Treating cancer with a CCK receptor inhibitor and an immune checkpoint inhibitor
Inventors
Smith, Jill P. • Weiner, Louis • Jablonski, Sandra • Nadella, Sandeep • Wang, Shangzi
Assignees
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Publication Number
US-12453735-B2
Publication Date
2025-10-28
Expiration Date
Abstract
Provided herein are methods for treating a cholecystokinin (CCK) receptor-expressing cancerous tumor in a subject. The methods comprising administering to the subject an effective amount of a CCK receptor inhibitor and an effective amount of an immune checkpoint inhibitor, wherein the CCK receptor inhibitor inhibits one or more CCK receptors selected from the group consisting of a CCK-A receptor, a CCK-B receptor and a CCK-C receptor, and wherein the immune checkpoint inhibitor is a programmed cell death protein 1 (PD1) inhibitor or a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor.
Core Innovation
The document describes treating a cholecystokinin (CCK) receptor-expressing cancer using a CCK receptor inhibitor, including CCK-A, CCK-B, and/or CCK-C, exemplified by L364,718 and proglumide. The approach is linked to blocking CCK receptor activity in CCK receptor-expressing tumors, including pancreatic ductal adenocarcinoma.
The document states that CCKR blockade decreases tumor fibrosis and alters the tumor immune microenvironment. It increases CD4+ and CD8+ tumor-infiltrating lymphocytes and decreases Foxp3+ Tregs, thereby increasing sensitivity to immunotherapy.
The document further states that combination treatment improves anti-tumor outcomes when a CCK receptor inhibitor is combined with an immune checkpoint inhibitor targeting PD-1 and/or CTLA-4. It reports reduced tumor growth, reduced metastases, and increased survival for combination therapy compared with PD-1 alone, and links improved responsiveness to an immune checkpoint therapy context for pancreatic cancer models expressing CCK-B receptors.
Claims Coverage
The provided claim coverage includes one independent claim. The inventive features center on administering proglumide together with gemcitabine for a CCK receptor-expressing pancreatic tumor, where proglumide decreases fibrosis of the tumor.
Proglumide with gemcitabine for a CCK receptor-expressing pancreatic tumor with fibrosis decrease
A method for treating a cholecystokinin (CCK) receptor-expressing pancreatic tumor in a subject by administering an effective amount of proglumide and an effective amount of gemcitabine, wherein the proglumide decreases fibrosis of the tumor.
The core claim coverage requires a CCK receptor-expressing pancreatic tumor and administration of proglumide plus gemcitabine, with proglumide decreasing tumor fibrosis.
Stated Advantages
Decreases tumor fibrosis.
Increases sensitivity to immunotherapy.
Increases CD4+ and CD8+ tumor-infiltrating lymphocytes and decreases Foxp3+ Tregs.
Reduces tumor growth in the reported combination setting.
Reduces metastases in the reported combination setting.
Increases survival for combination therapy compared with PD-1 alone.
Documented Applications
Treatment of a cholecystokinin (CCK) receptor-expressing pancreatic tumor in a subject.
Treatment of pancreatic ductal adenocarcinoma.
Treatment of chemotherapy-resistant or gemcitabine-resistant/refractory pancreatic tumors.
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