Announcement of the 2018 Nobel Prize in Physiology or Medicine by Professor Thomas Perlmann, Secretary of the Nobel Committee for Physiology or Medicine, on 1 October 2018. It was awarded jointly to James P. Allison and Tasuku Honjo “for their discovery of cancer therapy by inhibition of negative immune regulation.” This news is really exciting, not only because immunotherapy is now a hot topic at home and abroad, but also because its emergence has pushed the anti-cancer history to a new milestone. There is no doubt that the clinical use of “inhibitory immune checkpoints” for cancer treatment is the most important advance over the past 10 years. Blocking antibodies against the co-suppressor immune receptor PD-1 (or its ligand PD-L1) and CTLA-4 (cytotoxic T lymphocyte-associated protein 4) as a single drug has shown to be powerful in many cancers, including melanoma, renal cell carcinoma, and non-small cell lung cancer, some of the patients even treated. In the latest issue of Science Immunology, the new combination of immunotherapy has been strongly listed on the front page with “Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8+T cell dysfunction and maintain memory phenotype”.
Introduction of PD-1 and PD-L1
PD-1, programmed death 1, also known as CD279, is an important immunosuppressive molecule belonging to the CD28 superfamily and is a transmembrane protein encoded by the PDCD1 gene. PD-1 is a protein which express only induced. Specifically, T cells hardly express PD-1 when they are not activated, and they induce expression of PD-1 only after T cell activation. In addition, PD-1 is also expressed in activated B cells, natural killer cells (NK cells), monocytes, and part of tumor cells. PD-1 has two endogenous ligands: PD-L1 (also known as B7-H1 and CD 274) and PD-L2 (also known as B7-DC and CD273). PD-L1 (B7-H1) belongs to the B7 family and is often up-regulated on the surface of human tumor cells. PD-L1 is widely expressed, including expression in cancer cells and tumor infiltrating macrophages. The expressed PD-L1 induces apoptosis of anti-tumor T lymphocytes and promotes tumor growth. PD-L2 is mainly expressed by antigen presenting cells.
PD-1 binds to a ligand and transmits an inhibitory signal that reduces T cell proliferation. Inhibition of PD-1 receptors can overcome immune resistance in the tumor microenvironment. It has been reported that activated PD-1 binds to PD-L1, which facilitates the dephosphorylation of CD28 by activated PD-1, which can terminate CD28 signaling and regulate immunosuppressive function. Therefore, the role of the CD28/B7 (CD86 or CD80) pathway is important for PD-1 inhibitors. The PD-1 inhibitors are mainly targeted at PD-1 and PD-L1 currently, there are no PD-L2 inhibitors listed and clinically under investigation.
Fig 1. Mechanism of CTLA-4, PD-1 in cancer
Anti-PD-1/PD-L1 monoclonal antibody development and patent barriers
Although Professor Bian Youyou discovered PD-1 as early as 1992, it was until 2014 that pembrolizumab and nivolumab were officially approved by the FDA as drugs for the treatment of melanoma. It took 22 years from the discovery of PD-1 to clinical of PD-1 antibody inhibitors. PD-1/PD-L1 inhibitor is an immunological checkpoint monoclonal antibody, and it is a hot spot in tumor immunotherapy research in recent years. The listed nivolumab and pembrolizumab are PD-1 inhibitors, mainly used for the treatment of melanoma and non-small cell lung cancer, and for the treatment of renal cell carcinoma, bladder cancer, Hodgkin’s lymphoma until in large-scale clinical trials. PD-L1 inhibitor atezolizumab (trade name Tecentriq), durvalumab (trade name Imfinzi) and avelumab (trade name Bavencio) have been approved for the treatment of urethral epithelium cancer, several other drugs are still in early clinical trials. On September 28, 2018, the FDA approved the launch of Libtayo (cemiplimab-rwlc), jointly developed by Sanofi and Regeneron, which can be used for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. This is also the third anti-PD-1 antibody approved for approval by the FDA.
