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US-20260124295-A1 - USE OF LIPID NANOPARTICLES AND IMMUNE CHECKPOINT INHIBITORS IN THE TREATMENT OF CANCER

US20260124295A1US 20260124295 A1US20260124295 A1US 20260124295A1US-20260124295-A1

Abstract

Disclosed are methods of increasing sensitivity of a tumor to treatment with an immune checkpoint inhibitor (ICI). The methods comprise administering to a subject in need thereof a composition comprising a lipid nanoparticle comprising mRNA encoding SARS-CoV-2 Spike protein, and administering an ICI to the subject, where the composition comprising a lipid nanoparticle comprising mRNA encoding SARS-CoV-2 Spike protein is optionally administered within 100 days of administration of the ICI, including with 30 days of administration of the ICI. In some aspects, the methods comprising administering to a subject in need thereof a composition comprising a lipid nanoparticle comprising mRNA encoding non-tumor antigens, and administering an ICI to the subject where the composition comprising a lipid nanoparticle comprising mRNA encoding non-tumor antigens is optionally administered within 100 days of administration of the ICI, including with 30 days of administration of the ICI.

Inventors

  • Elias Sayour
  • Adam J. Grippin
  • Steven Hsesheng Lin
  • Hector Ruben MENDEZ-GOMEZ
  • Christiano Marconi
  • Dhruvkumar Miteshkumar Soni
  • Sage Alexander Copling

Assignees

  • UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INCORPORATED
  • BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM

Dates

Publication Date
20260507
Application Date
20251107

Claims (20)

