Anti-CTLA4 monoclonal antibodies: the past and the future in clinical application

Recently, two studies using ipilimumab, an anti-CTLA-4 monoclonal antibody (mab) demonstrated improvements in overall survival in the treatment of advanced melanoma. These studies utilized two different schedules of treatment in different patient categories (first and second line of treatment). However, the results were quite similar despite of different dosage used and the combination with dacarbazine in the first line treatment. We reviewed the result of randomized phase II-III clinical studies testing anti-CTLA-4 antibodies (ipilimumab and tremelimumab) for the treatment of melanoma to focus on practical or scientific questions related to the broad utilization of these products in the clinics. These analyses raised some considerations about the future of these compounds, their potential application, dosage, the importance of the schedule (induction/manteinance compared to induction alone) and their role as adjuvants. Anti-CTLA-4 antibody therapy represents the start of a new era in the treatment of advanced melanoma but we are on the steep slope of the learning curve toward the optimization of their utilization either a single agents or in combination

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer

Imaging of the carotid artery vulnerable plaque

Atherosclerosis involving the carotid arteries has a high prevalence in the population worldwide. This condition is significant because accidents of the carotid artery plaque are associated with the development of cerebrovascular events. For this reason, carotid atherosclerotic disease needs to be diagnosed and those determinants that are associated to an increased risk of stroke need to be identified. The degree of stenosis typically has been considered the parameter of choice to determine the therapeutical approach, but several recently published investigations have demonstrated that the degree of luminal stenosis is only an indirect indicator of the atherosclerotic process and that direct assessment of the plaque structure and composition may be key to predict the development of future cerebrovascular ischemic events. The concept of "vulnerable plaque" was born, referring to those plaque's parameters that concur to the instability of the plaque making it more prone to the rupture and distal embolization. The purpose of this review is to describe the imaging characteristics of "vulnerable carotid plaques.

Liver metastases from colorectal cancer treated with conventional and antiangiogenetic chemotherapy: evaluation with liver computed tomography perfusion and magnetic resonance diffusion-weighted imaging

OBJECTIVE: The objectives of the study were to determine whether perfusion computed tomography (CT-p) and magnetic resonance diffusion-weighted imaging (MR-DWI) can allow evaluation of the effects of chemotherapy combined with antiangiogenetic treatment on liver metastases in patients with advanced colorectal cancer and to determine if changes in CT-p and MR-DWI correlate with the response to therapy as assessed by conventional Response Evaluation Criteria in Solid Tumors (RECIST). METHODS: Eighteen patients with liver metastases from colorectal cancer underwent CT-p and MR-DWI before and 6 months after chemotherapy and antiangiogenetic treatment. Lesions were classified according to RECIST criteria (complete response [CR], partial response [PR], stable disease [SD], and progressive disease) and calculations of CT-p parameters including blood flow (BF), blood volume (BV), capillary permeability (CP), and MR-DWI apparent diffusion coefficient (ADC) values were performed; RECIST, CT-p, and MR-DWI measurements at baseline and follow-up were tested for statistically significant differences using the paired-samples t test. Baseline and follow-up perfusion parameters of the lesions were also compared on the basis of therapy response assessed by RECIST criteria using independent-samples t test. P < 0.05 was considered indicative of a statistically significant difference for all statistical test. RESULTS: Six patients (6/18; 33.3%) were classified as PR (), and the remaining 12 (12/18; 66.7%) were classified as SD. On a per-lesion basis, 2 (2/32; 6.3%) cannot be identified at follow-up, 6 (6/32; 18.8%) showed a decrease in size of more than 30%, and 24 (24/32; 75%) were substantially stable in size. No cases of progressive disease were demonstrated at follow-up. No statistically significant differences were demonstrated between PR, CR, and SD lesions for BF (P = 0.19), BV (P = 0.14), and ADC (P = 0.68) measurements, whereas CP was significantly higher in CR and PR lesions (P = 0.038). Considering differences between baseline and follow-up values, no statistically significant differences were noted between PR and CR lesions versus SD lesions for CT-p values (BF: P = 0.77; BV: P = 0.15; CP: P = 0.64). A statistically significant difference between PR and CR lesions and SD lesions was noted for ADC values (P = 0.047). CONCLUSION: Both CT-p and MR-DWI can detect therapy-induced modifications in lesion vascularization before significant changes in size are evident

Apoptosis of colorectal adenocarcinoma (COLO 201) by tumour necrosis factor-alpha (TNF-α) and/or interferon-gamma (IFN-γ), resulting from down-modulation of Bcl-2 expression

Fas antigen is constitutively expressed in the normal colon epithelium, but considerably diminished in most colorectal carcinomas. In the present study, we examine the relationship between Fas antigen expression and apoptosis using the colorectal carcinoma cell line COLO 201, on which a low grade of Fas antigen is expressed. Anti-Fas antibody had no effect on the induction of apoptosis of COLO 201. However, TNF-α and/or IFN-γ, independently and additively, up-regulated Fas antigen expression on COLO 201 and induced apoptosis in a dose-dependent manner. Both cytokines also increased the COLO 201 sensitivity to anti-Fas antibody, resulting from the down-modulation of Bcl-2 and the up-regulation of Bax. These findings indicate that cytokine(s) plus anti-Fas antibody (which mimics natural Fas ligand) are more effective in inducing apoptosis of COLO 201 than cytokine(s) alone. These findings suggest that immunotherapy in combination with cytokine(s) and lymphokine-activated killer (LAK) cells will become a more effective therapy for cancer than cytokine(s) or LAK cells alone, since the Fas ligand is expressed on activated T cells, natural killer cells and macrophages