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US-20260124285-A1 - PERSONALIZED CANCER VACCINES

US20260124285A1US 20260124285 A1US20260124285 A1US 20260124285A1US-20260124285-A1

Abstract

Personalized mRNA cancer vaccines, as well as methods for their optimization and for their use in subjects are provided. In some embodiments, personalized mRNA cancer vaccines and their uses are provided for subjects having particular characteristics, e.g., the presence of certain biomarkers.

Inventors

  • Michelle Brown
  • Igor Feldman
  • Robert Meehan
  • Celine Robert-Tissot
  • Wei Zheng

Assignees

  • MODERNATX, INC.

Dates

Publication Date
20260507
Application Date
20250710

Claims (20)

  1. 1 . A method of inducing an immune response against a tumor in a subject, the method comprising: (a) administering to a subject an effective amount of an immune checkpoint inhibitor; (b) measuring one or more biomarkers or biomarker levels in a biological sample collected from the subject, wherein the measuring is conducted before or on the day of the administering of (c); and (c) administering to the subject an effective amount of a personalized cancer vaccine, wherein the measurement of the one or more biomarkers or biomarker levels identifies the subject as likely to be responsive to the personalized cancer vaccine, and wherein the personalized cancer vaccine comprises: (i) an mRNA comprising an open reading frame that encodes at least two cancer antigen epitopes expressed in the tumor in the subject; and (ii) a lipid delivery vehicle, wherein the administration of the immune checkpoint inhibitor and the personalized cancer vaccine induces an immune response against the tumor in the subject.
  2. 2 . The method of claim 1 , wherein the measuring is conducted: (i) within 7 days prior to the administering of (c), optionally on the same day as the administering of (c); (ii) within 90 days prior to the time of the administering of (c); (iii) within 180 days prior to the time of the administering of (c); (iv) within 90 days from the time of the administering of (a), optionally at or approximately at day 90 following the administering of (a); or (v) within 180 days from the time of the administering of (a), optionally at or approximately at day 180 following the administering of (a).
  3. 3 . (canceled)
  4. 4 . The method of claim 1 , wherein the method further comprises comparing the measurement of the one or more biomarkers or biomarker levels to predetermined reference values or ranges.
  5. 5 . The method of claim 1 , wherein the one or more biomarkers or biomarker levels comprise tumor mutational burden (TMB), T cell-inflamed gene expression profile (GEP) score, T cell cytotoxicity activity (CYT) score, PD-L1 expression, minimal residual disease (MRD) level, and/or γδ T cells or a sub-type of γδ T cells.
  6. 6 . The method of claim 1 , wherein one or more of: (i) the one or more biomarkers comprise TMB, and the measurement of TMB in the biological sample collected from the subject is less than a predetermined reference value of TMB, optionally wherein the predetermined reference value of TMB is 175 non-synonymous mutations with an allele frequency of at least 5% per exome; (ii) the one or more biomarkers comprise T cell-inflamed GEP score, and the measurement of T-cell inflamed GEP score in the biological sample collected from the subject is less than a predetermined reference value of T-cell inflamed GEP score, optionally wherein the predetermined reference value of T cell-inflamed GEP score is 4; (iii) the one or more biomarkers comprise CYT score, and the measurement of CYT score in the biological sample collected from the subject is less than a predetermined reference value of CYT score, optionally wherein the predetermined reference value of CYT score is 4; (iv) the one or more biomarkers comprise PD-L1 expression, and the measurement of PD-L1 expression in the biological sample collected from the subject is less than a predetermined reference value of PD-L1 expression, optionally wherein the predetermined reference value of PD-L1 expression is 4, when normalized relative to one or more housekeeping genes; (v) the one or more biomarkers comprise MRD level, and the measurement of MRD level in the biological sample collected from the subject is greater than a predetermined reference value of MRD level, optionally wherein (a) the predetermined reference value of MRD level is 500 copies per mL of a mutated gene present in the tumor but not in healthy cells of the subject, in a biological sample comprising circulating tumor DNA (ctDNA), or (b) the predetermined reference value of MRD level is detectable ctDNA in a biological sample collected from the subject following primary treatment, optionally wherein the biological sample is a blood sample; and/or (vi) the one or more biomarkers comprise γδ T cells or a sub-type of γδ T cells, and the measurement of γδ T cells or a sub-type of γδ T cells in the biological sample collected from the subject is less than a predetermined reference value of γδ T cells or a sub-type of γδ T cells, wherein the sub-type of γδ T cells is regulatory γδ T cells, optionally wherein the predetermined reference value of γδ T cells or the sub-type of γδ T cells is 10% of T lymphocytes in peripheral blood mononuclear cells in a biological sample collected from the subject.
