Reviews on Recent Clinical Trials - Volume 1, Issue 2, 2006

Dendritic cells (DC) are the most potent antigen-presenting cells that initiate T cell-mediated immune responses against cancer. It has been almost a decade since the first trial of DC-based cancer immunotherapy was published. Despite the many clinical trials conducted since, few solid conclusions have been reached, and no specificimmunotherapy has routinely demonstrated meaningful anti-tumour responses. Clinical-grade DC can be obtained from three distinct cell populations in the blood - monocytes, CD34+ progenitors or direct isolation of circulating blood DC. This review discusses the science behind DC-based cancer immunotherapy, with a particular emphasis on the use of monocyte-derived DC in melanoma clinical trials, and the various potential avenues for improvement of patient clinical response rates.

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia among adults with an incidence that increases with age. Modern induction chemotherapy will result in complete remission in 50-90% of patients with de novo disease, but between 10 and 25% of patients will have primary refractory disease and the majority of those who gain remission will relapse within 3 years of diagnosis. Treatment of relapsed leukaemia is difficult and well-controlled trials in this group of patients are uncommon. Usually, patients are recruited to relatively small phase I and phase II trials examining the potential role for new drug approaches and many combination regimens based around high doses of cytarabine arabinoside, substitution of the anthracyclines mitoxantrone or idarubicin for daunorubicin or using amsacrine have become established. However, these trials are generally unrandomised and produce second CR rates of 10-70% relying on historical controls. This article reviews the results of published randomised trials in relapse and refractory AML. Questions addressed include the role of high dose cytarabine, with or without the addition of etoposide or mitoxantrone, the use of timed sequential chemotherapy regimens, and growth factors as a means to increase leukaemia cell sensitivity and interference with drug resistance proteins.

Colorectal cancer (CRC) is the second most common cancer in Western Europe. Combinations of oxaliplatin or irinotecan with fluorouracil have increased responses in first-line therapy up to 40%, but prognosis is still poor. Almost 80% of patients will progress during the first year of treatment and usually become refractory to all current therapies, including EGFR inhibitors. The likelihood of achieving a response to cetuximab-based therapy is not related to overt levels of epidermal growth factor receptor (EGFR) expression in the tumor. Whilst other markers of cetuximab activity, such as phosphorylation status of the EGFR, quantification of ligands and polymorphisms in the promoter or in first intronic region, have not been validated, response rate correlates with the intensity of patient skin reaction. Such a relationship is not as clear as with other anti EGFR therapies, such as the EGFR-specific tyrosine kinase inhibitor, gefitinib, where efficacy appears to correlate with mutations in the cytoplasmic domain of the receptor. Recently, EGFR mutations have been evaluated in CRC and were shown to occur at a very low frequency (<0.5%), supporting that, mutations on the EGFR gene, cannot explain cetuximab efficacy in irinotecan-refractory patients. We will review the current on-going EGFR inhibitor trials and discuss alternative pathways to EGFR, which can help to explain cetuximab resistance in CRC.

Targeted toxins represent a new class of agents with high specificity for tumor cells. Toxins in current clinical use for the treatment of brain tumors are mostly recombinant polypeptides consisting of a tumor-selective ligand coupled to a peptide toxin of bacterial origin. Targeted toxins are highly potent - one single molecule of toxin is enough to cause cell death. Toxins are able to kill tumor cells independent of any malignancy-associated genetic alterations and/or mutations. The blood-brain barrier has been a major obstacle for using targeted toxins for treatment of malignant glioma. Convection-enhanced delivery (CED), a method for delivery of large molecules to brain tissue via continuous interstitial microinfusion, has permitted direct administration of toxins to brain tumors or to surrounding brain tissue infiltrated by tumor cells. Four targeted toxins advanced to at least phase II clinical trials and are being used for treatment of adult or pediatric patients with recurrent or progressive malignant glioma. These are IL4-P. aeruginosa exotoxin (IL4-PE, NBI- 3001), tumor growth factor (TGF)α-P. aeruginosa exotoxin (TP-38), IL13-P. aeruginosa exotoxin (IL13-PE38), and transferrin-C. diphtheriae toxin (TransMID™, Tf-CRM107). All of these toxins have shown an acceptable profile of toxicity and safety in phase I and II clinical studies and have demonstrated some evidence for tumor response. Current phase I and II clinical protocols are exploring several parameters, such as placement of catheters for CED either intratumorally or in the brain tissue surrounding a tumor, surgical resection of tumor before or after toxin infusion, and single vs. repeated infusion. Two large randomized and controlled phase III multicenter studies using IL13-PE38 or TransMID™ are currently enrolling patients. This review summarizes the study protocols and key findings of all previously completed and currently ongoing clinical studies with targeted toxins for malignant glioma. It offers in addition an outlook into future areas of development of targeted toxins, such as improved delivery modes and non-invasive in vivo imaging of intracerebral and intratumoral distribution of toxin in patients.

