a level that is sufficient to stimulate the immune responses (e.g. CD4, and optionally CD8, T cell responses) against the H3K27M mutation in the subject.
  • the immune responses e.g. CD4, and optionally CD8, T cell responses
  • the term “approximately” , “about” , “around” , or alike, is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01%of the stated value. Unless obvious from context, all numerical values provided herein can be understood to be modified by the term.
  • composition comprising X may consist exclusively of X or may include something additional e.g. X + Y.
  • FIG. 1 shows the IFN- ⁇ ELISpot results.
  • PBMC peripheral blood mononuclear cells
  • EN-17 and EN-23 were cultured with antigen stimulation. After culture expansion and antigen stimulation, 20,000 cells from each sample were collected into each well for an ELISpot assay to detect IFN- ⁇ secreting cells.
  • PSG1 peptide stimulated group 1. The cells were stimulated with the corresponding peptide only once and expanded for 2-3 weeks.
  • PSG2 peptide stimulated group 2. The cells were stimulated with the corresponding peptide at the beginning of the culture expansion, and then re-stimulated with the antigen peptide before the ELISpot assay.
  • PHA phytohaemagglutinin, a positive control antigen for ELISpot.
  • NCG negative control group (no peptide stimulation) .
  • KQ The long peptide (18 aa) carrying the point mutation.
  • RM The short peptide (10 aa) carrying the point mutation.
  • FIG. 2 shows the EN-17 C27 TCR validation results.
  • EN-17 C27 is a candidate TCR cloned from CD4 T cells.
  • a selected PBMC sample was transduced with a retroviral vector carrying the candidate TCR.
  • Transduced PBMC cells were then subjected to different peptide stimulations and the T cell responses were examined using FACS.
  • the CD4 T cells and CD8 T cells were gated and studied separately. All the FACS results are shown in the same format, with the T cell activation markers shown along the X axis and SSC (i.e. side scatter, which is related to the granularity of cells, and thus is an optical measurement for each individual cells in the FACS analysis) shown along the Y axis.
  • SSC i.e. side scatter, which is related to the granularity of cells, and thus is an optical measurement for each individual cells in the FACS analysis
  • FIG. 3 shows the EN-10 C01 and C04 TCR validation results.
  • EN-10 C01 and C04 are two candidate TCRs cloned from CD8 T cells.
  • the selected PBMC samples were transduced with the corresponding retroviral vector carrying the candidate TCR.
  • Transduced PBMC cells were then subjected to different peptide stimulations and the T cell responses were examined using FACS. Only CD8 T cell responses are shown. CD4 T cell responses are weak (Data not shown) . All the FACS results are shown in the same format, with the T cell activation markers shown along the X axis and SSC shown along the Y axis.
  • the present disclosure provides a peptide vaccine that can be used to stimulate the CD4 T cell response, and optionally the CD8 T cell response as well, against the H3K27M mutation in subjects carrying the somatic mutation who have been administered with a pharmaceutical composition comprising the peptide vaccine. Due to the capability to stimulate significant T cell responses against this clinically crucial mutation that is strongly associated with human glioma, and especially the pediatric and adult DIPG, this peptide vaccine has the potential for treating the disease.
  • a pharmaceutical composition which comprises a peptide (i.e., peptide vaccine) having a length of at least 12 amino acid residues (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, etc. ) and comprises a 4-AA peptide segment RMSA (SEQ ID NO: 26) .
  • the pharmaceutical composition is capable, after administration to a subject according to a therapeutically effective regimen thereof, of stimulating CD4 T cell response against the H3K27M mutation in the subject. Further optionally and preferably, the pharmaceutical composition is further capable of stimulating the CD8 T cell responses.
  • the pharmaceutical composition comprising the peptide vaccine can stimulate only the CD4 T cell responses, but not the CD8 T cell responses, against the H3K27M mutation; whereas according some other embodiments, the pharmaceutical composition comprising the peptide vaccine can stimulate both the CD4 T cell responses and the CD8 cell responses, against the H3K27M mutation.
