A B S T R A C T PurposeA randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-␣) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported. Patients and MethodsSeven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-␣ 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up. ResultsMedian overall survival was greater in the sunitinib group than in the IFN-␣ group (26.4 v 21.8 months, respectively; hazard ratio [HR] ϭ 0.821; 95% CI, 0.673 to 1.001; P ϭ .051) per the primary analysis of unstratified log-rank test (P ϭ .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P ϭ .049). Within the IFN-␣ group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor-signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-␣ (P Ͻ .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-␣ (P Ͻ .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). ConclusionSunitinib demonstrates longer overall survival compared with IFN-␣ plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.
Adoptive T cell therapy, involving the ex vivo selection and expansion of antigen-specific T cell clones, provides a means of augmenting antigen-specific immunity without the in vivo constraints that can accompany vaccine-based strategies. A phase I study was performed to evaluate the safety, in vivo persistence, and efficacy of adoptively transferred CD8 ؉ T cell clones targeting the tumor-associated antigens, MART1͞MelanA and gp100 for the treatment of patients with metastatic melanoma. Four infusions of autologous T cell clones were administered, the first without IL-2 and subsequent infusions with low-dose IL-2 (at 0.25, 0.50, and 1.0 ؋ 10 6 units͞m 2 twice daily for the second, third, and fourth infusions, respectively). Forty-three infusions of MART1͞MelanA-specific or gp100-specific CD8 ؉ T cell clones were administered to 10 patients. No serious toxicity was observed. We demonstrate that the adoptively transferred T cell clones persist in vivo in response to low-dose IL-2, preferentially localize to tumor sites and mediate an antigen-specific immune response characterized by the elimination of antigen-positive tumor cells, regression of individual metastases, and minor, mixed or stable responses in 8 of 10 patients with refractory, metastatic disease for up to 21 mo.
We identified circulating CD8+ T-cell populations specific for the tumor-associated antigens (TAAs) MART-1 (27-35) or tyrosinase (368-376) in six of eleven patients with metastatic melanoma using peptide/HLA-A*0201 tetramers. These TAA-specific populations were of two phenotypically distinct types: one, typical for memory/effector T cells; the other, a previously undescribed phenotype expressing both naive and effector cell markers. This latter type represented more than 2% of the total CD8+ T cells in one patient, permitting detailed phenotypic and functional analysis. Although these cells have many of the hallmarks of effector T cells, they were functionally unresponsive, unable to directly lyse melanoma target cells or produce cytokines in response to mitogens. In contrast, CD8+ T cells from the same patient were able to lyse EBV-pulsed target cells and showed robust allogeneic responses. Thus, the clonally expanded TAA-specific population seems to have been selectively rendered anergic in vivo. Peptide stimulation of the TAA-specific T-cell populations in other patients failed to induce substantial upregulation of CD69 expression, indicating that these cells may also have functional defects, leading to blunted activation responses. These data demonstrate that systemic TAA-specific T-cell responses can develop de novo in cancer patients, but that antigen-specific unresponsiveness may explain why such cells are unable to control tumor growth.
SUMMARYWe developed an in vitro method for isolating and expanding autologous CD4+ T-cell clones with specificity for the melanoma-associated antigen NY-ESO-1. We infused these cells into a patient with refractory metastatic melanoma who had not undergone any previous conditioning or cytokine treatment. We show that the transferred CD4+ T cells mediated a durable clinical remission and led to endogenous responses against melanoma antigens other than NY-ESO-1.CD8+ cytotoxic T cells can be harvested from a patient with cancer, expanded in vitro, selected for specificity against a tumor-associated antigen, and infused back into the patient. Such autologous T cells have been shown in clinical trials to have a beneficial effect in some patients with cancer.  The cytotoxic antitumor effect of CD8+ T cells depends on CD4+ T cells, which provide CD8+ T cells with growth factors such as interleukin-2 and can mediate the destruction of tumor cells either directly or indirectly.  