Multi-target combinatory strategy to overcome tumor immune escape
Yingyan Yu()
Department of General Surgery of Ruijin Hospital, Shanghai Institute of Digestive Surgery, and Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Immune therapy has become the fourth approach after surgery, chemotherapy, and radiotherapy in cancer treatment. Many immune checkpoints were identified in the last decade since ipilimumab, which is the first immune checkpoint inhibitor to cytotoxic T-lymphocyte associated protein 4, had been approved by the US Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma in 2011. The use of several antibody drugs that target PD1/PD-L1 for various cancer treatments has been approved by the FDA. However, fewer people are benefitting from immune checkpoint inhibitor treatment in solid cancers. Approximately 80% of patients do not respond appropriately because of primary or acquired therapeutic resistance. Along with the characterization of more immune checkpoints, the combinatory treatment of multi-immune checkpoint inhibitors becomes a new option when monotherapy could not receive a good response. In this work, the author focuses on the combination therapy of multiple immune checkpoints (does not include targeted therapy of oncogenes or chemotherapy), introduces the current progression of multiple immune checkpoints and their related inhibitors, and discusses the advantages of combination therapy, as well as the risk of immune-related adverse events.
Unresectable malignant pleural mesothelioma, metastatic non-small cell lung cancer, hepatocellular carcinoma, advanced renal cell carcinoma, and unresectable or metastatic melanoma
Nivolumab
Opdivo®
15–25 d
Urothelial carcinoma, esophageal or GEJ cancer, metastatic gastric cancer and esophageal adenocarcinoma, advanced renal cell carcinoma, unresectable malignant pleural mesothelioma, esophageal squamous cell carcinoma, metastatic non-small cell lung cancer, hepatocellular carcinoma, and advanced melanoma
Pembrolizumab
Keytruda®
15–27 d
Renal cell carcinoma, triple-negative breast cancer, endometrial carcinoma, gastric cancer, esophageal or GEJ cancer, locally recurrent unresectable or metastatic triple-negative breast cancer, classical Hodgkin lymphoma, BCG-unresponsive bladder cancer, metastatic head and neck squamous cell carcinoma, metastatic urothelial carcinoma, advanced or metastatic gastric cancer or GEJ cancer, advanced melanoma, and solid tumors with specific genetic feature
PD1 (CD279)
Cemiplimab
Libtayo®
12–19 d
Advanced non-small cell lung cancer, advanced and metastatic basal cell carcinoma, and advanced skin squamous cell carcinoma
PD-L1 (CD274)
Atezolizumab
Tecentriq®
21–27 d
Unresectable hepatocellular carcinoma, metastatic non-small cell lung cancer, urothelial carcinoma, advanced bladder cancer, metastatic triple-negative breast cancer, and advanced melanoma
PD-L1
Durvalumab
Imfinzi®
17–21 d
Extensive-stage small cell lung cancer and advanced bladder cancer
n = 42MSI-H/dMMR tumors of colorectal and endometrial cancers
Manageable safety profiles with objective responses occurred in 32.5% of monotherapy, and 45.0% in combination cohort
[24]
Atkinson V, et al.
Phase I
PD1, LAG-3
Pembrolizumab, eftilagimod alpha
n = 24Metastatic melanoma
Well tolerated with overall response rate of 33% (in patients with pembrolizumab-refractory) to 50% (in patients with PD1 naïve)
[25]
McGregor BA, et al.
Phase II
PD1, CTLA4
Nivolumab and ipilimumab
n = 55Genitourinary cancers
The objective response rate was 6% to 37% in different cohorts, but 22 patients (40%) developed treatment-related grade 3 or higher toxicities
[26]
Powles T, et al.
Phase III
PD-L1, CTLA4
Durvalumab andtremelimumab
n = 346 (durvalumab)
Median overall survival was 14.4 months in the durvalumab monotherapy group, 15.1 months in the durvalumab plus tremelimumab group, while 12.1 months in the chemotherapy group. The study did not meet its coprimary endpoints
[27]
n = 342 (durvalumab plus tremelimumab)
n = 344 (chemotherapy)
Unresectable, locally advanced or metastatic urothelial carcinoma
Takahashi A, et al.
Phase II
PD1, CTLA4
Nivolumab andipilimumab
n = 57Unresectable advanced melanoma
The overall response rate 26.3% (with complete response 3.5% and partial response 22.8%), stable disease 21.1%, and progressive disease 52.6%. The adverse events of grade 3 or worse occurred in 56.1%
[28]
Gaudreau PO, et al.
Phase I/II
PD-L1, CTLA4
Durvalumab and tremelimumab
n = 40Non-small cell lung cancer
The trial is actively screening and enrolling patients
[29]
Ebata T, et al.
Phase I
PD-L1, IDO1
Atezolizumab and navoximod
n = 20Thymic cancer, pancreatic cancer, small-cell lung cancer, etc.
The treatment related adverse events of grade 3 were 10% to 30%. In stage 1, stable disease 50%, progressive disease 50%. In stage 2, stable disease 80%, progressive disease 20%
[30]
Hammers HJ, et al.
Phase I
PD1, CTLA4
Nivolumab and ipilimumab
n = 47Metastatic renal cell cancer
Manageable safety with objective response rate of 40.4%. The 2-year over survival was 67.3% and 69.6%
[31]
Jung KH, et al.
Phase I
PD-L1, IDO1
Atezolizumab, navoximod
n = 157Melanoma, pancreatic, prostate, etc.
The partial response or complete response was 9% to 11% with acceptable safety and tolerability
[32]
Wu RY, et al.
Pre-clinical
PD-L1, IDO1
Pembrolizumab or nivolumab, regorafenib
Animal experimentsMelanoma
Regorafenib alone caused a 45% tumor reduction. Anti-PD1 caused a slight tumor repression without statistical significance. The combined treatment significantly reduced for xenograft tumor volume and tumor weight
[33]
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