Search

US-12624107-B2 - Cancer immunotherapy by disrupting PD-1/PD-L1 signaling

US12624107B2US 12624107 B2US12624107 B2US 12624107B2US-12624107-B2

Abstract

The disclosure provides a method for immunotherapy of a subject afflicted with cancer, comprises administering to the subject a composition comprising a therapeutically effective amount of an antibody that inhibits signaling from the PD-1/PD-L1 signaling pathway. This disclosure also provides a method for immunotherapy of a subject afflicted with cancer comprising selecting a subject that is a suitable candidate for immunotherapy based on an assessment that the proportion of cells in a test tissue sample from the subject that express PD-L1 on the cell surface exceeds a predetermined threshold level, and administering a therapeutically effective amount of an anti-PD-1 antibody to the selected subject. The invention additionally provides rabbit mAbs that bind specifically to a cell surface-expressed PD-L1 antigen in a FFPE tissue sample, and an automated IHC method for assessing cell surface expression in FFPE tissues using the provided anti-PD-L1 Abs.

Inventors

  • John P. Cogswell
  • Stacie M. Goldberg
  • Ashok K GUPTA
  • Maria Jure-Kunkel
  • Xi-Tao Wang
  • Jon M. Wigginton

Assignees

  • BRISTOL-MYERS SQUIBB COMPANY

Dates

Publication Date
20260512
Application Date
20250429

Claims (6)

  1. 1 . A method of treating a renal cell carcinoma in a human subject in need thereof, comprising administering to the subject 3 mg/kg of nivolumab and 1 mg/kg of ipilimumab every 3 weeks for 4 cycles, followed by subsequently administering the nivolumab alone.
  2. 2 . The method of claim 1 , wherein the renal cell carcinoma is advanced.
  3. 3 . The method of claim 1 , further comprising administering to the subject an anti-cancer agent.
  4. 4 . The method of claim 3 , wherein the anti-cancer agent comprises a chemotherapy.
  5. 5 . The method of claim 2 , further comprising administering to the subject an anti-cancer agent.
  6. 6 . The method of claim 5 , wherein the anti-cancer agent comprises a chemotherapy.

Description

REFERENCE TO EARLIER FILED APPLICATIONS This application is a continuation of U.S. application Ser. No. 18/662,447, filed on May 13, 2024, which is a continuation of U.S. application Ser. No. 18/052,099, filed on Nov. 2, 2022, which is a continuation of U.S. application Ser. No. 16/827,580, filed on Mar. 23, 2020, which is a continuation of U.S. application Ser. No. 16/231,211, filed on Dec. 21, 2018 (issued as U.S. Pat. No. 10,604,575 on Mar. 31, 2020), which is a division of U.S. application Ser. No. 16/006,365, filed Jun. 12, 2018 (issued as U.S. Pat. No. 10,316,090 on Jun. 11, 2019), which is a continuation of U.S. application Ser. No. 14/950,748, filed Nov. 24, 2015 (issued as U.S. Pat. No. 10,072,082 on Sep. 11, 2018), which is a division of U.S. application Ser. No. 13/892,671, filed May 13, 2013 (issued as U.S. Pat. No. 9,212,224 on Dec. 15, 2015), which claims the benefit of U.S. Provisional Application No. 61/647,442, filed May 15, 2012, and U.S. Provisional Application No. 61/790,747, filed Mar. 15, 2013, all of which are incorporated herein by reference in their entireties. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA EFS-WEB The content of the electronically submitted sequence listing (Name: 3338_063000L_SequenceListing_ST26.xml, Size: 35,859 bytes; and Date of Creation: May 2, 2025) is incorporated herein by reference in its entirety. Throughout this application, various publications are referenced in parentheses by author name and date, or by Patent No. or Patent Publication No. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated in their entireties by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. However, the citation of a reference herein should not be construed as an acknowledgement that such reference is prior art to the present invention. FIELD OF THE INVENTION This invention relates to methods for immunotherapy of a cancer patient comprising administering to the patient antibodies that disrupt the PD-1/PD-L1 signaling pathway. A biomarker may be used as part of this treatment for identifying suitable patients for immunotherapy and for predicting the efficacy of anti-PD-1 treatment. BACKGROUND OF THE INVENTION Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system (Sjoblom et al., 2006). Although an endogenous immune response to cancer is observed in preclinical models and patients, this response is ineffective, and established cancers are viewed as “self” and tolerated by the immune system. Contributing to this state of tolerance, tumors may exploit several distinct mechanisms to actively suppress the host immune response (Topalian et al., 2011; Mellman et al., 2011). Among these mechanisms, endogenous “immune checkpoints” that normally terminate immune responses to mitigate collateral tissue damage can be co-opted by tumors to evade immune destruction. Intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including the development of the anti-CTLA-4 antibody (Ab), ipilimumab (YERVOY®), for the treatment of patients with advanced melanoma (Hodi et al., 2010). Programmed Death-1 (PD-1) is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. PD-1 is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA. Two cell surface glycoprotein ligands for PD-1 have been identified, Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2), that are expressed on antigen-presenting cells as well as many human cancers and have been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1 (Freeman et al., 2000; Latchman et al., 2001). Unlike CTLA-4, PD-1 primarily functions in peripheral tissues where activated T-cells may encounter the immunosuppressive PD-L1 (B7-H1) and PD-L2 (B7-DC) ligands expressed by tumor and/or stromal cells (Flies et al., 2011; Topalian et al., 2012a). Inhibition of the PD-1/PD-L1 interaction mediates potent antitumor activity in preclinical models (U.S. Pat. Nos. 8,008,449 and 7,943,743), and the use of Ab inhibitors of the PD-1/PD-L1 interaction for treating cancer has entered clinical trials (Brahmer et al., 2010; Flies et al., 2011; Topalian et al., 2012b; Brahmer et al., 2012). The promise of the emerging field of personalized medicine is that advances in pharmacogenomics will increasing be used to tailor therapeutics to defined sub-populations, and ultimately, individual patients in order to enhance efficacy and minimize adverse effects. Recent successes include, for example, the development of imatini