  • the peptide vaccine in the pharmaceutical composition provided in this present disclosure can distinguishingly stimulate the CD4 T cell response against H3K27M mutation.
  • the H3 can be either H3.1 or H3.3, whose wildtype sequences are listed in SEQ ID NO: 22 and SEQ ID NO: 24 respectively.
  • the subject carrying the H3.1K27M mutation or the H3.3K27M mutation may benefit from the peptide vaccine, who may have at least one of glioma (e.g., DIPG) , acute myeloid leukaemia (AML) , and melanoma, etc.
  • glioma e.g., DIPG
  • AML acute myeloid leukaemia
  • melanoma melanoma
  • the peptide comprises a 10-AA segment of RMSAP (S/A) TGGV (SEQ ID NO: 25) .
  • the peptide vaccine may comprise a 10-AA segment of RMSAPSTGGV (SEQ ID NO: 5) to thereby be able to stimulate the CD4, and optionally CD8, T cell responses against the H3.3K27M mutation in the subject, or alternatively may comprise a 10-AA segment of RMSAPATGGV (SEQ ID NO: 29) to thereby be able to stimulate the CD4, and optionally CD8, T cell responses against the H3.1K27M mutation in the subject, or alternatively may comprise both of the above two peptides, one of which comprise the 10-AA segment of SEQ ID NO: 25, and another of which comprise the 10-AA segment of SEQ ID NO: 29.
  • the peptide comprises a 18-AA segment of KQLATKAARMSAP (S/A) TGGV (SEQ ID NO: 1) .
  • the peptide vaccine may comprise an 18-AA segment of KQLATKAARMSAPSTGGV (SEQ ID NO: 2) to thereby be able to stimulate the CD4, and optionally CD8, T cell responses against the H3.3K27M mutation in the subject, or comprise an 18-AA segment of KQLATKAARMSAPATGGV (SEQ ID NO: 27) to thereby be able to stimulate the CD4, and optionally CD8, T cell responses against the H3.1K27M mutation in the subject, or alternatively comprise both.
  • the peptide in the pharmaceutical composition consists of the 18-AA sequence KQLATKAARMSAPSTGGV (SEQ ID NO: 2) that specifically targets H3.3K27M, which will be covered in more detail in Example 1 below for experimental data.
  • the peptide in the pharmaceutical composition consists of the 18-AA sequence KQLATKAARMSAPATGGV (SEQ ID NO: 27) that specifically targets H3.1K27M.
  • the pharmaceutical composition may comprise one single peptide as described above, or may comprise a combination of multiple peptides as described above.
  • the pharmaceutical composition may be formulated in a dosage form that allows the administration thereof into a subject in need.
  • the pharmaceutical composition may comprise, in addition to the peptide vaccine, an adjuvant, which may comprise, for example, poly ICLC.
  • the pharmaceutical composition may be formulated to allow administration via subcutaneous injection, but may also be formulated to allow other administration manners as known by the skilled artisan in the field.
  • a method of using the pharmaceutical composition as described above in the first aspect is further provided.
  • Such method may be directed to using the pharmaceutical composition for stimulating an immune response, especially the T cell responses, in a subject in need thereof, who may have a cancer (e.g., DIPG, glioma, AML, or melanoma, etc. ) and may carry the H3K27M mutation.
  • a cancer e.g., DIPG, glioma, AML, or melanoma, etc.
  • the method substantially comprises a step of: administering, on a therapeutically effective regimen, the pharmaceutical composition according to any one of the embodiments as described above in the first aspect to the subject, thereby inducing the immune response in the subject.
  • the immune response comprises CD4 T cell response against the H3K27M mutation, and optionally, the immune response further comprises CD8 T cell response against the H3K27M mutation.
  • the peptide vaccine in the pharmaceutical composition to be administered to the subject in the method disclosed herein may comprise the 4-AA RMSA (SEQ ID NO: 26) , or further optionally may comprise the 10-AA RMSAP (S/A) TGGV (SEQ ID NO: 25) , or further optionally may comprise the 18-AA KQLATKAARMSAP (S/A) TGGV (SEQ ID NO: 1) , i.e. one of the 18-AA KQLATKAARMSAP S TGGV (SEQ ID NO: 2) or the 18-AA KQLATKAARMSAP A TGGV (SEQ ID NO: 27) .