  7. 7 - 11 . (canceled)
  8. 12 . The method of claim 4 , wherein the measurement of at least one of the one or more biomarkers or biomarker levels is higher than a predetermined reference value or range for the biomarker or biomarker level.
  9. 13 . The method of claim 4 , wherein the measurement of at least one of the one or more biomarkers or biomarker levels is lower than a predetermined reference value or range for the biomarker or biomarker level.
  10. 14 . The method of claim 1 , wherein metastasis of the tumor has not been detected in the subject prior to administration of the immune checkpoint inhibitor and/or the personalized cancer vaccine to the subject.
  11. 15 . The method of claim 1 , wherein the lipid delivery vehicle comprises a lipid nanoparticle, a liposome, or a lipoplex.
  12. 16 . The method of claim 1 , wherein the lipid delivery vehicle comprises a lipid nanoparticle comprising an ionizable cationic lipid, a neutral lipid, cholesterol, and a PEG-modified lipid, optionally wherein the ionizable cationic lipid, the neutral lipid, the cholesterol, and the PEG-modified lipid are in a molar ratio of 20-60 mol % ionizable cationic lipid: 5-25 mol % neutral lipid: 25-55 mol % cholesterol: 0.5-15 mol % PEG-modified lipid, optionally wherein the ionizable cationic lipid comprises and optionally wherein the neutral lipid comprises 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); and optionally wherein the PEG-modified lipid comprises 1,2-dimyristoyl-sn-glycerol methoxypolyethylene glycol (PEG-DMG).
  13. 17 . The method of claim 1 , wherein the immune checkpoint inhibitor is an antibody or fragment thereof, optionally wherein the antibody or fragment thereof specifically binds to a molecule selected from the group consisting of PD-1, TIM-3, VISTA, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR and LAG3.
  14. 18 . The method of claim 1 , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or antigen-binding fragment thereof, optionally wherein: (a) the anti-PD-1 antibody or antigen-binding fragment thereof comprises: (i) light chain complementarity determining regions (CDRs) comprising a sequence of amino acids as set forth in SEQ ID NOs: 43, 44 and 45 and heavy chain CDRs comprising a sequence of amino acids as set forth in SEQ ID NOs: 48, 49 and 50; (ii) a light chain variable region comprising SEQ ID NO:46 and a heavy chain variable region comprising SEQ ID NO:51; and/or (iii) a light chain comprising SEQ ID NO: 47 and a heavy chain comprising SEQ ID NO: 52; or (b) the anti-PD-1 antibody or antigen-binding fragment thereof is pembrolizumab or a variant thereof.
  15. 19 . (canceled)
  16. 20 . The method of claim 1 , wherein the immune checkpoint inhibitor and/or the personalized cancer vaccine is administered to the subject following surgical resection of a primary tumor from the subject.
  17. 21 . The method of claim 1 , wherein the immune response to the tumor comprises an increase in a population of T cells specific to at least one of the cancer antigen epitopes in a biological sample collected from the subject, relative to the population of T cells in a comparable biological sample collected from the subject prior to induction of the immune response to the tumor, optionally wherein the population of T cells is detectable in a pre-treatment biological sample collected from the subject prior to administration of the personalized cancer vaccine and/or the immune checkpoint inhibitor to the subject.
  18. 22 . (canceled)
  19. 23 . The method of claim 21 , wherein the biological sample comprises peripheral blood mononuclear cells.
  20. 24 . The method of claim 1 , wherein a first T cell response to one of the cancer antigen epitopes is detectable in the subject following administration of the personalized cancer vaccine to the subject, optionally wherein additional T cell responses to an additional one or more of the cancer antigen epitopes are detectable in the subject following administration of the personalized cancer vaccine to the subject.

