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Checkpoint inhibitors are being added to standard-of-care chemotherapy in multiple clinical trials. Success has been reported in non–small and small cell lung carcinomas and urothelial, head and neck, gastric, and esophageal cancers, and promising results are already available in triple-negative breast and pancreatic malignancies. The potential mechanisms of synergy include immunogenic tumor cell death, antiangiogenesis, selective depletion of myeloid immunosuppressive cells, and lymphopenia, which reduces regulatory T cells and makes room for proliferation of effector T cells. However, chemotherapy regimens have not been optimized for such combinations, perhaps explaining some recent clinical trial disappointments. Approaches to make the most of chemoimmunotherapy include neoadjuvant and adjuvant schemes.Significance: Immunotherapy of cancer based on PD-1/PD-L1 blockade has prompted a revolution in cancer clinical management. Evidence in phase III clinical trials already supports combinations of immunotherapy with standard-of-care chemotherapy for a number of malignant diseases. This review focuses on such evidence and provides an overview of the potential synergistic mechanisms of action and the opportunities to optimize chemoimmunotherapy regimens.

Supplementary information regarding chemoimmunotehrapy clinical trials other than phase III or ongoing.

Purpose: Interleukin-8 (IL8) is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping protumoral vascularization and inflammation/immunity. We evaluated sequential levels of serum IL8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden.Experimental Design: IL8 levels were monitored by sandwich ELISAs in cultured tumor cells supernatants, tumor-xenografted mice serum, and in samples from 126 patients with cancer. We correlated IL8 serum levels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis.Results: IL8 concentrations correlated with the number of IL8-producing tumor cells in culture. In xenografted neoplasms, IL8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n = 16), renal cell carcinoma (RCC; n = 23), non–small cell lung cancer (NSCLC; n = 21), or hepatocellular carcinoma (HCC; n = 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n = 16; RCC, n = 23; HCC, n = 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n = 16) and immunomodulatory monoclonal antibodies (melanoma, n = 8). IL8 concentrations in urine (n = 18) were mainly elevated in tumors with direct contact with the urinary tract.Conclusions: IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance. Clin Cancer Res; 20(22); 5697–707. ©2014 AACR.

Supplementary Figure 4. Comparison of IL-8 serum concentrations with the serum concentration of IL-6 and c-reactive protein (CRP) in available samples from 14 melanoma and 19 RCC patients from Figure 2A. (**, p

Supplementary Figures S1-S3 and Supplementary Tables S1-S2.

Supplementary Figure 1B. Time course of the serum concentrations of IL-8 (lower panels) and tumor volume (upper panels) in Rag2-/-IL2Rγc-/- mice xenografted with the indicated cell lines. Individual mice are represented and at the time point indicated by the arrow the tumor was surgically removed. Serum IL-8 concentrations are depicted at 2h and 24h after surgery.

Supplementary Figure 2. Serum IL-8 levels before (day -1) and after (day 5-7) disease-reduction surgery of 7 patients: 1 hepatocellular carcinoma (HCC); 2 colorectal carcinoma (CRC); 1 pancreatic cancer (PC); 3 renal cell carcinoma (RCC).

Supplementary Figure 3. Quantitative RT-PCR analyses of the mRNA encoding IL-8 in malignant cells from the biopsy of three melanoma patients. The serum IL-8 levels at the time of the biopsy from each patient is provided under the graph.

Supplementary Table 2. Surgical patient description 2

Supplemental Legend

Supplementary Table 1. Patient description 1