Henk Mallo

Predictive factors for severe toxicity of sunitinib in unselected patients with advanced renal cell cancer

Sunitinib has been registered for the treatment of advanced renal cell cancer (RCC). As patient inclusion was highly selective in previous studies, experience with sunitinib in general oncological practice remains to be reported. We determined the efficacy and safety of sunitinib in patients with advanced RCC included in an expanded access programme. ECOG performance status >1, histology other than clear cell and presence of brain metastases were no exclusion criteria. Eighty-two patients were treated: 23% reached a partial response, 50% had stable disease, 20% progressed and six patients were not evaluable. Median progression-free survival (PFS) was 9 months and median overall survival (OS) was 15 months. Importantly, 47 patients (57%) needed a dose reduction, 35 (43%) because of treatment-related adverse events, 10 (12%) because of continuous dosing, and two because of both. Stomatitis, fatigue, hand–foot syndrome and a combination of grade 1–2 adverse events were the most frequent reasons for dose reduction. In 40 patients (49%), there was severe toxicity, defined as dose reduction or permanent discontinuation, which was highly correlated with low body surface area, high age and female gender. On the basis of age and gender, a model was developed that could predict the probability of severe toxicity.

On the Role of Melanoma-Specific CD8+ T-Cell Immunity in Disease Progression of Advanced-Stage Melanoma Patients

Cytotoxic T-cell immunity directed against melanosomal differentiation antigens is arguably the best-studied and most prevalent form of tumor-specific T-cell immunity in humans. Despite this, the role of T-cell responses directed against melanosomal antigens in disease progression has not been elucidated. To address this issue, we have related the presence of circulating melanoma-specific T cells with disease progression and survival in a large cohort of patients with advanced-stage melanoma who had not received prior treatment. In 42 (68%) of 62 patients, melanoma-specific T cells were detected, sometimes in surprisingly large numbers. Disease progression during treatment was more frequent in patients with circulating melanoma-specific T cells, and mean survival of patients with circulating melanoma-specific T cells was equal to the survival of patients without melanoma-specific T cells. These data suggest that the induction of melanosomal differentiation antigen-specific T-cell reactivity in advanced stage melanoma is a late event most likely due to antigen load and spreading and is not accompanied by a clinically significant antitumor effect. These melanoma-specific T cells may be functionally distinct from T cells raised during spontaneous regression or up vaccination.

Immunotherapy with concurrent subcutaneous GM-CSF, low-dose IL-2 and IFN-alpha in patients with progressive metastatic renal cell carcinoma.

The purpose of the study was to determine toxicity, efficacy and immunologic effects of concurrent subcutaneous injections of low-dose interleukin-2 (LD-IL-2), granulocyte–monocyte colony-stimulating factor (GM-CSF) and interferon-α 2b (IFNα) in progressive metastatic renal cell carcinoma. In a multicentre phase II study, 59 evaluable patients received two to six cycles of subcutaneous IL-2 (4 mIU m−2), GM-CSF (2.5 μg kg−1) and IFNα (5 mIU flat−1) for 12 days per 3 weeks with evaluation after every two cycles. Cycles were repeated in responding or stable patients. Data were analysed after a median of 30 months follow-up (range 16–48 months). In 42 patients, the immunologic response was studied and related to response and survival. The main toxicity were flu-like symptoms, malaise and transient liver enzyme elevations, necessitating IL-2 reduction to 2 mIU m−2 in 29 patients, which should be considered the maximal tolerable dose. The response was 24% (eight out of 34, three complete response (CR), five partial response (PR)) in patients with metachronic metastases and 12% (three out of 25, 2CR, 1PR) in patients with synchronic metastases. Overall response was 19% (11 out of 59). Median survival was 9.5 months. All tested patients showed expansion and/or activation of lymphocytes, T cells and subsets, NK cells, eosinophils and monocytes. Pretreatment HLA-DR levels on monocytes and number of CD4+HLA-DR+ cells correlated with response. Pretreatment number of CD4+HLA-DR+ cells and postimmunotherapy levels of lymphocytes, CD3+, CD4+ and CD8+ T cells, but not of NK or B cells, correlated with prolonged survival. Immunotherapy with concurrent subcutaneous GM-CSF, LD-IL-2 and IFNα has limited toxicity, can be given as outpatient treatment and can induce durable CR. Response and survival with this form of immunotherapy seem to be more dependent on expansion/activation of T cells than of NK cells.

T-Cell Immune Function in Tumor, Skin, and Peripheral Blood of Advanced Stage Melanoma Patients: Implications for Immunotherapy

Purpose: To predict the potential antitumor effect of antigen-specific T cells in melanoma patients, we investigated T-cell effector function in relation to tumor-escape mechanisms. Experimental Design: CD8+ T cells isolated from tumor, adjacent normal skin, and peripheral blood of 17 HLA-A2+ patients with advanced-stage melanoma were analyzed for their antigen specificity and effector function against melanocyte differentiation antigens MART-1, gp100, and tyrosinase by using HLA-A2/peptide tetramers and functional assays. In addition, the presence of tumor-escape mechanisms PD-L1/PD-1 pathway, FoxP3 and loss of HLA or melanocyte differentiation antigens, both required for tumor cell recognition and killing, were studied. Results: Higher percentages of melanocyte antigen-specific CD8+ T cells were found in the melanoma tissues as compared with adjacent normal skin and peripheral blood. Functional analysis revealed 2 important findings: (i) in 5 of 17 patients, we found cytokine production after specific peptide stimulation by tumor-infiltrating lymphocytes (TIL), not by autologous peripheral blood lymphocytes (PBL); (ii) CD8+ T cells from 7 of 17 patients did not produce cytokines after specific stimulation, which corresponded with significant loss of tumor HLA-A2 expression. The presence of other tumor-escape mechanisms did not correlate to T-cell function. Conclusions: Our data show that functional T-cell responses could be missed when only PBL and not TIL are evaluated, emphasizing the importance of TIL analysis for immunomonitoring. Furthermore, loss of tumor HLA-A2 may explain the lack of T-cell functionality. These findings have important implications for selecting melanoma patients who may benefit from immunotherapy. Clin Cancer Res; 17(17); 5736–47. ©2011 AACR.

