Advances in cancer immunity have promoted a major breakthrough in the field of cancer therapy. This is mainly associated with the successful development of immune checkpoint inhibitors (ICIs) for multiple types of human tumors. Blockade with different ICIs, including programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, may activate the immune system of the host against malignant cells. However, only a subgroup of patients with cancer would benefit from immune checkpoint blockade. Some patients experience primary resistance to initial immunotherapy, and a majority eventually develop acquired resistance to ICIs. However, the mechanisms involved in the development of drug resistance to immune checkpoint blockade remain unclear. Recent studies supported that combination of ICIs and anti-angiogenic agents could be a promising therapeutic strategy for overcoming the low efficacy of ICIs. Moreover, through their direct anti-cancer effect by inhibiting tumor growth and metastasis, anti-angiogenic drugs reprogram the tumor milieu from an immunosuppressive to an immune permissive microenvironment. Activated immunity by immune checkpoint blockade also facilitates anti-angiogenesis by downregulating the expression of vascular endothelial growth factor and alleviating hypoxia condition. Many clinical trials showed an improved anti-cancer efficacy and prolonged survival following the addition of anti-angiogenic agents to ICIs. This review summarizes the current understanding and clinical development of combination therapy with immune checkpoint blockade and anti-angiogenic strategy.

The emergence and continuous development of immune checkpoint inhibitors (ICIs) therapy brings a revolution in cancer therapy history, but the major hurdle associated with their usage is the concomitant ICIs-related toxicities that present a challenge for oncologists. The toxicities may involve non-specific symptoms of multiple systems as for the unique mechanism of formation, which are not easily distinguishable from traditional toxicities. A few of these adverse events are self-limiting and readily manageable, but others may limit treatment, cause interruption and need to be treated with methylprednisolone or tumor necrosis factor-α (TNF-α) antibody infliximab, and even directly threaten life. Early accurate recognition and adequate management are critical to the patient's prognosis and overall survival (OS). Several biomarkers such as the expression of programmed cell death ligand 1 (PD-L1), tumor mutation burden (TMB), and microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) have been proved to be the predictors for anti-tumor efficacy of ICIs, but there is a gap in clinical needs for effective biomarkers that predict toxicities and help filter out the patients who may benefit most from these costly therapies while avoiding major risks of toxicities. Here, we summarize several types of risk factors correlated with ICIs-related toxicities to provide a reference for oncologists to predict the occurrence of ICIs-related toxicities resulting in a timely process in clinical practice.