|Phase||Code Name (CD)||Organization||Condition|
|Clinical||[89Zr]BMS-936558;[89Zr]Nivolumab||Bristol-Myers Squibb (Originator);||Diagnostics; Cancer|
|Phase I||2661380; AMP-224; B7-DCIg||National Cancer Institute; MedImmune (Originator); GlaxoSmithKline;||Cancer, colorectal metastatic; Cancer|
|Phase I||MGD-013||MacroGenics (Originator);||Cancer, solid tumor; Hematologic-blood cancer|
|Phase I||PF-06801591||Pfizer (Originator);||Lymphoma, Hodgkin’s (classical); Cancer, solid tumor|
|Phase I||XmAb-20717||Xencor (Originator);||Cancer, head and neck (squamous cell carcinoma); Cancer, gastrointestinal; Cancer, liver (hepatocellular carcinoma); Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, endometrium; Melanoma; Triple negative breast cancer; Cancer, colorectal; Cancer, kidney (renal cell carcinoma, clear cell); Cancer, bladder (urothelial carcinoma)|
|Phase I||BI-754091||Boehringer Ingelheim (Originator);||Cancer, bladder; Cancer, breast; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Lymphoma, follicular; Cancer, kidney (renal cell carcinoma); Cancer, ovary; Cancer, stomach; Melanoma; Cancer, colorectal|
|Phase I||CC-90006||AnaptysBio (Originator); Celgene;||Psoriasis, plaque; Psoriasis|
|Phase I||ABBV-181||AbbVie (Originator);||Cancer, lung (small cell) (SCLC); Cancer, solid tumor; Cancer, ovary; Cancer, colorectal|
|Phase I||GSL-010; WBP-3055||WuXi PharmaTech (Originator); WuXi PharmaTech; Harbin Gloria Pharmaceuticals (Originator);||Cancer|
|Phase I||AK-104||Akeso Biopharma (Originator);||Cancer, solid tumor|
|Phase I||LZM-009||Livzon (Originator);||Cancer, solid tumor|
|Phase I||Sym-021||Symphogen (Originator);||Lymphoma; Cancer, solid tumor|
|Phase I||AB-122||Arcus Biosciences (Originator);||Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, kidney (renal cell carcinoma); Cancer, ovary; Triple negative breast cancer; Digestive-gastrointestinal cancer|
|Phase I||Pd-1-pik||Huashan Hospital of Fudan University (Originator);||Glioblastoma multiforme|
|Phase I||CS-1003||CStone Pharmaceuticals (Originator);||Cancer, solid tumor|
|Phase I||HLX-10||Henlix Biotech (Originator);||Cancer, solid tumor|
|Phase I||MEDI-5752||MedImmune (Originator);||Cancer, solid tumor|
|Phase I||RO-7121661||Roche (Originator);||Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Melanoma|
|Phase I/II||JNJ-3283; JNJ-63723283||Janssen Research & Development (Originator);||Cancer, bladder (urothelial carcinoma, transitional cell); Multiple myeloma; Cancer, solid tumor; Cancer, prostate (castration-resistant), metastatic|
|Phase||Code Name (CD)||Generic Name
|Phase I/II||GSK-2302025A||GlaxoSmithKline (Originator);||Melanoma, metastatic|
|Phase I/II||AGEN-2034w||AGEN-2034||Ludwig Institute for Cancer Research (Originator); Recepta Biopharma; Memorial Sloan-Kettering Cancer Center (Originator); Agenus (Originator);||Cancer, cervix; Cancer, solid tumor; Infections|
|Phase I/II||AK-105||Akeso Biopharma (Originator);||Lymphoma, Hodgkin’s (classical); Cancer, solid tumor|
|Phase II||CT-011; MDV-9300||Pidilizumab||National Cancer Institute; CureTech (Originator); Hadassah Medical Organization; Dana-Farber Cancer Institute;||Cancer, breast metastatic; Leukemia, acute myeloid; Hepatitis C (HCV); Cancer, liver (hepatocellular carcinoma); Cancer, prostate; Melanoma, metastatic; Multiple myeloma; Lymphoma, diffuse large B-cell; Lymphoma, follicular; Cancer, colorectal metastatic; Cancer, kidney (renal cell carcinoma); Glioma; Cancer, pancreas (adenocarcinoma)|
|Phase II||CBT-501; GB-226||Genolimzumab||Genor Biopharma (Originator); CBT Pharmaceuticals;||Cancer, liver (hepatocellular carcinoma); Cancer, solid tumor; Lymphoma, primary mediastinal large B-cell; T-cell lymphoma, peripheral; Sarcoma, alveolar soft part|
|Phase II||INCMGA-00012; MGA-012||Incyte; Incyte (Originator); MacroGenics (Originator);||Cancer, merkel cell; Cancer, anus (squamous cell); Cancer, bladder; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Cancer, colorectal metastatic; Cancer, kidney (renal cell carcinoma); Melanoma|
