IP Library › Granted Patent US 12,318,413
Granted Patent B2
US 12,318,413 · App. 17/814,314 · Granted Jun 3, 2025

Methods for enhancing immune checkpoint blockade therapy by modulating the microbiome

Inventors: Jennifer Wargo (Houston, TX); Vancheswaran Gopalakrishnan (Houston, TX)
Assignee: BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM
A61K35/741A61K9/0053A61K35/17A61K45/06A61P35/00A61P35/02C12N1/20C12Q1/04A61K2035/115
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Quick Facts
Patent No.
US 12,318,413
App. No.
17/814,314
Granted
Jun 3, 2025
Kind
B2
Abstract

Provided herein are methods and compositions for the treatment of cancer by modulating the microbiome to enhance the efficacy of immune checkpoint blockade. The microbiome may be modulated by the administration of butyrate and/or butyrate-producing bacteria. Also provided herein are methods of determining a response to an immune checkpoint inhibitor by identifying if a subject has a favorable microbial profile.

Claims (23)

1. A method of treating a cancer in a human subject in need thereof comprising administering a therapeutically effective amount of a human programmed cell death 1 (PD-1) axis binding antagonist to the subject, wherein the subject has been determined to have an increased relative abundance, or the same or substantially the same relative abundance, of bacteria belonging to the family Ruminococcaceae in their gut microbiome compared to one or more other human subjects having the cancer and the one or more subjects respond to therapy with the human PD-1 axis binding antagonist, and wherein the administering treats the cancer in the human subject.

2. The method of claim 1 , wherein the cancer is a skin cancer.

3. The method of claim 1 , wherein the cancer is basal-cell skin cancer, squamous-cell skin cancer, melanoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, keratoacanthoma, spindle cell tumors, sebaceous carcinomas, microcystic adnexal carcinoma, Paget's disease of the breast, atypical fibroxanthoma, leiomyosarcoma, or angiosarcoma.

4. The method of claim 1 , wherein the cancer is a melanoma.

5. The method of claim 4 , wherein the melanoma is metastatic melanoma, Lentigo Maligna, Lentigo Maligna Melanoma, Superficial Spreading Melanoma, Nodular Melanoma, Acral Lentiginous Melanoma, or Desmoplastic Melanoma.

6. The method of claim 1 , wherein the PD-1 axis binding antagonist is administered intratumorally, intraarterially, intravenously, intravascularly, intrapleuraly, intraperitoneally, intratracheally, intrathecally, intramuscularly, endoscopically, intralesionally, percutaneously, subcutaneously, regionally, stereotactically, orally, or by direct injection or perfusion.

7. The method of claim 1 , wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-1 binding antagonist, a PD-L1 binding antagonist, a PD-L2 binding antagonist, or combinations thereof.

8. The method of claim 7 , wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.

9. The method of claim 8 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2.

10. The method of claim 8 , wherein the PD-1 binding antagonist is a monoclonal antibody or antigen binding fragment thereof.

11. The method of claim 8 , wherein the PD-1 binding antagonist is nivolumab, pembrolizumab, pidillizumab, AMP-514, REGN2810, BMS 936559, MPDL3280A, or AMP-224.

12. The method of claim 1 , further comprising administering at least one additional anticancer treatment.

13. The method of claim 12 , wherein the at least one additional anticancer treatment is administered intratumorally, intraarterially, intravenously, intravascularly, intrapleuraly, intraperitoneally, intratracheally, intrathecally, intramuscularly, endoscopically, intralesionally, percutaneously, subcutaneously, regionally, stereotactically, orally, or by direct injection or perfusion.

14. The method of claim 12 , wherein the at least one additional anticancer treatment is surgical therapy, chemotherapy, radiation therapy, hormonal therapy, immunotherapy, small molecule therapy, receptor kinase inhibitor therapy, anti-angiogenic therapy, cytokine therapy, cryotherapy, or a biological therapy.

15. The method of claim 14 , wherein the biological therapy is a monoclonal antibody, siRNA, miRNA, antisense oligonucleotide, ribozyme, or gene therapy.

16. The method of claim 12 , wherein the at least one additional anticancer treatment is an immune checkpoint inhibitor.

17. The method of claim 1 , wherein the bacteria belong to the genus Ruminococcus or the genus Faecalibacterium.

18. The method of claim 1 , wherein the bacteria are selected from one or more of the species Faecalibacterium prausnitzii, Ruminococcus albus, Ruminococcus bromii, Ruminococcus callidus, Ruminococcus flavefaciens, Ruminococcus champanellensis, Ruminococcus faecis, Ruminococcus gauvreauii, Ruminococcus gnavus, Ruminococcus hansenii, Ruminococcus hydro genotrophicus, Ruminococcus lactaris, Ruminococcus luti, Ruminococcus obeum, Ruminococcus palustris, Ruminococcus pasteurii, Ruminococcus productus, Ruminococcus schinkii , and Ruminococcus torques.

