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KR-102961530-B1 - Neoadjuvant Immunotherapy with PD-L1 inhibitor in treating cancer

KR102961530B1KR 102961530 B1KR102961530 B1KR 102961530B1KR-102961530-B1

Abstract

The present invention relates to a method for treating a tumor or inhibiting tumor growth, comprising administering a therapeutically effective amount of a PD-L1 (programmed death-ligand 1) inhibitor (e.g., an anti-PD-L1 antibody) as neoadjuvant therapy to a cancer patient in need, followed by performing surgical resection. In particular, the present invention relates to a method of administering a PD-L1 inhibitor as a preoperative neoadjuvant therapy to a patient with surgically resectable upper gastrointestinal cancer, e.g., surgically resectable localized gastric cancer, esophageal cancer, or liver cancer. It has been confirmed that the administration of a PD-L1 inhibitor, particularly an anti-PD-L1 antibody, exhibits excellent therapeutic effects as a preoperative neoadjuvant therapy for patients with surgically resectable localized gastric cancer, esophageal cancer, and liver cancer.

Inventors

  • 김흥태
  • 이성영
  • 김성호

Assignees

  • 주식회사 이뮨온시아

Dates

Publication Date
20260508
Application Date
20240413

Claims (20)

  1. As a pharmaceutical composition for treating tumors or inhibiting tumor growth in patients with upper gastrointestinal cancer, A therapeutically effective amount of an anti-PD-L1 antibody comprising HCDR1, HCDR2, and HCDR3 contained in the heavy chain variable region (HCVR) of SEQ ID NO. 1 and LCDR1, LCDR2, and LCDR3 contained in the light chain variable region (LCVR) of SEQ ID NO. 2, which specifically binds to PD-L1, The above antibody is administered to the patient at a dose of 10 mg/kg to 30 mg/kg as neoadjuvant therapy prior to surgical resection of the tumor. Pharmaceutical composition.
  2. In paragraph 1, The above upper digestive tract cancer is stomach cancer, esophageal cancer, or liver cancer. Pharmaceutical composition.
  3. In paragraph 1, The above anti-PD-L1 antibody comprises a heavy chain variable region including HCDR1 of SEQ ID NO. 5, HCDR2 of SEQ ID NO. 6, and HCDR3 of SEQ ID NO. 7, and a light chain variable region including LCDR1 of SEQ ID NO. 8, LCDR2 of SEQ ID NO. 9, and LCDR3 of SEQ ID NO. 10. Pharmaceutical composition.
  4. In paragraph 3, The above light chain variable region comprises the amino acid sequence of SEQ ID NO. 2. Pharmaceutical composition.
  5. In paragraph 4, The amino acids at positions 3 and 5 of the above light chain variable region are the same as the amino acids at positions 3 and 5 of SEQ ID NO. 2. Pharmaceutical composition.
  6. In paragraph 4, The above heavy chain variable region comprises the amino acid sequence of SEQ ID NO. 1. Pharmaceutical composition.
  7. In paragraph 1, The above anti-PD-L1 antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO. 3 and a light chain having the amino acid sequence of SEQ ID NO. 4. Pharmaceutical composition.
  8. In paragraph 1, The above upper digestive tract cancer is resectable Pharmaceutical composition.
  9. In paragraph 1, The above upper digestive tract cancer is recurrent. Pharmaceutical composition.
  10. In paragraph 1, The above upper digestive tract cancer is metastatic Pharmaceutical composition.
  11. In paragraph 1, The above upper digestive tract cancer is surgically treated with a curative purpose. Pharmaceutical composition.
  12. In paragraph 2, The above gastric cancer is a gastric submucosal tumor or gastric adenocarcinoma (GC). Pharmaceutical composition.
  13. In paragraph 2, The above-mentioned esophageal cancer is esophageal squamous cell carcinoma (ESCC). Pharmaceutical composition.
  14. In paragraph 2, The above liver cancer is hepatocellular carcinoma (HCC). Pharmaceutical composition.
  15. In paragraph 1, As the above neoadjuvant therapy, an anti-PD-L1 antibody is administered at one or more doses prior to surgical resection of the tumor. Pharmaceutical composition.
  16. In paragraph 15, Each of the above doses is administered at intervals of 10 to 18 days. Pharmaceutical composition.
  17. In Paragraph 16, As the above neoadjuvant therapy, an anti-PD-L1 antibody is administered 2 to 6 times at intervals of 10 to 18 days prior to surgical resection of the tumor. Pharmaceutical composition.
  18. delete
  19. In paragraph 1, As the above neoadjuvant therapy, an anti-PD-L1 antibody is administered at a dose of 20 mg/kg Pharmaceutical composition.
  20. In paragraph 1, Surgical resection of the above tumor is performed between 11 and 84 days after the last administration of the anti-PD-L1 antibody. Pharmaceutical composition.

