Combination therapy to treat brain cancer
Inventors
BREDLAU, Amy-Lee • Lowy, Israel • Skolnik, Jeffrey • Yan, Jian • Ferraro, Bernadette • Walters, Jewell • Sylvester, III, Albert J. • Kraynyak, Kimberly A. • Morrow, Matthew P. • Gillespie, Elisabeth
Assignees
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Publication Number
US-12350318-B2
Publication Date
2025-07-08
Expiration Date
Abstract
Provided herein are methods of treating brain cancer in a subject, comprising evaluating one or more biological samples from a subject who has brain cancer for the presence of a miRNAs and administering interleukin-12 (IL-12); an immunogenic composition of human telomerase reverse transcriptase (hTERT), Wilms Tumor-1 (WT-1), and prostate specific membrane antigen (PSMA); and an anti-programmed cell death receptor 1 (PD-1) antibody to said subject if the subject has an increased expression level of the mIR-331-3p miRNA or isomiRs thereof and the miR-1537-3p miRNA or isomiRs thereof relative to a control population of subjects. Also provided herein are methods of treating brain cancer in a subject, comprising measuring an expression level of at least one mRNA biomarker selected from SYNGR3, OTX1, GABBR2, LHX1, CADM3, MLLT11, MNX1, GRB14, SLC34A2, PHYHIP, WNT10B, SLC17A6, CRLF1, HOXD13, TGFβR3, UBA7, SFRP4, or any combination thereof, in a tumor sample from a subject and administering IL-12; an immunogenic composition hTERT, WT-1, and PSMA; and an anti-PD-1 antibody to said subject if the expression level of SYNGR3, OTX1, GABBR2, LHX1, CADM3, MLLT11, MNX1, GRB14, SLC34A2, PHYHIP, WNT10B, SLC17A6, CRLF1 and HOXD13 is decreased or if the expression level of TGFβR3, UBA7, SFRP4 is increased.
Core Innovation
The invention provides a method of treating glioblastoma in a subject characterized by an unmethylated O6-methylguanine methyltransferase (MGMT) gene promoter and increased pre-treatment expression level of a miR-331-3p miRNA and a miR-1537-3p miRNA, or isomiRs thereof, relative to a control population of subjects. The treatment comprises administering an anti-programmed cell death receptor 1 (PD-1) antibody, interleukin-12 (IL-12), and an immunogenic composition comprising a DNA plasmid composition encoding human telomerase reverse transcriptase (hTERT) antigen, Wilms Tumor-1 (WT-1) antigen, and prostate specific membrane antigen (PSMA) antigen.
The disclosed regimen is specified in terms of the immunogenic DNA plasmids and their encoded antigens, combined with anti-PD-1 and IL-12 for glioblastoma treatment. The method is tied to biomarker-defined subject selection based on MGMT promoter methylation status and miRNA expression changes versus a control population.
The document further supports biomarker measurement and patterning using pre-treatment miRNA expression from plasma or primary tumor samples, including miR-331-3p and miR-1537-3p, or isomiRs thereof. It also associates immune efficacy and survival endpoints, including progression-free survival and overall survival at 12 and 18 months, with the biomarker-stratified combination therapy regimen involving IL-12 plus the immunogenic DNA plasmid composition and an anti-PD-1 antibody.
Claims Coverage
The partial content identifies one independent claim, with multiple dependent claims refining the selection biomarkers, the antibody specification, and additional regimen context. The independent claim contains 3 major inventive components.
Mgmt unmethylated plus miR-331-3p/miR-1537-3p stratified subject selection
Treating glioblastoma in a subject characterized by an unmethylated O6-methylguanine methyltransferase (MGMT) gene promoter and increased pre-treatment expression level of miR-331-3p and miR-1537-3p, or isomiRs thereof, relative to a control population of subjects.
Combined administration of anti-pd-1 antibody, il-12, and multi-antigen DNA plasmid immunogenic composition
Administering to the subject an anti-programmed cell death receptor 1 (PD-1) antibody, interleukin-12 (IL-12), and an immunogenic composition comprising a DNA plasmid encoding hTERT antigen, a DNA plasmid encoding WT-1 antigen, and a DNA plasmid encoding PSMA antigen.
Outcome-linked association at 18 months post tumor resection
The control population of subjects is a population of subjects having glioblastoma characterized by an unmethylated MGMT promoter administered IL-12; and the anti-PD-1 antibody is deceased at 18 months post tumor resection.
Across the identified independent claim, the claim coverage centers on biomarker-defined glioblastoma treatment using an MGMT-unmethylated, miR-331-3p/miR-1537-3p increased pre-treatment expression selection, together with combined administration of anti-PD-1 antibody and IL-12 plus an immunogenic DNA plasmid composition encoding hTERT, WT-1, and PSMA, with an association to an 18-month post tumor resection endpoint in the described context.
Stated Advantages
Documented Applications
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