  1. 1 . A method of increasing sensitivity of a tumor to treatment with an immune checkpoint inhibitor (ICI), the method comprising (a) administering to a subject in need thereof a composition comprising a lipid nanoparticle comprising mRNA encoding SARS-CoV-2 Spike protein and (b) administering an ICI to the subject.
  2. 2 . The method of claim 1 , wherein the composition comprising a lipid nanoparticle comprising mRNA encoding SARS-CoV-2 Spike protein is administered within 100 days of administration of the ICI.
  3. 3 . The method of claim 1 , wherein the ICI is a PD-L1 inhibitor, a PD-1 inhibitor, or a CTLA4 inhibitor, such as an anti-PD-L1 antibody, anti-PD-1 antibody, or anti-CTLA4 antibody.
  4. 4 . The method of claim 1 , wherein the subject is suffering from non-small cell lung cancer or melanoma.
  5. 5 . The method of claim 1 , wherein the lipid nanoparticle comprises mRNA, SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC].
  6. 6 . The method of claim 1 , wherein the lipid nanoparticle comprises mRNA, ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2-(polyethylene glycol 2000)-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol.
  7. 7 . The method of claim 1 , wherein the composition comprising a lipid nanoparticle comprising mRNA encoding SARS-CoV-2 Spike protein is administered within 30 days of administration of the ICI.
  8. 8 . The method of claim 1 , wherein the composition comprising a lipid nanoparticle comprising mRNA encoding SARS-CoV-2 Spike protein is administered ipsilaterally with respect to the tumor.
  9. 9 . A method of increasing sensitivity of a tumor to treatment with an immune checkpoint inhibitor (ICI), the method comprising (a) administering to a subject in need thereof a composition comprising a lipid nanoparticle comprising mRNA encoding a viral antigen and (b) administering an ICI to the subject, wherein the composition comprising a lipid nanoparticle comprising mRNA encoding a non-tumor antigen is administered within 100 days of administration of the ICI.
  10. 10 . The method of claim 9 , wherein the composition comprising a lipid nanoparticle comprising mRNA encoding a viral antigen is administered within 30 days of administration of the ICI.
  11. 11 . The method of claim 9 , wherein the viral antigen comprises SARS-CoV-2 Spike protein or pp65.
  12. 12 . The method of claim 9 , wherein the ICI is a PD-L1 inhibitor, a PD-1 inhibitor, or a CTLA4 inhibitor, such as an anti-PD-L1 antibody, anti-PD-1 antibody, or anti-CTLA4 antibody.
  13. 13 . The method of claim 9 , wherein the subject is suffering from non-small cell lung cancer or melanoma.
  14. 14 . The method of claim 9 , wherein the lipid nanoparticle comprises (a) mRNA, SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC] or (b) mRNA, ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2-(polyethylene glycol 2000)-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol.
  15. 15 . The method of claim 1 , wherein the composition comprising a lipid nanoparticle comprising mRNA encoding SARS-CoV-2 Spike protein is administered ipsilaterally with respect to the tumor.
  16. 16 . A method of treating a subject with an immune checkpoint inhibitor (ICI)-resistant tumor, the method comprising (a) administering to a subject in need thereof a composition comprising a lipid nanoparticle comprising mRNA encoding SARS-CoV-2 Spike protein and (b) administering an ICI to the subject.
  17. 17 . The method of claim 1 , wherein the composition comprising a lipid nanoparticle comprising mRNA encoding SARS-CoV-2 Spike protein is administered within 100 days of administration of the ICI.
  18. 18 . The method of claim 1 , wherein the ICI is a PD-L1 inhibitor, a PD-1 inhibitor, or a CTLA4 inhibitor, such as an anti-PD-L1 antibody, anti-PD-1 antibody, or anti-CTLA4 antibody.
  19. 19 . The method of claim 1 , wherein the lipid nanoparticle comprises (a) mRNA, SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC] or (b) mRNA, ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2-(polyethylene glycol 2000)-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol.
  20. 20 . The method of claim 1 , wherein the composition comprising a lipid nanoparticle comprising mRNA encoding SARS-CoV-2 Spike protein is administered ipsilaterally with respect to the tumor.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority of U.S. Provisional Patent Application No. 63/717,622, filed on Nov. 7, 2024, and U.S. Provisional Patent Application No. 63/849,674, filed on Jul. 23, 2025, the disclosures of which are hereby incorporated by reference in their entireties. GRANT FUNDING DISCLOSURE This invention was made with government support under Grant Numbers R37 CA251978, R01 CA266857, T32CA196561, P50CA221703, R01 FD007268, and CA016672, awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION This application relates to use of lipid nanoparticles comprising nucleic acid molecules to enhance efficacy of immune checkpoint inhibitors in the treatment of cancer. BACKGROUND While immune checkpoint inhibitors (ICI) have substantially extended survival in a subset of patients, the majority fail to respond to these treatments. These poor responses are attributed to immunosuppressive tumor microenvironments (TMEs) characterized by tolerogenic dendritic cells (DCs), myeloid suppressor cells and regulatory T cells. There are currently no clinically available methods to improve responses to ICI by modifying the TME. COVID mRNA vaccines induce robust stimulation of cytokine secretion. However, the impact of COVID mRNA vaccines on immune therapy is unknown. SUMMARY Personalized mRNA vaccines sensitize tumors to ICIs in part by unleashing a cytokine/chemokine cascade that broadly activates immune cells. Since this cascade is not dependent on mRNA species, mRNA vaccines encoding non-tumor-specific antigens might also be used to reset immunotolerance and sensitize response to ICIs. The disclosure demonstrates that mRNA vaccines that do not encode tumor antigen (e.g., targeting SARS-CoV-2 spike protein) dramatically augment responses to ICIs. To illustrate, in two cohorts of patients with non-small cell lung cancer and metastatic melanoma, receipt of a COVID mRNA vaccine within 100 days of ICI initiation was associated with near doubling of overall survival. Preclinical models confirmed that mRNA vaccines targeting SARS-CoV-2 sensitize response to ICIs. By inducing a surge in interferon-α and Th1 chemokines, spike mRNA vaccines mediate antigen presenting cell co-localization with T cells in lymphoid organs for induction of anti-tumor immunity. Due to increases in PD-L1 on tumor cells, concomitant ICI treatment elicits increased PD-1+ T cells and epitope spreading against cancer associated antigens. Similar correlates of response were seen in both patients and healthy volunteers. Together, these results demonstrate that clinically available mRNA vaccines targeting non-tumor antigens are potent immune modulators capable of sensitizing tumors to ICIs. Various aspects of the disclosure are summarized below: 1. A method of increasing sensitivity of a tumor to treatment with an immune checkpoint inhibitor (ICI), the method comprising (a) administering to a subject in need thereof a composition comprising a lipid nanoparticle comprising mRNA and (b) administering an ICI to the subject.2. A method of treating a subject with an immune checkpoint inhibitor (ICI)-resistant tumor, the method comprising (a) administering to the subject in need thereof a composition comprising a lipid nanoparticle comprising mRNA and (b) administering an ICI to the subject.3. The method of aspect 1 or 2, wherein the ICI is a PD-L1 inhibitor, a PD-1 inhibitor, or a CTLA4 inhibitor, such as an anti-PD-L1 antibody, anti-PD-1 antibody, or anti-CTLA4 antibody.4. The method of any one of aspects 1-3, wherein the mRNA does not encode a tumor antigen, such as a tumor antigen derived from the subject.5. The method of aspect 4, wherein the mRNA encodes a viral antigen, such as SARS-CoV-2 Spike protein.6. The method of any one of aspects 1-5, wherein the composition comprising a lipid nanoparticle comprising mRNA is administered to the subject within 100 days (e.g., 51-100 days or 100 days) before or after the ICI is administered to the subject, optionally within 100 days after ICI administration, optionally within 51-100 days after administering the ICI to the subject.7. The method of aspect 6, wherein the composition comprising a lipid nanoparticle comprising mRNA is administered to the subject within 30 days before or after the ICI is administered to the subject.8. The method of any one of aspects 1-7, wherein the subject is suffering from non-small cell lung cancer or melanoma.9. The method of any one of aspects 1-8, wherein the lipid nanoparticle comprises mRNA, SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC].10. The method of any one of aspects 1-8, wherein the lipid nanoparticle comprises mRNA, ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2-(polyethylene glycol 2000)-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phos