Robert E. Hawkins

E16061 Background: Markers of the systemic inflammatory response have prognostic value in ccRCC prior to starting treatment. Dynamic changes during therapy and their role in predicting prognosis are not well characterised. Methods: A retrospective analysis was conducted of a randomised, double-blind phase II study evaluating cediranib vs cediranib and saracatinib in patients with relapsed metastatic ccRCC (COSAK). Haemoglobin (Hb), neutrophil count (N0) platelet count (Plt), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were recorded at randomisation, 8-weeks and progression (PD). Change in mean values at each time point were compared. Baseline prognostic values for overall survival (OS) were assessed using Cox regression. Absolute changes in parameters were calculated at 8 weeks and PD, patients were grouped around the upper or lower quartile. Prognostic value of dynamic changes was assessed at 8 weeks and PD using the Kaplan-Meier method. Results: 138 patients were assessed; median OS was 12.0 months (IQR 8.1-15.6 months). Outcomes in the combination arm were similar to single agent arm (HR 1.28 (1.00–1.63)). On multivariate analysis at baseline, MSKCC score (0/1-2/≥3) (HR 2.52 (1.60 -3.96)), CRP ( < 10/≥10mg/L) (HR 1.72 (1.04 – 2.86)) and N0 ( < 7.5/≥7.5x109) (HR 2.38 (1.43 – 3.96)) were independent predictors of OS. Mean CRP was significantly different at baseline, 8 weeks and PD (64.9, 42.3 and 85.7 mg/L respectively, p < 0.001). Mean N0 count at baseline was 5.3 x109/L and was significantly higher 6.3x 109/L at PD (p < 0.001). Mean Hb at baseline, 8 weeks and PD was 11.5, 13.0 and 12.9g/L respectively (P < 0.001). A rise in CRP or N0 at 8 weeks was predictive of poor outcome ((HR 1.62 (1.10-2.56) and (HR 1.77 (1.19-2.61) respectively). A fall in Hb was predictive of poor outcome at 8 weeks (HR 1.75 (1.18-2.60)) and PD (HR 1.80 (1.20-2.76)). Conclusions: Dynamic changes occur in prognostic markers in patients receiving VEGF-targeted therapy in ccRCC and may predict OS.

Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the ‘Immunoscore’ into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).

439 Background: High-Dose Interleukin-2 (HD IL2) remains a good option for treatment of metastatic renal cancer. As a first-line treatment, in carefully selected patients, it can produce high rates of response ( OR 50%; CR 25%) (Shablak A et al., J Immunotherapy 2011, 34(1):107-122). Its use after targeted therapies is controversial and there are reports of increased toxicity, particularly an increased incidence of cardiovascular toxicity (and possibly a reduced response rate (Cho DC et al., J Immunotherapy 2009, 32(2):181-520). However, there is potential to use it either in patients who have failed treatment with targeted therapy or as a consolidation therapy after successful treatment with a targeted agent. Methods: Here we present the outcomes of 16 patients treated with first-line immunotherapy with HD-IL2 after targeted therapy: of these 8 had been treated after failure of 1-3 lines of targeted therapy and 8 have been treated as consolidation after initial response to sunitinib. The histological characteristics of the tumours all fitted into the “favourable” group as defined previously by us and all had high levels of expression of CAIX (> 80%). All had ECOG PS 0/1, a satisfactory baseline stress echo, an interval of at least 8 weeks from last dose of targeted agent to start of HD-IL2 and at most 2 organs of disease. Results: Toxicity is indistinguishable from that of patients without prior treatment and no patient needed inotropic support or admission to intensive care. The number of doses given per cycle was also similar to that in unpretreated patients. Overall the response rates are excellent – with 9/13 evaluable patients having RECIST defined response and 6/13 having a complete remission. To date none of the patients in complete remission have realpsed but follow up is relatively short with the longest being 24 months. The responses have been particularly striking following treatment with mTor inhibitors. Conclusions: Overall, HD IL2 can be given safely in carefully selected patients after targeted therapies. It appears to be effective as a salvage therapy and potentially as a consolidation therapy. Updated results will be presented.

Adoptive cellular therapy provides the promise of a potentially powerful general treatment for cancer. Although this is a complex and challenging field, there have been major advances in basic and translational research resulting in clinical trial activity that is now beginning to confirm this promise. However, these trials are also identifying new challenges and this review focuses on these clinical issues. For tumors such as melanoma, in which tumor-specific T cells can be readily identified and isolated, the adoptive transfer of "tumor-infiltrating lymphocytes" (TILs) already appears to offer significant patient benefit and this approach now warrants further development. Genetically engineered T cells offer a means to endow peripheral blood T cells with antitumor activity and in principle these techniques could allow the treatment of a wide range of cancers. Genetic engineering also offers the means to endow T cells with new properties and enhanced functions. There have been clear proof-of-principle trials showing responses with T cell receptor (TCR)-engineered T cells and this can be built on with further development. By contrast, other trials have produced significant toxicity related to expression of target antigen on normal tissue, particularly with enhanced receptors. The challenge ahead lies in understanding how to achieve the balance between targeted antitumor immune responses while avoiding toxicity associated with on-target destruction of antigen-expressing normal tissues. Cellular therapy of cancer will need continued preclinical evaluation as well as carefully designed clinical trials addressing the various issues. For these challenges to be fully assessed, and for progression to a widely used, effective and safe therapy, development as cooperative groups is an appropriate way forward.

T cells genetically engineered to express tumour-targeting receptors are attractive anti-cancer therapeutic agents. Human T cells engrafted with a chimeric receptor specific for the B-cell lymphoma antigen CD19 fused to the CD3zeta receptor (aCD19z) are functional in vitro. Current successful clinical protocols targeting melanoma use pre-conditioning chemotherapy in combination with T cells. This study demonstrated that interleukin-2 expanded aCD19z T cells combined with cyclophosphamide effectively treated five-day established Raji B-cell lymphoma in an immunocompromised model system with 50% of mice surviving >100 days. This observation strongly supports the combination of antibody targeted T cells with chemotherapy as a novel approach for the therapy of CD19(+) B-cell malignancies.

Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m² twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m² for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent.

The idiotypic determinants of B-cell lymphomas, formed by cell-specific rearrangement of the immunoglobulin genes, are unique and are therefore a suitable target against which to direct immunotherapy. Recent advances in our understanding of the fundamental mechanisms behind an effective immune response, coupled with advances in genetic engineering techniques, have led to a renewed interest in immunotherapy. Early clinical studies have confirmed the immunogenicity of the idiotypic antigen in patients with lymphoma. This review discusses the different methods of idiotypic vaccination currently under investigation in the clinic, including protein, genetic, and cellular vaccines. Protein vaccines are the most clinically advanced, with phase III trials of idiotypic protein linked to GM-CSF currently underway. DNA vaccines are easier to produce but to date only appear to be weakly immunogenic in man. Dendritic cell vaccines have shown promise but their use may be limited by the complexity of this approach. This review also highlights other approaches not yet in the clinic but that have shown promise in the laboratory, such as viral vaccines and T-cell therapy.