  • the subject may carry the HLA-A*02 allele to thus allow the CD8 T cell response to be stimulated in addition to the CD4 T cell response.
  • CD8 T cell responses may also be stimulated.
  • the subject may carry at least one of an HLA-DRB1*07: 01 allele or an HLA-DRB1*01: 01 allele for definitive CD4 T cell response, but may also carry other alleles to also have CD4 T cell response.
  • the administration of the pharmaceutical composition comprising the peptide vaccine may be through subcutaneous injection, but may be through other administration routes.
  • the present disclosure further provides a T-cell that expresses a T-cell receptor (TCR) or a functional fragment thereof.
  • TCR T-cell receptor
  • the TCR or its functional fragment is capable of binding to a peptide/MHC II complex, wherein the peptide in the peptide/MHC II complex has a length of at least 12 amino acid residues and comprises the 4-AA segment RMSA (SEQ ID NO: 26) , or further optionally comprises the 10-AA segment RMSAP (S/A) TGGV (SEQ ID NO: 25) , or further optionally comprises the 18-AA KQLATKAARMSAP (S/A) TGGV (SEQ ID NO: 1) .
  • the TCR or its functional fragment is further capable of binding to a complex formed between the peptide and MHC I.
  • the peptide comprises KQLATKAARMSAPSTGGV (SEQ ID NO: 2) , and further optionally, the peptide has a length of 18 AA, and consists of KQLATKAARMSAPSTGGV (SEQ ID NO: 2) .
  • the TCR or the fragment thereof is incapable of bind to a complex between a second peptide and MHC II complex, and the second peptide comprises an amino acid sequence of KQLATKAARKSAPSTGGV (SEQ ID NO: 6) .
  • the TCR has a specific binding to the K27M mutant peptide, but not to the wildtype peptide, of the H3.3 variant, conferring capability for specifically stimulating the CD4 T cell responses against the H3.3K27M mutation, but not the wildtype H3.3.
  • the peptide comprises KQLATKAARMSAPATGGV (SEQ ID NO: 27) , and further optionally, the peptide has a length of 18 AA, and consists of KQLATKAARMSAPATGGV (SEQ ID NO: 27) .
  • the TCR or the fragment thereof is incapable of bind to a complex between a second peptide and MHC II complex, and the second peptide comprises an amino acid sequence of KQLATKAARKSAPATGGV (SEQ ID NO: 28) .
  • the TCR has a specific binding to the K27M mutant form, but not to the wildtype form, of H3.1, conferring capability for specifically stimulating the CD4 T cell responses against the H3.1K27M mutation, but not the wildtype H3.1.
  • the TCR is heterologous to the T-cell.
  • the TCR is transduced or transfected into the T-cell via a vector, such as a retroviral vector.
  • Example 1 is provided for the testing of one specific embodiment of the peptide vaccine (i.e., the 18-AA KQLATKAARMSAPSTGGV (SEQ ID NO: 2) ) in terms of its capabilities to induce or stimulate immune responses, especially the CD4 T cell responses and/or CD8 T cell responses against the H3.3K27M mutation, after its administration into DIPG patients.
  • the peptide vaccine i.e., the 18-AA KQLATKAARMSAPSTGGV (SEQ ID NO: 2)
  • the 18-AA KQLATKAARMSAPSTGGV SEQ ID NO: 2
  • IEDB Immune Epitope Database
  • IEDB recommended 2.22 MHC-II binding predictions module
  • ‘12-18’ was used as the ‘Select length (s) ’ to let algorithm to predict all epitopes containing the H3K27M mutation with the length from 12AA to 18AA.
  • the ‘IEDB recommended 2.22’ used a Consensus approach, combining NN-align, SMM-align, CombLib and Sturniolo if any corresponding predictor is available for the HLA allele, otherwise NetMHCIIpan is used.
  • a series of candidate peptide vaccines are designed.