19. The method of claim 18 , wherein the bacteria are selected from the species Ruminococcus bromii and Faecalibacterium prausnitzii.

20. The method of claim 19 , wherein the bacteria are Faecalibacterium prausnitzii.

21. A method of treating a cancer in a human subject in need thereof comprising administering a therapeutically effective amount of a human programmed cell death 1 (PD-1) axis binding antagonist to the subject, wherein the subject has been determined to have an increased relative abundance, or the same or substantially the same relative abundance, of bacteria belonging to the genus Ruminococcus or the genus Faecalibacterium in their gut microbiome compared to one or more other human subjects having the cancer that and the one or more subjects respond to therapy with the human PD-1 axis binding antagonist, and wherein the administering treats the cancer in the human subject.

22. The method of claim 1 , wherein the subject is further determined to have (a) high alpha-diversity of the gut microbiome; (b) a high abundance of butyrate-producing bacteria in the gut microbiome; (c) one or more bacteria selected from the group consisting of the species in Table 1 with an enrichment index (ei) greater than 0.5 in the gut microbiome; or (d) one or more of the bacteria species in Table 2 designated with a response status of responder (R) in the gut microbiome.

23. The method of claim 21 , wherein the subject is further determined to have (a) high alpha-diversity of the gut microbiome; (b) a high abundance of butyrate-producing bacteria in the gut microbiome; (c) one or more bacteria selected from the group consisting of the species in Table 1 with an enrichment index (ei) greater than 0.5 in the gut microbiome; or (d) one or more of the bacteria species in Table 2 designated with a response status of responder (R) in the gut microbiome.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 21, 2022
From: WARGO, JENNIFER; GOPALAKRISHNAN, VANCHESWARAN
To: BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM
Reel/Frame 061500/0567 →
Continuity (5)
Division 16337820
Provisional Application 62400372 · Sep 27, 2016
Provisional Application 62508885 · May 19, 2017
Provisional Application 62557566 · Sep 12, 2017
Related Publication 20230109343A1 · Apr 6, 2023
References Cited (141)
US 11395838B2 · Wargo et al. · 2022 [cited by applicant]
US 20160193257A1 · Honda et al. · 2016 [cited by applicant]
US 20180243351A1 · Hlavka · 2018 [cited by applicant]
US 20180303934A1 · Clube et al. · 2018 [cited by applicant]
US 20200129569A1 · Wargo et al. · 2020 [cited by applicant]
US 20240173361A1 · Wargo et al. · 2024 [cited by applicant]
CA 2987129 · 2015 [cited by applicant]
CN 105296590 · 2016 [cited by applicant]
CN 108884159 · 2018 [cited by applicant]
EP 3411052 · 2020 [cited by applicant]
WO WO1995001994 · 1995 [cited by applicant]
WO WO9615660 · 1996 [cited by applicant]
WO WO1998042752 · 1998 [cited by applicant]
WO WO2000037504 · 2000 [cited by applicant]
WO WO2001014424 · 2001 [cited by applicant]
WO WO2005003168 · 2005 [cited by applicant]
WO WO2005009465 · 2005 [cited by applicant]
WO WO200600317 · 2006 [cited by applicant]
WO WO2006072625 · 2006 [cited by applicant]
WO WO2006072626 · 2006 [cited by applicant]
WO WO2006121168 · 2006 [cited by applicant]
WO WO2007042573 · 2007 [cited by applicant]
WO WO2008084106 · 2008 [cited by applicant]
WO WO2008132601 · 2008 [cited by applicant]
WO WO2009044273 · 2009 [cited by applicant]
WO WO2009101611 · 2009 [cited by applicant]
WO WO2009114335 · 2009 [cited by applicant]
WO WO2010027827 · 2010 [cited by applicant]
WO WO2010065939 · 2010 [cited by applicant]
WO WO2011008369 · 2011 [cited by applicant]
WO WO2011014438 · 2011 [cited by applicant]
WO WO2011066342 · 2011 [cited by applicant]
WO WO2011094027 · 2011 [cited by applicant]
WO WO2012071411 · 2012 [cited by applicant]
WO WO2012160448 · 2012 [cited by applicant]
WO WO2013006490 · 2013 [cited by applicant]
WO WO2013025779 · 2013 [cited by applicant]
