Reviews on the research progress of PD-1/PD-L1 inhibitors for t

  • The general

    Triple-negative breast cancer (TNBC) refers to breast cancer with negative expression of human epidermal growth factor receptor-type 2 (Her-2), estrogen receptor (ER) and progesterone receptor (PR).

    TP53 deletion and somatic cell copy number mutation are common in TNBC, so there is obvious genetic instability, which is more immunogenic than other types of breast cancer. At present, the main treatment for advanced TNBC is chemotherapy, and the 5-year survival rate of patients is less than 30%. TNBC patients are in need of innovative treatments to reduce the recurrence and mortality of the disease.

    In recent years, immunotherapy, especially monoclonal antibody PD-1 targeting programmed cell death protein 1 (PD-1) and its programmed death ligand 1, PD-1 /PD-L1 inhibitor has become a hot spot for the treatment of malignant tumors. Studies have found that PD-L1 is highly expressed in a variety of cancer cells, including melanoma, non-small cell carcinoma, ovarian cancer, and breast cancer. PD-1/PD-L1 inhibitors are used in a variety of cancer treatments in clinical trials and showedsome effects. Here in this article, reviews on the research progress of PD-1/PD-L1 inhibitors in the treatment of TNBC were given.

    The background

    PD-1/PD-L1 pathway and tumor immunotherapy PD-1 is localized on the PDCD1 gene and belongs to the CD28 family. It is mainly expressed on the surface of immune cell membranes such as activated T cells, B cells and NK cells, and is also expressed on the surface of some tumor cells. It participates in immunotranslation and exerts an immunosuppressive effect, and its ligands are PD-L1 (CD274 or B7-H1) and PD-L2 (CD273 or B7-DC).

    PD-L1 is a transmembrane protein consisting of 290 amino acid subunits, mainly expressed in mature CD4+ cells, CD8+ T cells, B cells, monocytes, macrophages, dendritic cells and other immune cells, as well as high expression on the surface of various tumor cells; about 20-30% of breast cancers express PD-L1, more common in TNBC; PD-L2 is a transmembrane protein composed of 274 amino acid residues, but only expressed on macrophages, dendrites Cells and some B cell subsets and have limited effect.

    PD-L1 regulates organ-specific tolerance in normal tissues and mediates immune escape of tumor cells in tumor tissues. The PD-1/PD-L1 pathway may assist tumor immune escape by inducing T cell tolerance, inhibiting T cell proliferation, inhibiting cytokine secretion, and impeding antigen presentation. Blocking the PD-1/PD-L1 signaling pathway and increasing the T cell immune effect has become an important means of anti-tumor immunotherapy.

    Some study cases

    The study about treatment TNBC with PD-1 Inhibitors and treatment with Pembrolizumab isa Multicenter, Non-randomized Phase Ib Study. (KEYNOTE-12 published data on the treatment of TNBC with PD-1 immunotherapy, keytruda (Pembrolizumab).

    In 111 patients with TNBC, the positive rate of PD-1 was 58.6%, of which 32 patients were involved in the safety and anti-tumor activity evaluation of Pembrolizumab. Treatment-related adverse reactions included joint pain (18.8%), fatigue (18.8%), muscle pain (18.8%), nausea (15.6%), and 5 (15.6%) patients developed ≥3 toxicity and treatment-related death. Twenty-seven patients underwent antitumor activity assessment with an overall response rate (ORR) of 18.5%, including 1 complete response (CR), 4 partial remission (PR), 7 stable disease (SD), and median progression-free survival. Median progression-free survival (PFS) was 1.9 months and the median overall survival (OS) was 10.2 months.

    In another phase II clinical study, KEYNOTE-086, Pembrolizumab, as a first-line treatment for PD-L1 positive metastatic TNBC, demonstrated significant efficacy and better tolerance, with an ORR of 23%, CR4%, PR19%, and SD17%. The PFS was 2.1 months and the median reaction time was 8.4 months.

    An ongoing phase III study of KEYNOTE-119 divided patients with metastatic TNBC who had been treated with anthracycline or paclitaxel and disease progression in a 1:1 ratio, randomized into either the Pembrolizumab treatment group or the single-agent chemotherapy group ( including capecitabine, eribulin, gemcitabine or vinorelbine).

    The study compared OS, ORR, disease control rate (DCR), PFS, and overall response rates in both groups and is set to be completed in May 2019. Another randomized, double-blind, placebo-controlled phase III clinical trial (KEYNOTE-355) included 858 patients with metastatic TNBC who have not received treatment or have a treatment interval greater than 6 months. The study compared the efficacy and safety indicators of total remission rate, remission, and disease control rate between Pembrolizumab combined with cytotoxic drugs and placebo combined with cytotoxic drugs. It is expected to be completed in this November 2019.

    TNBC treatment with Nivolumab

    In a phase II clinical study, TONIC randomized 50 patients with metastatic TNBC who underwent ≤3 line palliative care and disease progression to 5 groups, receiving 2 weeks of induction therapy, including radiotherapy, Doxorubicin (15 mg·w-1), oral cyclophosphamide (50 mg·d-1), cisplatin (40 mg·m-2·w-1), and a blank control group, followed by treatment with 3 mg·kg-1 Nivolumab. The results showed an ORR of 22%, including 1 (2%) CR, 11 (22%) PR, and 1 (2%) SD, with a clinical benefit rate of 26% and a median response time of 10.9 months. Initial results suggest that patients receiving treatment with doxorubicin or cisplatin may be able to achieve better therapeutic outcomes.

    To be continued in Part Two…