Dirk Jaeger

Localization and Density of Immune Cells in the Invasive Margin of Human Colorectal Cancer Liver Metastases Are Prognostic for Response to Chemotherapy

Analysis of tumor-infiltrating lymphocytes (TIL) in primary human colorectal cancer (CRC) by in situ immunohistochemical staining supports the hypothesis that the adaptive immune response influences the course of human CRC. Specifically, high densities of TILs in the primary tumor are associated with good prognosis independent of other prognostic markers. However, the prognostic role of TILs in metastatic CRC lesions is unknown, as is their role in response or resistance to conventional chemotherapy. We analyzed the association of TIL densities at the invasive margin of CRC liver metastases with response to chemotherapy and progression-free survival in a set of 101 large section samples. High-resolution automated microscopy on complete tissue sections was used to objectively generate cell densities for CD3, CD8, granzyme B, or FOXP3 positive immune cells. A predictive scoring system using TIL densities was developed in a training set and tested successfully in an independent validation set. TIL densities at the invasive margin of liver metastases allowed the prediction of response to chemotherapy with a sensitivity of 79% and specificity of 100%. The association of high density values with longer progression-free survival under chemotherapy was statistically significant. Overall, these findings extend the impact of the local immune response on the clinical course from the primary tumor also to metastatic lesions. Because detailed quantification of TILs in metastatic lesions revealed a strong association with chemotherapy efficacy and prognosis, we suggest that the developed scoring system may be used as a predictive tool for response to chemotherapy in metastatic CRC.

Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial

Summary Background There are few effective treatments for advanced urothelial carcinoma after progression following platinum-based chemotherapy. We assessed the activity and safety of nivolumab in patients with locally advanced or metastatic urothelial carcinoma who progressed after prior platinum-based therapy. Methods This phase 1/2 multicentre open-label study enrolled patients aged ≥18 years with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra unselected by programmed death ligand-1 (PD-L1). Tumour PD-L1 membrane expression was assessed. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or study treatment discontinuation, whichever occurred later. The primary endpoint was objective response rate by investigator assessment. All patients who received at least one dose of any study medication were analysed. Here we report an interim analysis of this ongoing trial. CheckMate 032 is registered with ClinicalTrials.gov, NCT01928394. Findings Between June 2014 and April 2015, 86 patients with metastatic urothelial carcinoma were enrolled and 78 were treated with nivolumab monotherapy. At data cutoff (March 24, 2016), minimum follow-up was 9 months. A confirmed investigator-assessed objective response was achieved in 19 (24·4%) of 78 patients (95% CI 15·3–35·4). Grade 3/4 treatment-related adverse events occurred in 17 (21·8%) of 78 patients, the most common being laboratory abnormalities: asymptomatic elevated lipase in four (5·1%) and asymptomatic elevated amylase three (3·8%) patients. Serious adverse events were reported in 36 (46·2%) of 78 patients. Two (2·6%) of 78 patients discontinued due to treatment-related adverse events (pneumonitis and thrombocytopenia) and subsequently died. Interpretation Nivolumab monotherapy was associated with significant and durable clinical responses and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data indicate a favourable benefit:risk profile for nivolumab and support further investigation of nivolumab monotherapy in advanced urothelial carcinoma.

Phase II Trial of Biweekly Infusional Fluorouracil, Folinic Acid, and Oxaliplatin in Patients With Advanced Gastric Cancer

PURPOSE To evaluate the toxicity and activity of infusional fluorouracil (FU), folinic acid (FA), and oxaliplatin, administered every 2 weeks in patients with metastatic gastric cancer. PATIENTS AND METHODS Forty-one previously untreated patients with measurable adenocarcinoma of the stomach were eligible for the study. Patients received FU 2.6 g/m(2) (24-hour continuous infusion), FA 500 mg/m(2) (2-hour intravenous infusion), and oxaliplatin 85 mg/m(2) (2-hour intravenous infusion) every 2 weeks for 6 weeks. Treatment was continued until progression of disease was observed. RESULTS All patients were assessable for toxicity and 37 of 41 patients were assessable for response. Patient characteristics were: sex (male, 28; female,13), median age 60 years (range, 20 to 77 years), and median Eastern Cooperative Oncology Group performance status of 1. Response was evaluated every 6 weeks. Of 37 assessable patients, one complete and 15 partial remissions were observed (overall response rate, 43%). Stable disease was observed in 12 patients (32%) and progressive disease in nine patients (24%). The median overall survival was 9.6 months. WHO grade 3 or 4 hematologic toxicities included neutropenia in two patients (4.9%) and thrombocytopenia in one patient (2.4%). Other WHO grade 3 or 4 toxicities included diarrhea in three patients (7.3%) and vomiting in two patients (4.9%). There were no cases of grade 3 peripheral neuropathy and no treatment-related deaths. CONCLUSION Biweekly fluorouracil, folinic acid, and oxaliplatin is active and well-tolerated in patients with advanced gastric cancer. Response rates, time to progression, and overall survival were comparable to those achieved with other combination chemotherapy regimens, including FOLFOX6, with significantly less toxicity.