WO WO2013067492 · 2013 [cited by applicant]
WO WO2014022021 · 2014 [cited by applicant]
WO WO2015016718 · 2015 [cited by applicant]
WO WO2015066625 · 2015 [cited by applicant]
WO WO2015075688 · 2015 [cited by applicant]
WO WO2015095241 · 2015 [cited by applicant]
WO WO2015153639 · 2015 [cited by applicant]
WO WO2015156419A1 · 2015 [cited by applicant]
WO WO2016063263 · 2016 [cited by applicant]
WO WO2016196605 · 2016 [cited by applicant]
WO WO2017172894 · 2017 [cited by applicant]
WO 2018026913 · 2018 [cited by applicant]
WO 2018064165 · 2018 [cited by applicant]
WO WO2018115519 · 2018 [cited by applicant]
WO 2019099482 · 2019 [cited by applicant]
WO 2019152667 · 2019 [cited by applicant]
WO 2019178494 · 2019 [cited by applicant]
WO WO2019191390 · 2019 [cited by applicant]
Borody et al. “Fecal microbiota transplantation and emerging applications” [cited by applicant]
Bultman, et al., “Microbial-Derived Butyrate: Oncometabolite or Tumor-Suppressive Metabolite?” Cell Host & Microbe, 16: 143-145, 2014. [cited by applicant]
Chaput, et al., “Baseline Gut Microbiota Predicts Clinical Response and Colitis in Metastatic Melanoma Patients Treated with Ipilimumab,” [cited by applicant]
Chen, et al., “Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight Into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade,” [cited by applicant]
Dubin et al., “Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis.” [cited by applicant]
Extended European Search Report Issued in Corresponding European Patent Application No. 17857329.1, dated Aug. 7, 2020. [cited by applicant]
Frankel, et al., “Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients,” [cited by applicant]
Garrett, “Cancer and the Microbiota,” [cited by applicant]
Gopalkrishnan, et al. “Gut Microbiome Modulates Response to Anti-PD-1 Immunotherapy in Melanoma Patients,” [cited by applicant]
Gueimonde, et al., Antibiotic Resistance in Probiotic Bacteria, Frontiers in Microbiology, 4(202): 1-6, 2013. [cited by applicant]
International Search Report and Written Opinion Issued in Corresponding PCT Patent Application No. PCT/US2017/053717, mailed Feb. 2, 2018. [cited by applicant]
International Search Report and Written Opinion Issued in Corresponding PCT Patent Application No. PCT/US2019/024519, dated Oct. 24, 2019. [cited by applicant]
International Search Report and Written Opinion Issued in Corresponding PCT Patent Application No. PCT/US2019/62659, mailed Mar. 30, 2020. [cited by applicant]
International Search Report and Written Opinion Issued in Corresponding PCT Patent Application No. PCT/US2020/013808, mailed Jun. 2, 2020. [cited by applicant]
Jenq et al., “Intestinal Blautia Is Associated with Reduced Death from Graft-versus-Host Disease” [cited by applicant]
Klieve, et al., “Ruminococcus Bromii, Identification and Isolation as a Dominant Community Member in the Rumen of Cattle Fed A Barley Diet,” Journal of Applied Microbiology, 103: 2065-2073, 2007. [cited by applicant]
Litvak et al., “Dysbiotic Proteobacteria expansion: a microbial signature of epithelial dysfunction” [cited by applicant]
Maronpot et al., “Relevance of Animal Carcinogenesis to Huma Cancer Predictions and Prevention”, [cited by applicant]
Matson, et al., “The Commensal Microbiome is Associated with Anti-PD-1 Efficacy in Metastatic Melanoma Patients,” Science, 359(6371): 104-108, 2018. [cited by applicant]
Miquel et al., “Faecalibacterium prausnitzii and human intestinal health”, [cited by applicant]
Moco, et al., “Metabolomics View on Gut Microbiome Modulation by Polyphenol-Rich Foods,” Journal of Proteome Research, 11(10): 4781-4790, 2012. [cited by applicant]
Patyar et al., “Bacteria in cancer therapy: a novel experimental strategy”, [cited by applicant]
Pitt, et al., “Fine-Tuning Cancer Immunotherapy: Optimizing the Gut Microbiome,” [cited by applicant]
Pitt, et al., “Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors,” Immunity, 44(6), 1255-1269, 2016. [cited by applicant]