Description

RELATED APPLICATIONS This application is a continuation of International Patent Application No. PCT/US2024/011156, filed Jan. 11, 2024, which claims priority under 35 U.S.C. § 119 (e) to U.S. Provisional Application Ser. No. 63/438,452, entitled “PERSONALIZED MRNA CANCER VACCINES”, filed Jan. 11, 2023; U.S. Provisional Application Ser. No. 63/445,166, entitled “PERSONALIZED MRNA CANCER VACCINES”, filed Feb. 13, 2023; U.S. Provisional Application Ser. No. 63/448,235, entitled “PERSONALIZED MRNA CANCER VACCINES”, filed Feb. 24, 2023; U.S. Provisional Application Ser. No. 63/490,746, entitled “PERSONALIZED MRNA CANCER VACCINES”, filed Mar. 16, 2023; U.S. Provisional Application Ser. No. 63/459,199, entitled “PERSONALIZED MRNA CANCER VACCINES”, filed Apr. 13, 2023; U.S. Provisional Application Ser. No. 63/461,141, entitled “PERSONALIZED MRNA CANCER VACCINES”, filed Apr. 21, 2023; U.S. Provisional Application Ser. No. 63/505,107, entitled “PERSONALIZED MRNA CANCER VACCINES”, filed May 31, 2023; U.S. Provisional Application Ser. No. 63/509,406, entitled “PERSONALIZED MRNA CANCER VACCINES”, filed Jun. 21, 2023; and U.S. Provisional Application Ser. No. 63/589,621, entitled “PERSONALIZED CANCER VACCINES”, filed Oct. 11, 2023; the entire contents of each of which are herein incorporated by reference. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING The present application contains a Sequence Listing submitted electronically in XML format, the contents of which are herein incorporated by reference in their entirety. Said XML file, created Jul. 30, 2025, is named “131986-7011_SL.xml” and is 55,392 bytes in size. BACKGROUND Recent breakthroughs in cancer immunotherapy (e.g., checkpoint inhibitors and chimeric antigen receptor-T cell therapies) have demonstrated that powerful anti-tumor responses can be achieved by activating large numbers of T cells in a variety of cancer settings. Several checkpoint inhibitor biologic agents (e.g., anti-CTLA-4 [anti-cytotoxic T lymphocyte-associated antigen-4], anti-PD-1 [anti-programmed cell death protein 1], and anti-PD-L1 [anti-programmed death-ligand 1]) are currently approved for human use in several cancer types, including metastatic melanoma, non-small cell lung carcinoma and bladder carcinoma. These inhibitory receptors and their ligands play complementary roles in down-regulating adaptive immunity; PD-1/PD-L1 contributes to T cell exhaustion in peripheral tissues, and CTLA-4 inhibits earlier T cell activation events (Sharma and Allison 2015). Though it is clear that single agent checkpoint inhibitor therapy can provide significant benefit for some patients, many patients have incomplete or no response to therapy presenting a clear unmet need. SUMMARY Provided herein are personalized cancer vaccines specific to mutations present in a subject's tumor. Also provided are methods of inducing an immune response to a tumor in a subject, e.g., by administering a personalized cancer vaccine to the subject. The present disclosure also provides methods for optimizing personalized cancer vaccines, e.g., to increase their efficacy in stimulating an immune response. The efficacy the vaccines and methods provided herein can, in some embodiments, be related to characteristics of subjects, e.g., certain biomarker(s) in the subjects. Such characteristics can, in some embodiments, be useful in identifying subjects for administration of personalized cancer vaccines and/or predicting subjects' responses to personalized cancer vaccines. According to some aspects, methods of inducing an immune response against a tumor in a subject are provided herein, the method comprising: (a) administering to a subject an effective amount of an immune checkpoint inhibitor;(b) measuring one or more biomarkers or biomarker levels in a biological sample collected from the subject, wherein the measuring is conducted before or on the day of the administering of (c); and(c) administering to the subject an effective amount of a personalized cancer vaccine, wherein the measurement of the one or more biomarkers or biomarker levels identifies the subject as likely to be responsive to the personalized cancer vaccine, and wherein the personalized cancer vaccine comprises:(i) an mRNA comprising an open reading frame that encodes at least two cancer antigen epitopes expressed in the tumor in the subject; and(ii) a lipid delivery vehicle, wherein the administration of the immune checkpoint inhibitor and the personalized cancer vaccine induces an immune response against the tumor in the subject. In some embodiments, the measuring is conducted within 7 days prior to the administering of (c). In some embodiments, the measuring is conducted on the same day as the administering of (c). In some embodiments, the measuring is conducted within 90 days prior to the time of the administering of (c). In some embodiments, the measuring is conducted within 180 days prior to the time of the administering of (c). In some embodiments, the measuring