  • a longer peptide vaccine candidate designed to have 18 amino acids i.e. KQLATKAA RMSAPSTGGV (SEQ ID NO: 2) , with the point mutation residue M located at the 10 th position from the N-terminus of the peptide vaccine.
  • KQLATKAA RMSAPSTGGV SEQ ID NO: 2
  • Newly-diagnosed DIPG patients aged 5 and above were selected. After signing the consent, patients with HLA-A*02 subtype and with H3.3K27M genotyping results from the tumor biopsy were given the vaccine treatment.
  • the peptide vaccine is first prepared in an appropriate pharmaceutical composition, with three dosage forms (dose #1, #2 and #3) designed (see Table 3) , which all showed good safety profiles.
  • dose #1, #2 and #3 designed (see Table 3) , which all showed good safety profiles.
  • dose #3 is finally used for the experiments with patients.
  • the peptide vaccine is administered (in the dosage formulation dose #3 in Table 2) through subcutaneous injection two weeks after conformal radiotherapy is completed.
  • the day of the first vaccine injection is defined as Day 1 (D1) .
  • the injections will be administered on D3, D15, D29, D57, D85, and thereafter, one injection every 8 weeks until disease progression.
  • Periphery blood samples were collected from different time points and used for pharmacokinetic (PK) and pharmacodynamic (PD) studies and for TCR cloning work. Blood samples used for TCR cloning were collected from patients after the fifth and sixth vaccine injections.
  • All PBMC samples used in TCR cloning were collected from patients received vaccination dose #3.
  • the PBMC sample used for TCR cloning from patient EN17 was collected after the patient received his/her sixth vaccine injection.
  • the PBMC sample used for TCR cloning from patient EN10 was collected after the patient received his/her sixth vaccine injection.
  • the PBMC sample used for TCR cloning from patient EN23 was a combined PBMC sample, from the patient’s PBMC samples after the patient received his/her third and fourth vaccine injections.
  • Periphery blood samples from vaccinated DIPG patients were collected and Peripheral Blood Mononuclear Cells (PBMCs) were collected by Ficoll Gradient.
  • PBMC samples were stimulated with corresponding peptides for 2-3 weeks after which cells were seeded into IFN- ⁇ detecting ELISpot plates and restimulated with the corresponding peptides.
  • An enhancement of IFN- ⁇ signal was considered as the presence of antigen-specific T cells (FIG. 1) .
  • the sample was then single cell RNA sequenced by 10 ⁇ Genomics.
  • Candidate TCRs were picked based on the transcription profile, introduced into primary human T cells and validated by pulsing the corresponding peptide (FIG. 2 and FIG. 3) .
  • FIG. 2 and FIG. 3 we use the data to illustrate that our vaccination approach indeed provoked strong tumor antigen specific immune responses.
  • FIG. 1 shows an IFN- ⁇ ELISpot result.
  • PBMC samples EN-17; EN-273 responded to the stimulation of the long peptide (KQ) , but not to the stimulation of the short peptide (RM) . Therefore, T cell responses were detected specifically to the stimulation of the long peptide. Most likely, these are CD4 T cell responses.
  • PB samples were collected from vaccinated patients at different time points.
  • PBMCs were isolated from the blood samples. Isolated PBMCs were subjected to culture conditions optimised for T cell expansion and antigen stimulation.
  • Autologous B or DC cells culturally expanded separately were used as antigen-presenting cells (APCs) to present the long peptide antigen (MHC class II antigen) .
  • APCs antigen-presenting cells
  • B cells and DCs are also suitable to present the short peptide (MHC class I antigen) .
  • Patient T cells were expanded and stimulated by the peptide antigen for a few weeks. To monitor the T cell status along the time course, a small fraction of the cultured T cells were collected at different time points.
  • T cell responses were subjected to a 2nd round of antigen stimulation and the T cell responses were measured by ELIspot and FACS. Samples shown significant T cell activation signals were subjected to single-cell transcriptome sequencing.
  • Candidate TCRs were selected from the single-cell transcriptome data analysis and individually subjected to the downstream functional validation.
  • the TCR was introduced to a selected PBMC sample with suitable HLA subtypes through viral transduction using a retroviral vector.