Png et al., “Mucolytic Bacteria With Increased Prevalence in IBD Mucosa Augmentin VitroUtilization of Mucin by Other Bacteria” Am. J. Gastroenterol. 2010, 105, 2420-2428. [cited by applicant]
Poutahidis Theofilis, et al., “Gut Microbiota and the Paradox of Cancer Immunotherapy,” [cited by applicant]
Roh et al., “Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance.” [cited by applicant]
Routy, et al. “Gut Microbiome Influences Efficacy of PD-1-Based Immunotherapy Against Epithelial Tumors,” [cited by applicant]
Segata et al., “Metagenomic biomarker discovery and explanation.” [cited by applicant]
Sivan, et al., “Commensal Bifidobacterium Promotes Antitumor Immunity and Facilitates Ant-PD-L1 Efficacy,” [cited by applicant]
Smelt, et al., “Probiotics Can Generate FoxP23 T-Cell Responses in the Small Intestine an Simultaneously CD4 and CD8 T Cell Activation in the Large Intestine,” PLOS One, 8(7):e68952, 1-12, 2013. [cited by applicant]
Taur, et al., “The Effects of Intestinal Tract Bacterial Diversity on Mortality Following Allogenic Hematopoietic Stem Cell Transplantation,” [cited by applicant]
Tumeh, et al., “PD-1 Blockade Induces Responses by Inhibiting Adaptive Immune Resistance,” [cited by applicant]
Vetizou, et al., “Anticancer Immunotherapy by CTLA-4 Blockade Relies on the Gut Microbiota,” [cited by applicant]
Viaud, et al., “Gut Microbiome and Anticancer Immune Response: Really Hot Sh*t!” Cell Death and Differentiation, 22(2): 199-214, 2014. [cited by applicant]
Wang et al., “Bifidobacterium can mitigate intestinal immunopathology in the context of CTLA-4 blockade.” [cited by applicant]
Wang et al., “P038 Fecal Microbiota Transplant (FMT) For Immuno-checkpoint Inhibitor-Induced Colitis (ICI-C) In A 50 Year Old Female With Bladder Cancer” Gastroenterology 2018, 154(1S), S19-S20. [cited by applicant]
Wei et al., “Bacterial targeted tumour therapy-dawn of a new era”, [cited by applicant]
Durnov L.A et al., Pediatric Oncology. [cited by applicant]
Extended Search Report issued in related European Patent Application No. 19886594.1, dated Oct. 24, 2022. [cited by applicant]
Office Action issued in corresponding Russian Patent Application No. 2019108925, dated Jul. 4, 2022. [cited by applicant]
Brief Medical Encyclopedia, Renal Stone Disease—Substance Dependencies. [cited by applicant]
Extended European Search Report in corresponding EP Application No. 20740867.5, dated Aug. 11, 2022. [cited by applicant]
Berger, et al. “Flavonifractor (Eubacterium) plautii bloodstream infection following acute cholecystitis”, [cited by applicant]
National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE), 2017. [cited by applicant]
Office Action issued in corresponding Chinese Application No. 202080019540.8 dated Oct. 17, 2023. [cited by applicant]
Office Action issued in corresponding European Application No. 20740867 dated May 22, 2023. [cited by applicant]
Office Action issued in corresponding Japanese Application No. 2021529087, dated Nov. 20, 2023. [cited by applicant]
Prados et al., “Regression of established subcutaneous B16-F10 murine melanoma tumors after gef gene therapy associated with the mitochondrial apoptotic pathway”, [cited by applicant]
Rudzki, J. “Management of adverse events related to checkpoint inhibition therapy”, [cited by applicant]
Wang et al., “Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis”, [cited by applicant]
Wen et al.., “Research progress of intestinal flora and ulcerative colitis”, [cited by applicant]
Karimi, G et al., “Single-species versus dual-species probiotic supplementation as an emerging therapeutic strategy for obesity”, [cited by applicant]
Kamiya, S., “Intestinal Disease, Liver Disease”, [cited by applicant]
Office Action issued in corresponding Canadian Application No. 3038076, dated Jan. 16, 2024. [cited by applicant]
Office Action issued in corresponding Japanese Application No. 2019516669, dated Nov. 28, 2023. (English Translation Provided). [cited by applicant]
Ohno, K et al., “Microbiome therapy (bacteria transplant, fecal microorganism transplant)”, [cited by applicant]