Description

Neoadjuvant Immunotherapy with PD-L1 inhibitor in treating cancer The present invention relates to a method for treating a tumor or inhibiting tumor growth, comprising administering a therapeutically effective amount of a PD-L1 (programmed death-ligand 1) inhibitor (e.g., anti-PD-L1 antibody IMC-001 or a biological equivalent thereof) as neoadjuvant therapy to a cancer patient and subsequently performing surgical resection. In particular, the present invention relates to a method of administering a PD-L1 inhibitor as a preoperative neoadjuvant therapy to a patient with surgically resectable upper gastrointestinal cancer, e.g., localized gastric cancer, esophageal cancer, or liver cancer. Immune evasion has recently garnered attention as one of the major characteristics of cancer, and its mechanisms are being elucidated through advancements in tumor immunology. Immune checkpoints are a concept that includes immunosuppressive regulatory molecules designed to prevent immune cells from attacking self cells; as one of the mechanisms by which tumor cells evade immune surveillance, these immune checkpoints are utilized to create an immunosuppressive environment within the tumor. Immunotherapy treatment strategies that achieve anticancer effects by activating the suppressed anti-tumor immune system have garnered attention, and representative immune checkpoint inhibitors, such as CTLA-4 inhibitors or PD-1/PD-L1 inhibitors, have recently demonstrated improved survival rates in various cancer types, establishing themselves as one of the standard immunotherapy treatments and presenting a new paradigm for cancer treatment (Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252-64, 2012). There are research results in lung cancer showing that the therapeutic effect of immune checkpoint inhibitors is higher as the number of tumor mutations increases, particularly as the number of clonal neoantigens increases, and that even if the total number of mutations is high, the therapeutic effect of PD-1 inhibitors is low when the number of subclonal neoantigens is high (McGranahan N, Furness AJ, Rosenthal R, et al: Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351:1463-9, 2016). In addition, considering that the number of subclonal neoantigens increases and the immunosuppressive microenvironment advances with tumor evolution as cancer progresses, it is possible that the therapeutic effect of immune checkpoint inhibitors is higher in early-stage localized cancer than in stage 4 metastatic cancer (Jamal-Hanjani M, Quezada SA, Larkin J, et al: Translational implications of tumor heterogeneity. Clin Cancer Res 21:1258-66, 2015; and Gil Del Alcazar CR, Huh SJ, Ekram MB, et al: Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition. Cancer Discov 7:1098-1115, 2017). Immun checkpoint inhibitors such as pembrolizumab, nivolumab, and ipilimumab have already been proven effective in treating unresectable locally advanced or metastatic gastric cancer, esophageal cancer, and hepatocellular carcinoma by showing improvements in survival rates or reductions in tumor size. Meanwhile, surgical resection is a treatment option for surgically treatable gastric, esophageal, and hepatocellular carcinoma. However, postoperative tumor recurrence is common, and early recurrence is also observed. Therefore, there is an urgent need for safe and effective therapies to treat surgically treatable cancers. FIG. 1 schematically illustrates the procedure of a clinical trial according to one embodiment of the present invention. FIG. 2 illustrates the clinical tumor response as a result of a clinical trial according to one embodiment of the present invention. PR indicates a partial response, and SD indicates a stable disease. FIG. 3 illustrates clinical tumor responses as a result of a clinical trial according to one embodiment of the present invention. mPR indicates a metabolic partial response, mSD indicates a metabolic stable disease, and mPD indicates a metabolic progressive disease. FIG. 4 illustrates a pathological response as a result of a clinical trial according to one embodiment of the present invention. The following detailed description of the invention will be described with reference to specific drawings (where drawings are available) regarding specific embodiments in which the invention may be practiced, but the invention is not limited thereto and is limited only by the appended claims to all scopes identical or equivalent to those described in the claims. It should be understood that various embodiments of the invention are different but need not be mutually exclusive. For example, specific shapes, structures, and characteristics described herein may be modified from one embodiment to another or realized by combining multiple embodiments without departing from the technical spirit and scope of the invention. Technical and academ