Cancer immunotherapies have changed the landscape of cancer treatment during the past few decades. Among them, immune checkpoint inhibitors, which target PD-1, PD-L1 and CTLA-4, are increasingly used for certain cancers; however, this increased use has resulted in increased reports of immune-related adverse events (irAEs). These irAEs are unique and are different to those of traditional cancer therapies, and typically have a delayed onset and prolonged duration. IrAEs can involve any organ or system. These effects are frequently low grade and are treatable and reversible; however, some adverse effects can be severe and lead to permanent disorders. Management is primarily based on corticosteroids and other immunomodulatory agents, which should be prescribed carefully to reduce the potential of short-term and long-term complications. Thoughtful management of irAEs is important in optimizing quality of life and long-term outcomes.

Immune-related adverse events of checkpoint inhibitors.

Agents targeting programmed death receptor 1 (PD-1) or its ligand (PD-L1) have shown antitumor activity in the treatment of metastatic breast cancer (MBC). The aim of this study was to assess the activity of avelumab, a PD-L1 inhibitor, in patients with MBC. In a phase 1 trial (JAVELIN Solid Tumor; NCT01772004), patients with MBC refractory to or progressing after standard-of-care therapy received avelumab intravenously 10 mg/kg every 2 weeks. Tumors were assessed every 6 weeks by RECIST v1.1. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Membrane PD-L1 expression was assessed by immunohistochemistry (Dako PD-L1 IHC 73-10 pharmDx). A total of 168 patients with MBC, including 58 patients with triple-negative breast cancer (TNBC), were treated with avelumab for 2–50 weeks and followed for 6–15 months. Patients were heavily pretreated with a median of three prior therapies for metastatic or locally advanced disease. Grade ≥ 3 treatment-related AEs occurred in 13.7% of patients, including two treatment-related deaths. The confirmed objective response rate (ORR) was 3.0% overall (one complete response and four partial responses) and 5.2% in patients with TNBC. A trend toward a higher ORR was seen in patients with PD-L1+ versus PD-L1− tumor-associated immune cells in the overall population (16.7% vs. 1.6%) and in the TNBC subgroup (22.2% vs. 2.6%). Avelumab showed an acceptable safety profile and clinical activity in a subset of patients with MBC. PD-L1 expression in tumor-associated immune cells may be associated with a higher probability of clinical response to avelumab in MBC.

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Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study.

Purpose: The microenvironment of head and neck squamous cell carcinomas (HNSCC) is highly immunosuppressive. HNSCCs expressing elevated levels of PD-L1 have especially poor outcome. Exosomes that carry PD-L1 and suppress T-cell functions have been isolated from plasma of patients with HNSCC. The potential contributions of PD-L1+ exosomes to immune suppression and disease activity are evaluated. Experimental Design: Exosomes isolated from plasma of 40 HNSCC patients by size exclusion chromatography were captured on beads using anti-CD63 Abs, stained for PD-1 and PD-L1 and analyzed by flow cytometry. The percentages and mean fluorescence intensities (MFI) of PD-L1+ and PD-1+ exosome/bead complexes were correlated with the patients’ clinicopathologic data. PD-L1high or PD-L1low exosomes were incubated with activated CD69+ human CD8+ T cells ± PD-1 inhibitor. Changes in CD69 expression levels on T cells were measured. Patients’ plasma was tested for soluble PD-L1 (sPD-L1) by ELISA. Results: Levels of PD-L1 carried by exosomes correlated with patients’ disease activity, the UICC stage and the lymph node status (P = 0.0008–0.013). In contrast, plasma levels of sPD-L1 or exosome PD-1 levels did not correlate with any clinicopathologic parameters. CD69 expression levels were inhibited (P Conclusions: PD-L1 levels on exosomes, but not levels of sPD-L1, associated with disease progression in HNSCC patients. Circulating PD-L1+ exosomes emerge as useful metrics of disease and immune activity in HNSCC patients. Significance: Circulating PD-L1high exosomes in HNC patients’ plasma but not soluble PD-L1 levels associate with disease progression. Clin Cancer Res; 24(4); 896–905. ©2017 AACR.

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Clinical Significance of PD-L1+ Exosomes in Plasma of Head and Neck Cancer Patients

Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy for the management of solid tumor malignancies. In ovarian cancer, this is in part due to an immunosuppressive cytokine and cellular tumor microenvironment which suppresses adoptively transferred T cells. We engineered an armored CAR T cell capable of constitutive secretion of IL-12, and delineate the mechanisms via which these CAR T cells overcome a hostile tumor microenvironment. In this report, we demonstrate enhanced proliferation, decreased apoptosis and increased cytotoxicity in the presence of immunosuppressive ascites. In vivo, we show enhanced expansion and CAR T cell antitumor efficacy, culminating in improvement in survival in a syngeneic model of ovarian peritoneal carcinomatosis. Armored CAR T cells mediated depletion of tumor associated macrophages and resisted endogenous PD-L1-induced inhibition. These findings highlight the role of the inhibitory microenvironment and how CAR T cells can be further engineered to maintain efficacy.

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Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment.