Nordenberg, et al., “Growth Inhibitions of Murine Melanoma by Butyric Acid and Dimethysulfoxide”, [cited by applicant]
Office Action and Search Report in corresponding Chinese Application No. 201780072679.7, dated Jan. 17, 2022 (English Translation). [cited by applicant]
Wang et al., “Current Treatment Status and Progress of Anti-PD-1 Antibody Therapy for Advanced Melanoma”, [cited by applicant]
Barcenilla, A., et al., “Phylogenetic Relationships of Butyrate-Producing Bacteria from the Human Gut,” Applied and Environmental Microbiology, 66(4): 1654-1661, American Society for Microbiology, United States (Apr. 20… [cited by applicant]
Brandt, L.J., et al., “An overview of fecal microbiota transplantation: techniques, indications, and outcomes,” Gastrointestinal Endoscopy, 78(2):240-249, American Society for Gastrointestinal Endoscopy, United States (… [cited by applicant]
Dankort, D., et al., “Braf [cited by applicant]
Duncan, S.H., et al., “Growth requirements and fermentation products of [cited by applicant]
Kuzu, O.F., et al., “Current State of Animal (Mouse) Modeling in Melanoma Research,” Cancer Growth and Metastasis, 8(S1):81-94, Sage Publishing, United States (Aug. 2015). [cited by applicant]
Lopez-Siles, M., et al., “Changes in the Abundance of [cited by applicant]
Louis, P., et al., “Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine,” FEMS Microbiology Letters, 294(1):1-8, O (Feb. 2009). [cited by applicant]
Ma., W., et al., “Current status and perspectives in translational biomarker research for PD-1/PD- L1 immune checkpoint blockade therapy ,” Journal of Hematology & Oncology, 9(47): 1-21, BioMed Central, United Kingdom (… [cited by applicant]
Martin-Orozco, N., et al., “T Helper 17 Cells Promote Cytotoxic T Cell Activation in Tumor Immunity,” Immunity, 31(5):787-798, Elsevier, The Netherlands (Nov. 2009). [cited by applicant]
Pardoll, D.M., et al., “The blockade of immune checkpoints in cancer immunotherapy,” Nature Reviews Cancer, 12:252-264, Springer Nature, Germany (Apr. 2012). [cited by applicant]
Walker, A.W., et al., “The species composition of the human intestinal microbiota differs between particle-associated and liquid phase communities,” Environmental Microbiology, 10(12):3275-3283, Blackwell Publishing Ltd… [cited by applicant]
Youngster, I., et al., “Oral, frozen fecal microbiota transplant (FMT) capsules for recurrent [cited by applicant]
Petition for Post Grant Review of U.S. Pat. No. 11,395,838, Case PGR2023-00026, filed Apr. 26, 2023, pp. 1-101. [cited by applicant]
Patent Owner Preliminary Response, Case PGR2023-00026, filed Aug. 22, 2023, pp. 1-87. [cited by applicant]
Declaration of Matthew Robinson, Case PGR2023-00026, filed Apr. 26, 2023, pp. 1-107. [cited by applicant]
Declaration of Wendy S. Garrett, Case PGR2023-00026, filed Aug. 22, 2023, pp. 1-78. [cited by applicant]
Petitioner's Preliminary Reply to Patent Owner's Preliminary Response, Case PGR2023-00026, filed Sep. 28, 2023, pp. 1-13. [cited by applicant]
Patent Owner's Sur-Reply, Case PGR2023-00026, filed Oct. 12, 2023, pp. 1-14. [cited by applicant]
Decision Denying Institution of Post-Grant Review, Case PGR2023-00026, mailed Nov. 21, 2023, pp. 1-46. [cited by applicant]
Petitioner's Request for Director Review, Case PGR2023-00026, filed Dec. 21, 2023, pp. 1-19. [cited by applicant]
Order Denying Director Review, Case PGR2023-00026, mailed Jan. 17, 2024, pp. 1-3. [cited by applicant]
Vital, M., et al., Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data, mBio, 5(2):e00889, pp. 1-14, American Society for Microbiology, United States (Apr. 2014). [cited by applicant]
Third Party Observations against corresponding application EP17857329.1, filed Jan. 11, 2023, pp. 1-23. [cited by applicant]
Office Action, U.S. Appl. No. 16/337,820, mailed Apr. 9, 2021, pp. 1-11. [cited by applicant]
Office Action, U.S. Appl. No. 16/337,820, mailed Sep. 27, 2021, pp. 1-7. [cited by applicant]
Office Action, U.S. Appl. No. 18/440,808, mailed Jun. 27, 2024, pp. 1-6. [cited by applicant]