Growth factors such as interleukin-2 can act in an autocrine manner, which in principle would allow an infusion of CD4+ T cells to proliferate in the patient and stimulate endogenous antitumor CD8+ T cells. Until recently, however, a means of isolating and expanding antitumor CD4+ T cells in numbers sufficient for cellular therapy has not been feasible. The identification of HLA class II-restricted epitopes in tumor-associated antigens such as NY-ESO-1 and tyrosinase and the development of methods for the isolation and expansion of CD4+ T cells in vitro gave us the opportunity to implement a clinical trial to evaluate the safety, in vivo persistence, and antitumor efficacy of autologous CD4+ T-cell clones for the treatment of metastatic melanoma. We describe a patient with refractory metastatic melanoma who had a long-term complete remission after receiving autologous NY-ESO-1-specific CD4+ T-cell clones. CASE REPORTThe patient was 52 years old when he presented with recurrent melanoma and pulmonary and left iliac and inguinal metastases. His tumor had not responded to high-dose interferon alfa, four cycles of high-dose interleukin-2, and local excision. Baseline staging with magnetic resonance imaging of the brain and computed tomography (CT) of the chest, abdomen, and pelvis showed metastatic disease in the posterior right pleura, right hilum, and
Inflammatory processes in chronic rejection remain a serious clinical problem in organ transplantation. Activated cellular infiltrate produces high levels of both superoxide and nitric oxide. These reactive oxygen species interact to form peroxynitrite, a potent oxidant that can modify proteins to form 3-nitrotyrosine. We identified enhanced immunostaining for nitrotyrosine localized to tubular epithelium of chronically rejected human renal allografts.Western blot analysis of rejected tissue demonstrated that tyrosine nitration was restricted to a few specific polypeptides. Immunoprecipitation and amino acid sequencing techniques identified manganese superoxide dismutase, the major antioxidant enzyme in mitochondria, as one of the targets of tyrosine nitration. Total manganese superoxide dismutase protein was increased in rejected kidney, particularly in the tubular epithelium; however, enzymatic activity was significantly decreased. Exposure ofrecombinant human manganese superoxide dismutase to peroxynitrite resulted in a dosedependent (IC50 = 10 ,uM) decrease in enzymatic activity and concomitant increase in tyrosine nitration. Collectively, these observations suggest a role for peroxynitrite during development and progression of chronic rejection in human renal allografts. In addition, inactivation of manganese superoxide dismutase by peroxynitrite may represent a general mechanism that progressively increases the production of peroxynitrite, leading to irreversible oxidative injury to mitochondria.
Purpose: Diarrhea (with or without colitis) is an immune-related adverse event (irAE) associated with ipilimumab. A randomized, double-blind, placebo-controlled, multicenter, multinational phase II trial was conducted to determine whether prophylactic budesonide (Entocort EC), a nonabsorbed oral steroid, reduced the rate of grade ≥2 diarrhea in ipilimumab-treated patients with advanced melanoma. Experimental Design: Previously treated and treatment-naïve patients (N = 115) with unresectable stage III or IV melanoma received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) with daily blinded budesonide (group A) or placebo (group B) through week 16. The first scheduled tumor evaluation was at week 12; eligible patients received maintenance treatment starting at week 24. Diarrhea was assessed using Common Terminology Criteria for Adverse Events (CTCAE) 3.0. Patients kept a diary describing their bowel habits. Results: Budesonide did not affect the rate of grade ≥2 diarrhea, which occurred in 32.7% and 35.0% of patients in groups A and B, respectively. There were no bowel perforations or treatment-related deaths. Best overall response rates were 12.1% in group A and 15.8% in group B, with a median overall survival of 17.7 and 19.3 months, respectively. Within each group, the disease control rate was higher in patients with grade 3 to 4 irAEs than in patients with grade 0 to 2 irAEs, although many patients with grade 1 to 2 irAEs experienced clinical benefit. Novel patterns of response to ipilimumab were observed. Conclusions: Ipilimumab shows activity in advanced melanoma, with encouraging survival and manageable adverse events. Budesonide should not be used prophylactically for grade ≥2 diarrhea associated with ipilimumab therapy. (Clin Cancer Res 2009;15 (17):5591-8) Localized melanoma can be effectively treated by surgery (1), but new therapies for unresectable disease are urgently needed. Dacarbazine is the commonly used standard treatment for advanced melanoma (2, 3), but no systemic treatment has shown improved survival compared with dacarbazine in randomized clinical trials (4-7). Recent immunotherapy trials have shown median overall survival (OS) time of 11.4 months with highdose interleukin 2 (8) and 11.7 months for tremelimumab (9). A recent meta-analysis of 42 phase II trials done by the cooperative groups between 1975 and 2005 in patients with metastatic melanoma documented a median survival time of 6.2 months, with a 25.5% 1-year survival rate (10).Ipilimumab (Bristol-Myers Squibb and Medarex) is a fully human monoclonal antibody directed against CTL antigen-4 . CTLA-4 is a key negative regulator of the T-cell immune response, and preclinical animal studies have shown that blocking CTLA-4 enhances adaptive immune responses and induces tumor regression (16,17). In clinical trials,
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