Since the approval of anti-CTLA4 therapy (ipilimumab) for late-stage melanoma in 2011, the development of anticancer immunotherapy agents has thrived. The success of many immune-checkpoint inhibitors has drastically changed the landscape of cancer treatment. For some types of cancer, monotherapy for targeting immune checkpoint pathways has proven more effective than traditional therapies, and combining immunotherapy with current treatment strategies may yield even better outcomes. Numerous preclinical studies have suggested that combining immunotherapy with radiotherapy could be a promising strategy for synergistic enhancement of treatment efficacy. Radiation delivered to the tumor site affects both tumor cells and surrounding stromal cells. Radiation-induced cancer cell damage exposes tumor-specific antigens that make them visible to immune surveillance and promotes the priming and activation of cytotoxic T cells. Radiation-induced modulation of the tumor microenvironment may also facilitate the recruitment and infiltration of immune cells. This unique relationship is the rationale for combining radiation with immune checkpoint blockade. Enhanced tumor recognition and immune cell targeting with checkpoint blockade may unleash the immune system to eliminate the cancer cells. However, challenges remain to be addressed to maximize the efficacy of this promising combination. Here we summarize the mechanisms of radiation and immune system interaction, and we discuss current challenges in radiation and immune checkpoint blockade therapy and possible future approaches to boost this combination.

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Combining Immunotherapy and Radiotherapy for Cancer Treatment: Current Challenges and Future Directions.

PD-L1 is an immunoinhibitory molecule that suppresses the activation of T cells, leading to the progression of tumors. Overexpression of PD-L1 in cancers such as gastric cancer, hepatocellular carcinoma, renal cell carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, and bladder cancer is associated with poor clinical outcomes. In contrast, PD-L1 expression correlates with better clinical outcomes in breast cancer and merkel cell carcinoma. The prognostic value of PD-L1 expression in lung cancer, colorectal cancer, and melanoma is controversial. Blocking antibodies that target PD-1 and PD-L1 have achieved remarkable response rates in cancer patients who have PD-L1-overexpressing tumors. However, using PD-L1 as an exclusive predictive biomarker for cancer immunotherapy is questionable due to the low accuracy of PD-L1 immunohistochemistry staining. Factors that affect the accuracy of PD-L1 immunohistochemistry staining are as follows. First, antibodies used in different studies have different sensitivity. Second, in different studies, the cut-off value of PD-L1 staining positivity is different. Third, PD-L1 expression in tumors is not uniform, and sampling time and location may affect the results of PD-L1 staining. Therefore, better understanding of tumor microenvironment and use of other biomarkers such as gene marker and combined index are necessary to better identify patients who will benefit from PD-1/PD-L1 checkpoint blockade therapy.

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PD-L1 expression in human cancers and its association with clinical outcomes

The role of immunotherapy in combination with traditional treatment regime in improving the survival of cancer patients has attracted more and more attention. Especially the abscopal effect that describes the phenomenon of localized radiotherapy leading to regression of distant unirradiated tumors and the role of enhanced radiotherapy-induced immunogenic cell death and activation of immune system have become a focus of the studies. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known a powerful stimulator of the generation, migration and activation of antigen presenting cells such as dendritic cells (DC) and macrophages. Here we report a case of a 67-year-old refractory metastatic pancreatic cancer patient who obtained evident abscopal effect and survival benefit from concurrent localized radiotherapy and GM-CSF.

Abscopal effect of metastatic pancreatic cancer after local radiotherapy and granulocyte-macrophage colony-stimulating factor therapy.

BACKGROUND The inflammatory response indexes, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), have prognostic value for a variety of cancers. However, their prognostic value for small-cell lung cancer (SCLC) has been rarely reported. In this study, we monitored changes of NLR and PLR along with the clinical outcomes in patients with limited-stage and extensive-stage SCLC who received standard treatments. MATERIALS AND METHODS We retrospectively reviewed the records of 153 patients who were pathologically diagnosed with SCLC and collected their hematological data at different time points during disease and treatment process. Kaplan-Meier analysis and Cox proportional hazards models were used to determine the prognostic significance of NLR and PLR for overall survival (OS) and progression-free survival (PFS). RESULTS The median OS and PFS for all patients were 23.3 months and 11.0 months, respectively. After applying cutoffs of 3.2 for NLR and 122.7 for PLR, NLR, but not PLR, showed independent prognostic significance. High-NLR group was associated with shorter median OS (high vs low, 18.0 months vs 31.0 months, P<0.01) and shorter PFS (high vs low, 9.3 months vs 13.0 months, P=0.006). The cumulative 3-year OS rate and 3-year PFS rate of high-NLR group versus low-NLR group were 14.3% versus 37.3% and 8.6% versus 22.9%, respectively. In the multivariate analysis, both disease stage and NLR at diagnosis were independent prognostic factors for OS and PFS. CONCLUSION The NLR at diagnosis showed significant prognostic value for clinical outcomes in SCLC patients treated with chemoradiotherapy. As an effective biomarker of host immune status, NLR could potentially help monitoring disease progression and adjusting treatment plans.

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Xin Wang

Papers

PD-L1 expression in human cancers and its association with clinical outcomes

Abscopal effect of metastatic pancreatic cancer after local radiotherapy and granulocyte-macrophage colony-stimulating factor therapy.

Pretreatment neutrophil-to-lymphocyte ratio as a survival predictor for small-cell lung cancer.