Surgery for Recurrent Pancreatic Ductal Adenocarcinoma

Objective:This study evaluates the outcome of patients who underwent surgery for recurrent pancreatic cancer. Summary Background Data:Recurrence of pancreatic ductal adenocarcinoma occurs in up to 80% of pancreatic cancer patients within 2 years of a potential curative resection because, in most cases, occult (local and/or distant) micrometastases are present at the time of the initial resection. Methods:Thirty patients were operated for recurrent pancreatic cancer between October 2001 and April 2005. Median time between the initial resection and recurrence was 12.0 months. While 15 patients were resected, 15 patients either underwent palliative bypass or only exploration. Prospectively recorded data were analyzed retrospectively. Survival analysis was performed using Kaplan-Meier estimation and log-rank test. Results:The overall median survival of patients with recurrent disease was 29.0 months. After the first reresection/exploration for recurrent disease, the median survival was 11.4 months. There was a tendency of increased median survival in the group of patients undergoing resection (17.0 months) compared with the bypass/exploration group (9.4 months), although this difference was not significant (P = 0.084). In addition, patients with a prolonged interval (>9 months) from resection to recurrence were more likely to benefit from reresection compared with patients with recurrence within 9 months (median survival 17.0 vs. 7.4 months; P = 0.004). The in-hospital morbidity and mortality rate of resected patients was 20% and 6.7% compared with 13.3% and 0% of patients who underwent only exploration/palliative bypass. Conclusion:Resection for recurrent pancreatic cancer can be carried out safely. Further studies are required to address the question whether a subgroup of patients might actually benefit from this procedure.

Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer

Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.

Tumor-infiltrating lymphocytes in colorectal tumors display a diversity of T cell receptor sequences that differ from the T cells in adjacent mucosal tissue

Tumors from colorectal cancer (CRC) are generally immunogenic and commonly infiltrated with T lymphocytes. However, the details of the adaptive immune reaction to these tumors are poorly understood. We have accrued both colon tumor samples and adjacent healthy mucosal samples from 15 CRC patients to study lymphocytes infiltrating these tissues. We apply a method for detailed sequencing of T-cell receptor (TCR) sequences from tumor-infiltrating lymphocytes (TILs) in CRC tumors at high throughput to probe T-cell clones in comparison with the TCRs from adjacent healthy mucosal tissue. In parallel, we captured TIL counts using standard immunohistochemistry. The variation in diversity of the TIL repertoire was far wider than the variation of T-cell clones in the healthy mucosa, and the oligoclonality was higher on average in the tumors. However, the diversity of the T-cell repertoire in both CRC tumors and healthy mucosa was on average 100-fold lower than in peripheral blood. Using the TCR sequences to identify and track clones between mucosal and tumor samples, we determined that the immune response in the tumor is different than in the adjacent mucosal tissue, and the number of shared clones is not dependent on distance between the samples. Together, these data imply that CRC tumors induce a specific adaptive immune response, but that this response differs widely in strength and breadth between patients.

Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients

The immune response influences the clinical course of colorectal cancer (CRC). Analyzing the invasive margin of human CRC liver metastases, we identified a mechanism of immune cell exploitation by tumor cells. While two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10, CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5. CCR5 blockade in patient-derived functional in vitro organotypic culture models showed a macrophage repolarization with anti-tumoral effects. These anti-tumoral effects were then confirmed in a phase I trial with a CCR5 antagonist in patients with liver metastases of advanced refractory CRC. Mitigation of tumor-promoting inflammation within the tumor tissue and objective tumor responses in CRC were observed.

Targeting the Tumor Microenvironment: Focus on Angiogenesis

Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established. Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors (colorectal cancer, renal cell carcinoma, and breast cancer) and multiple myeloma. Here we illustrate important aspects in the interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and summarize derived targeted therapies.

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

Dalil Hannani, Marie Vétizou, David Enot, Sylvie Rusakiewicz, Nathalie Chaput, David Klatzmann, Melanie Desbois, Nicolas Jacquelot, Nadège Vimond, Salem Chouaib, Christine Mateus, James P Allison, Antoni Ribas, Jedd D Wolchok, Jianda Yuan, Philip Wong, Michael Postow, Andrzej Mackiewicz, Jacek Mackiewicz, Dirk Schadendorff, Dirk Jaeger, Alan J Korman, Keith Bahjat, Michele Maio, Luana Calabro, Michele WL Teng, Mark J Smyth, Alexander Eggermont, Caroline Robert, Guido Kroemer, Laurence Zitvogel

Diarrhea Is a Positive Outcome Predictor for Sorafenib Treatment of Advanced Hepatocellular Carcinoma

Objective: This study was performed to identify clinical predictors for better survival in patients with advanced hepatocellular carcinoma (HCC) under sorafenib treatment. Methods: Between December 2007 and January 2010, 46 patients with advanced HCC were treated with sorafenib until significant tumor progression or intolerable toxicity. We prospectively collected clinical baseline data as well as data on the incidence and severity of toxic side effects of sorafenib to be correlated with progression-free survival and overall survival (OS), respectively. Results: Only 26.1% (n = 12) of patients tolerated sorafenib without requiring dose reduction. The most frequent grade 3 toxicities were diarrhea (32.6%), hand-foot skin reaction (13.0%), fatigue (4.3%), and nausea/vomiting (2.2%). Eastern Cooperative Oncology Group performance status (p = 0.034) and portal vein infiltration (p = 0.021) significantly correlated with OS. Furthermore, we found a significant correlation between OS and appearance of grade 2 or 3 diarrhea with a median actuarial survival of 11.8 months (95% CI 6.9–16.6) compared to 4.2 months in patients with grade 0 or 1 diarrhea (95% CI 0.0–9.1; p = 0.009). In contrast, appearance of hand-foot skin reaction did neither correlate with progression-free survival nor with OS. Conclusion: Appearance of grade 2 or 3 diarrhea indicates a better OS of HCC patients undergoing sorafenib treatment.