Summary: Background: A recently emerging respiratory disease named coronavirus disease 2019 (COVID-19) has quickly spread across the world. This disease is initiated by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and uncontrolled cytokine storm, but it remains unknown as to whether a robust antibody response is related to clinical deterioration and poor outcome in laboratory-confirmed COVID-19 patients. Methods: Anti-SARS-CoV-2 IgG and IgM antibodies were determined by chemiluminescence analysis (CLIA) in COVID-19 patients from a single center in Wuhan. Median IgG and IgM levels in acute and convalescent-phase sera (within 35 days) for all included patients were calculated and compared among severe and nonsevere patients. Immune response phenotyping based on late IgG levels and neutrophil-to-lymphocyte ratio (NLR) was characterized to stratify patients with different disease severities and outcome. Laboratory parameters in patients with different immune response phenotypes and disease severities were analyzed. Findings: A total of 222 patients were included in this study. IgG was first detected on day 4 of illness, and its peak levels occurred in the fourth week. Severe cases were more frequently found in patients with high IgG levels, compared to those who with low IgG levels (51.8% versus 32.3%; p=0.008). Severity rates for patients with NLR ^hi IgG ^hi , NLR ^hi IgG ^lo , NLR ^lo IgG ^hi , and NLR ^lo IgG ^lo phenotype was 72.3%, 48.5%, 33.3%, and 15.6%, respectively (p<0.0001). Furthermore, severe patients with NLR ^hi IgG ^hi , NLR ^hi IgG ^lo had higher proinflammatory cytokines levels including IL-2, IL-6 and IL-10, and decreased CD4+ T cell count compared to those with NLR ^lo IgG ^lo phenotype (p<0.05). Recovery rate for severe patients with NLR ^hi IgG ^hi , NLR ^hi IgG ^lo , NLR ^lo IgG ^hi , and NLR ^lo IgG ^lo phenotype was 58.8% (20/34), 68.8% (11/16), 80.0% (4/5), and 100% (12/12), respectively (p=0.0592). Dead cases only occurred in NLR ^hi IgG ^hi and NLR ^hi IgG ^lo phenotypes. Interpretation: COVID-19 severity is associated with increased IgG response, and an immune response phenotyping based on late IgG response and NLR could act as a simple complementary tool to discriminate between severe and nonsevere COVID-19 patients, and further predict their clinical outcome. Research in context: Evidence before this study: Following SARS-CoV-2 infection, a high viral load and overexuberant host immune response involving innate and acquired immunity, simultaneously contributes to the pathogenesis of COVID-19 and organ injury. Through searching PubMed and the China National knowledge infrastructure databases up to March 12, 2020, no published article focusing on anti-SARS-CoV-2 IgG-mediated immune response was identified. Added value of this study: We evaluated antibody response within 35 days after symptom onset in laboratory-confirmed case with COVID-19 as one component of an overall exaggerated immune activation in severe SARS-CoV-2 infection, and developed an immune phenotyping based on late IgG response and NLR that could help determine disease severity and clinical outcome of COVID-19 patients. Severe cases were more frequently found in patients with high IgG levels, compared to those who with low IgG levels (51.8% versus 32.3%). Severity rates for patients with NLR ^hi IgG ^hi , NLR ^hi IgG ^lo , NLR ^lo IgG ^hi , and NLR ^lo IgG ^lo phenotype was 72.3%, 48.5%, 33.3%, and 15.6%, respectively. Furthermore, severe patients with NLR ^hi IgG ^hi , NLR ^hi IgG ^lo had higher proinflammatory cytokines levels including IL-2, IL-6 and IL-10, and decreased CD4+ T cell count compared to those with NLR ^lo IgG ^lo phenotype. Recovery rate for severe patients with NLR ^hi IgG ^hi , NLR ^hi IgG ^lo , NLR ^lo IgG ^hi , and NLR ^lo IgG ^lo phenotype was 58.8% (20/34), 68.8% (11/16), 80.0% (4/5), and 100% (12/12), respectively. Implications of all the available evidence: COVID-19 severity is associated with a high viral load and overexuberant IgG response. We developed an immune response phenotyping based on NLR and IgG that could act as a simple complementary tool to discriminate between severe and nonsevere COVID-19 patients and would be helpful in guiding clinical decision.

Immune checkpoint inhibitors (ICIs) have been applied to clinical practice and achieved significant therapeutic benefit in a variety of human malignancies. These drugs not only enhance the body’s antitumor immune response but also produce side effects called immune-related adverse events (irAEs). Although checkpoint inhibitor pneumonitis (CIP) has a low clinical incidence, it is likely to cause the delay or termination of immunotherapy and treatment-related death in some severe cases. An increasing number of CIP cases have been reported since 2015, which are attributed to the augmentation of approvals and uses of ICIs, but a comprehensive understanding of CIP is still lacking. This review focuses on the epidemiology, clinical characteristics, treatment strategies, and underlying mechanisms of CIP to strengthen the recognition of pulmonary toxicity among clinicians and researchers.

Immunotherapy, represented by immune checkpoint inhibitors (ICIs), has made a revolutionary difference in the treatment of malignant tumors, and considerably extended patients’ overall survival (OS). In the world medical profession, however, there still reaches no clear consensus on the optimal duration of ICIs therapy. As reported, immunotherapy response patterns, immune-related adverse events (irAEs) and tumor stages are all related to the diversity of ICIs duration in previous researches. Besides, there lacks clear clinical guidance on the intermittent or continuous use of ICIs. This review aims to discuss the optimal duration of ICIs, hoping to help guide clinical work based on the literature.