  • the T cells (CD4 + and CD8 + T cells) from the transduced PBMC sample express the candidate TCR as a foreign transgene.
  • the transduced PBMC sample was expanded and subjected to antigen stimulation.
  • FACS analysis was used to exam the T cell responses. In FACS analysis, CD4 + T cells and CD8 + T cells were gated separately to specifically exam each type’s immune responses. More details are provided in the following.
  • PBMC samples post vaccination
  • ELISpot Samples with enhanced IFN- ⁇ post restimulation, in this ELISpot experiment, EN-17 and EN-23 PSG2-KQ samples were then single cell RNA-sequenced.
  • candidate TCRs were selected based on the transcription profile and subjected to functional validation experiments. More specifically, candidate TCRs were retrovirally (viral backbone pMP71) introduced into primary human T cells. Corresponding peptides were pulsed into TCR transduced T cells and flow cytometry analyses were used to monitor the responses.
  • FIG. 2 shows the functional validation results of EN-17 C27, a candidate TCR cloned from the CD4 T compartment of EN-17 PBMC sample. The CD4 T cells and CD8 T cells were gated and studied separately.
  • CD134 OX40 is an activation marker for CD4 T cells.
  • CD4 T cells upregulate the cell-surface expression of CD134 in response to antigen stimulation.
  • CD107a, CD137, and CD69 are three other T cell activation markers.
  • Both CD4 and CD8 T cells upregulate the expression of CD107a and CD137 and CD69 in response to antigen stimulation.
  • FIG. 2 shows that EN-17 C27 (a TCR cloned from CD4 T cells) is validated as an H3K27M antigen specific TCR. It does NOT respond to the stimulation of the short peptides (RMS or RKS, Fig. 2A) . It specifically responded to the stimulation of the long peptide carrying the point mutation (KQ-RMS) , but not to the long peptide without the point mutation (KQ-RKS) (Fig. 2A) .
  • EN-17 C27 is a CD4 TCR being introduced into PBMC cells as a foreign TCR. Both CD4 and CD8 T cells can be transduced by the retroviral vector. When EN-17 C27 is introduced into a CD8 T cell, it still interacts with its cognate antigen (KQ-RMS presented by class II HLA) . However, in this case, the interaction can NOT be reinforced by the CD4 molecule as the host cell is a CD8 T cell. Moreover, the CD8 molecule is helpless to the TCR and antigen interaction. This is a good test on the candidate TCR. A good candidate TCR, with high binding-affinity to its antigen can trigger T cell responses independent of CD4 or CD8. The data show that EN-17 C27 can trigger CD8 T cell responses independent of CD4 (FIG. 2B) .
  • EN-17 C27 is an H3K27M antigen specific CD4 TCR with high antigen-binding affinity.
  • 7 antigen-specific CD4 TCRs from the vaccinated patient samples (6 from patient EN-17 and 1 from patient EN-23) .
  • CD8 TCRs The cloned CD8 TCRs are functionally weak compared to the CD4 TCRs (FIG. 3) .
  • FIG. 3 shows the functional validation results of the two CD8 TCRs cloned.
  • Both TCRs were cloned from a single patient sample EN-10. Both TCRs can only trigger weak responses in CD4 T cells (data not shown) . Therefore, they have low binding-affinity to the antigen.
  • EN-10 C01 cannot distinguish the peptide antigen with or without the point mutation (FIG. 3A) , but EN-10 C04 is specific to the mutated peptide (FIG. 3B) .
  • C01 showed a better response to the long peptide than the short peptide (FIG. 3) . Since CD8 TCRs can only recognize antigen peptide with 8-12 aa.
  • RMS short peptide vaccine
  • CD8 and CD4 T cell responses were detected in the peripheral blood of vaccinated patients. Importantly, stronger immune responses were detected in the CD4 T compartment than in CD8 T cells. These data shows that the peptide vaccine can stimulate anticancer immunity in DIPG patients. Moreover, CD4 T cell mediated immune responses triggered by the long peptide vaccine may play a more significant role in cancer treatment than CD8 T cell responses.

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