Biomarkers associated with checkpoint immune therapy and methods of using same
Inventors
Assignees
Publication Number
US-12275986-B2
Publication Date
2025-04-15
Expiration Date
2041-01-06
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Abstract
Provided herein are methods for treating cancer in a subject comprising administering an ICB therapy to a subject having cancer, wherein the subject's cancer comprises one or more mutations in two or more genes associated with responsiveness to immune checkpoint blockade (ICB).
Core Innovation
The invention provides methods for treating cancer, specifically by administering immune checkpoint blockade (ICB) therapy to patients whose cancers harbor mutations in two or more genes associated with responsiveness to ICB. The method comprises detecting mutations in a defined panel of genes in a biological sample from a cancer patient, and administering ICB therapy if mutations are found in at least two genes from this panel. Such panels include, for example, a 52-gene panel relevant to non-small cell lung cancer (NSCLC) and a related 42-gene panel applicable to melanoma, bladder, and colorectal cancer. The identification of mutations is performed using molecular analysis techniques such as next generation sequencing, whole exome sequencing, targeted sequencing, or DNA/RNA microarray analysis.
The problem addressed by this invention is the need for improved, clinically useful biomarkers to predict which cancer patients are likely to respond to ICB therapy. Existing biomarkers like PD-L1 expression and high tumor mutational burden (TMB) have significant limitations, such as inconsistency in predictive value, difficulties in establishing cut-off values, and technical challenges in measurement. As described, only a minority of patients actually benefit from ICB therapy, while the treatment has high costs and potential for severe side effects. Therefore, there is an unmet need for better methods to select patients who can benefit from ICB therapies.
The invention solves this problem by establishing that the presence of mutations in at least two genes from a set of genes associated with ICB responsiveness predicts significant clinical benefit from ICB therapy, outperforming current biomarkers such as TMB and PD-L1 status. The method not only selects patients likely to respond but does so with broader applicability across several major cancer types, including NSCLC, melanoma, bladder, and colorectal cancer. The methods are also compatible with a variety of sample types, including tissue biopsies and liquid biopsies.
Claims Coverage
There is one independent claim in this patent, covering two main inventive features.
Determining mutations in a defined panel of genes associated with ICB therapy response in NSCLC
The method involves detecting the presence or absence of a mutation in each of a plurality of genes in a biological sample from a subject with non-small cell lung cancer (NSCLC), where the plurality of genes consists of: ABLI, ASXLI, ATM, BCOR, BRCA2, BRIP1, CARD11, CD79B, CDC73, CIC, EPHA3, EPHAS, EPHA, EPHB1, ERBB4, ERCC4, FGFR4, FLT3, FOXL2, HGF, INHBA, JAK3, MAX, MDC1, MED12, MET, MGA, MRE11, MSH2, NF2, NFKBIA, NOTCH1, NOTCH2, NTRK3, NUF, PARP1, PAX5, PGR, PIK3C2G, PIK3C3, PIK3CG, PIM1, POLE, PPM1D, PPP2RIA, PTPRD, RET, STAT3, TENT, TET1, TSC2, and ZFHX3.
Administering ICB therapy based on detection of two or more gene mutations
Immune checkpoint blockade (ICB) therapy is administered to the subject having cancer when the subject has mutations in two or more of the defined plurality of genes associated with ICB responsiveness. This decision criterion is the central requirement for clinical intervention under the method.
The claims cover a method for treating NSCLC by detecting mutations in a comprehensive, specified gene panel and administering ICB therapy only when mutations are present in at least two of these genes, thus providing a biomarker-driven therapeutic approach.
Stated Advantages
The compound mutation signature predicts ICB efficacy better than current biomarkers, such as PD-L1 status and tumor mutational burden (TMB).
Compound mutation identification is a straightforward process that can be achieved with different platform technologies, including archival tissue and liquid biopsies.
The compound mutation signature is easier to implement clinically as a biomarker compared to other established biomarkers.
The approach selects a greater fraction of patients who benefit from ICB therapy than those identified by existing biomarkers and encompasses both high TMB and functionally relevant gene mutations.
Documented Applications
Treatment of cancer patients, including those with non-small cell lung cancer (NSCLC), bladder cancer, skin cancer (including melanoma), renal cell carcinoma, colorectal cancer, esophagastric cancer, head and neck cancer, glioma, and breast cancer, by administering ICB therapy to individuals identified as responsive through the compound gene mutation signature.
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