|Phase II/III||BCD-100||Biocad (Originator);||Cancer, lung (non-small cell) (NSCLC); Cancer, kidney (clear cell carcinoma); Melanoma|
|Phase II/III||BMS-986213||Relatlimab/nivolumab||Bristol-Myers Squibb (Originator);||Cancer, gastroesophageal junction (adenocarcinoma); Cancer, gastrointestinal; Cancer, solid tumor; Cancer, stomach; Melanoma|
|Phase III||ANB-011; TSR-042; WBP-285; P0GVQ9A4S5 (UNII code)||Dostarlimab (Prop INN; USAN)||Tesaro; AnaptysBio (Originator);||Cancer, ovary (epithelial); Cancer, liver; Carcinoma, primary peritoneal (ovarian); Malignant mixed mullerian tumor (MMMT) of the uterus and adnexa; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Primary malignant mixed müllerian tumor of the ovary; Cancer, ovary; Cancer, fallopian tube|
|Phase III||PDR-001||Spartalizumab (Rec INN)||Novartis (Originator);||Neuroendocrine cancer; Cancer, liver (hepatocellular carcinoma); Cancer, nasopharynx; Multiple myeloma; Cancer, lung (non-small cell) (NSCLC); Cancer, solid tumor; Lymphoma, diffuse large B-cell; Cancer, colorectal metastatic; Cancer, ovary; Melanoma; Triple negative breast cancer|
|Phase III||HR-301210; INCSHR-01210; SHR-1210||Camrelizumab (Rec INN)||Affiliated Hosp Acad Milit Science PLA; Atridia; Jiangsu Hengrui (Originator);||Cancer, hepatobiliary; Osteosarcoma; Lymphoma, Hodgkin’s (classical); Cancer, liver (hepatocellular carcinoma); Cancer, nasopharynx; Lymphoma, extranodal NK-T-cell ; Cancer, breast; Soft tissue sarcoma; Cancer, lung (non-small cell) (NSCLC); Cancer, colorectal metastatic; Cancer, stomach; Melanoma; Esophageal carcinoma (squamous cell); Cancer, lung (small cell) (SCLC) (extensive)|
Problems and prospects
According to incomplete statistics, more than 800 clinical trials around the world are exploring the anti-tumor effects of PD-1/PD-L1 inhibitors, which fully demonstrates the degree of acceptance of PD-1/PD-L1 inhibitors. Therefore, this is the statement that the PD-1/PD-L1 inhibitor is regarded as a “medicine”. However, although PD-1/PD-L1 inhibitors have been used in cancer treatment indications continue to increase, which has brought new hopes to many cancer patients. But it should be soberly realized that at present, only about 20% to 40% of patients actually benefit from this expensive treatment. Among the approved indications for PD-1/PD-L1 inhibitors, only patients who meet certain conditions may benefit from treatment. The precise treatment of PD-1/PD-L1 inhibitors still has a long way to go. In addition, even in patients who are effective for PD-1/PD-L1 inhibitors, most of them will inevitably develop resistance after receiving treatment for a period of time. Several clinical trials such as MYSTIC and IMvigor211 related to PD-1/PD-L1 inhibitors have not continued to be invincible, but have all failed. This shows that the PD-1/PD-L1 inhibitor is not a panacea. The well-known oncology journal Lancet Oncology also called for the return of rationality to PD-1/PD-L1 inhibitors.
Therefore, it is necessary to explore how to cooperate with various “weapons” such as surgery, interventional therapy, chemotherapy, radiotherapy, and targeted therapy to continuously improve the therapeutic effect of tumors. We expected more PD-1 (or PD-L1) inhibitors to show excellent results at immune checkpoints in reactivating the adaptive or innate immunity for defeating cancers.
1. Veillette, A., & Davidson, D. (2018). Developing combination immunotherapies against cancer that make sense. Science immunology, 3(29), eaav1872.
2. Sunshine, J., & Taube, J. M. (2015). Pd-1/Pd-L1 Inhibitors. Current opinion in pharmacology, 23, 32-38.
3. Hao, C., Tian, J., Liu, H., Li, F., Niu, H., & Zhu, B. (2017). Efficacy and safety of anti-PD-1 and anti-PD-1 combined with anti-CTLA-4 immunotherapy to advanced melanoma: A systematic review and meta-analysis of randomized controlled trials. Medicine, 96(26).