Phase I clinical study with multiple peptide vaccines in combination with tetanus toxoid and GM-CSF in advanced-stage HLA-A*0201-positive melanoma patients.

Successful induction of functional tumor-specific T cells by peptide vaccination in animal models has resulted in many clinical trials to test this approach in advanced-stage melanoma patients. In this phase I clinical trial, 11 end-stage melanoma patients were vaccinated intradermally with 3 peptides: MART-1(26-35) E27L (ELAGIGILTV), tyrosinase(368-376) N375Q (YMDGTMSQV), and gp100(209-217) T210M (IMQVPFSV), admixed with tetanus toxoid and granulocyte-monocyte colony stimulating factor. The peptide vaccine was well tolerated at all tested doses, and led to grade 1-2 toxicity only. Although all patients did show a rise in antitetanus IgG titers, in only 3 patients peptide-specific CD8+ T-cells were induced. In 2 cases, the response was directed against MART-1(26-35) and consisted of 0.2% and 3.3% of the CD8+ population; however, in both instances these cells did not produce interferon-γ on stimulation with the unmodified peptide. The third patient mounted a small (0.1%) response against gp100. In a fourth patient, a nonfunctional tyrosinase-specific response (0.6%) was found that was present before vaccination, but was not affected in size nor in function by the vaccine. None of the 11 patients responded clinically according to response evaluation criteria in solid tumors criteria. Although this study is a small scale phase I clinical trial, the efficacy that was observed was disappointingly low. In accordance with previously published peptide vaccination studies, these results add to the increasing evidence that peptide vaccination in itself is not potent enough as an effective melanoma immunotherapy in advanced-stage patients.

Extended Continuous Oral Temozolomide in Patients with Progressive Metastatic Renal Cell Carcinoma Not Responding to Interferon Alpha 2b

Abstract The aim of the study was to evaluate the toxicity and efficacy of oral extended continuous temozolomide in patients with progressive metastatic renal cell carcinoma (RCC) not responding to immunotherapy after removal of the primary tumor. Patients with progressive metastatic RCC received protracted temozolomide 100 mg/m2 orally on days 1-21 every 28 days. Response was assessed after 2 cycles to be followed by another 2 cycles in the absence of progression. After 4 cycles only patients with further remission and acceptable toxicity were to continue. No objective responses were observed in 12 patients and the trial was stopped prematurely in stage 1. Six patients remained stable during 4 cycles of temozolomide (4 months), only one of these remained stable for another 2 months after having stopped treatment. Five patients progressed after the initial 2 cycles and one after the first cycle. Overall survival was 15.5 months (range 1-36 months). Repeated cycles of 3 weeks oral temozolomide 100 mg/m2 followed by one week rest proved tolerable though this regimen may only have limited activity against metastatic RCC.

INTERFERON ALPHA-2B AS MEDICAL SELECTION FOR NEPHRECTOMY IN PATIENTS WITH SYNCHRONOUS METASTATIC RENAL CELL CARCINOMA: A CONSECUTIVE STUDY

OBJECTIVE Up to 25% of the patients with synchronous metastatic renal cell carcinoma (mRCC) treated with nephrectomy and interferon alpha-2b (IFN-alpha) will progress rapidly at metastatic sites and undergo needless surgery for an asymptomatic primary. We reversed the timing of surgery and immunotherapy and evaluated the role of initial IFN-alpha as selection for nephrectomy. PATIENTS AND METHODS Sixteen patients with mRCC and the primary in-situ received initial IFN-alpha for 8 weeks (2 weeks 5x3x10(6)IU/wk; 2 weeks 5x6x10(6)IU/wk; 2 weeks 5x9x10(6)IU/wk and 2 weeks 3x9x10(6)IU/wk). Patients with either partial remission (PR) or stable disease (SD) underwent nephrectomy followed by IFN-alpha maintenance at 3x9x10(6)IU/wk. Patients were evaluated with regard to age, sex, metastatic sites, morbidity, response, nephrectomy rate, time to progression and survival. RESULTS Thirteen patients received 2 months of preoperative IFN-alpha; 3 stopped during the 2 months period due to progressive disease (PD). Eight patients developed either a PR (n=3) or SD (n=5) at metastatic sites and underwent nephrectomy. Survival at 1 year is 50% (4/8 patients). Median progression-free survival was 6 months (3-17 months). Two of the 3 patients with PR developed a CR after 2 months maintenance following surgery. Eight patients with PD did not undergo surgery and had a median survival of 4 months (range 1-8 months). CONCLUSIONS Absence of progression at metastatic sites following IFN-alpha with the primary tumor in place may be used as selection for nephrectomy in patients with an intermediate prognosis. Currently, a randomized study is underway to assess the role of initial versus delayed nephrectomy in combination with IFN-alpha with regard to morbidity and survival.