The management of thyroid carcinomas commonly involves thyroidectomy, radioactive iodine to ablate any thyroid remnant in patients at high risk of recurrence, and suppressive thyroid hormone replacement. However many tumors will de-differentiate and become refractory to radioactive iodine. After progressive dedifferentiation the prognosis for these patients is poor, with no curative options available as these tumors respond poorly to currently available agents. In this review, we examine the unique biology of thyroid cancer and the various intracellular pathways which are currently the subject of intensive focus. Trials evaluating the efficacy of cytotoxic chemotherapeutic agents in iodinerefractory thyroid carcinoma and current novel therapeutic approaches will be emphasized.

Placebo-controlled clinical trials have shown that atorvastatin is beneficial in patients with myocardial ischemia, established coronary artery disease, hypertension and 3 other cardiovascular risk factors (e.g. left-ventricular hypertrophy, type 2 diabetes, smoking), and in diabetes, but not in patients with calcific aortic stenosis. Recently, intensive low density lipoprotein (LDL)-cholesterol lowering with atorvastatin 80 mg/day has been shown to have a greater clinical benefit than atorvastatin 10 mg/day in patients with coronary heart disease and one other high-risk factor (previous myocardial infarction, coronary revascularization or angina), and to be superior to moderate lipid lowering with pravastatin (40 mg/day) in patients with an acute coronary syndrome. However, a smaller study comparing lovastatin 5 mg/day with atorvastatin 80 mg/day was unable to detect any difference in outcomes in patients with stable coronary disease, despite the greater LDL-cholesterol lowering with the atorvastatin, possibly because it was not powered to do so. In a retrospective cohort study, atorvastatin 10 mg/day, pravastatin 20 mg/day, simvastatin 20 mg/day, lovastatin 20 mg/day and fluvastatin 20 mg/day had similar efficacy as secondary prevention after acute myocardial infarction. At present, the evidence from clinical trials is favouring the intensity of the effect on LDL-cholesterol and/or C-reactive protein (CRP) with atorvastatin 80 mg, rather than the use of atorvastatin per se, when greater benefits are observed with the 80 mg dose of atorvastatin compared to other statins. Thus, at present, it is not clear whether atorvastatin is superior to other statins in some indications (coronary heart disease, acute coronary syndromes) or whether it is the intensive lipid lowering that is responsible for the superiority. Atorvastatin has little or no ability to increase high density lipoprotein (HDL)-cholesterol, and this may be a disadvantage in patients with metabolic syndrome or diabetes, where low HDLcholesterol is a key feature. Thus, other statins should probably be preferred to atorvastatin in patients with diabetes/metabolic syndrome. Alternatively, atorvastatin can be used in combination with a fibrate to increase HDLcholesterol in patients with diabetes/metabolic syndrome.

Genetic mutations affecting the capacity of basal keratinocytes to adhere firmly to the underneath derma lead to severe, often lethal, blistering disorders of the skin known as Epidermolysis Bullosa (EB). About 400000-500000 people worldwide are affected and no definitive treatments have yet been developed. Gene therapy might represent an alternative therapeutic approach for these devastating inherited disorders. In the last 10 years pre-clinical studies have shown that human epidermal stem cells can be stably transduced using integrating vectors allowing long-term genetic correction of the adhesion defects affecting EB keratinocytes both in vitro and in vivo after transplantation onto immunodeficient animals. In addition tremendous progress have been achieved in the clinical applications of cultured keratinocytes (cell therapy) for the regeneration of the epidermis over full thickness wounds or the restoration of damaged corneal surfaces. The combination of (i) optimised culturing conditions not altering the epidermal stemness, (ii) gene transfer vectors able to target epidermal stem cells very efficiently and (iii) surgical procedures allowing the grafting of large skin areas have therefore led our group to submit the first phase I/II gene therapy clinical trial for Junctional Epidermolysis Bullosa.

Alefacept is an immunobiologic agent that has been recently introduced in the treatment of plaque psoriasis. The author presents a brief review of the drug, its efficacy and safety profile. Recent case reports of the use of alefacept in conjunction with other conditions as well as the drug's possible use for treatment of other conditions are reviewed as

Efalizumab is a humanized, monoclonal IgG1 antibody that binds to the α-subunit of lymphocyte function associated antigen (LFA)-1, blocking the interaction between LFA-1 and intercellular adhesion molecule-1. The result is a reduction in T cell activation, an inhibition of the trafficking and recruitment of T cells to the dermis and epidermis, and a decrease in the reactivation of T cells at several steps in the psoriasis pathogenesis. The clinical responses seen in efalizumab trials have demonstrated that this medication is efficacious, especially in long-term treatment. Adverse events observed in efalizumab-treated patients have been minor. Psoriasis rebound following discontinuation of treatment, while serious, has been controlled through transition to other therapies. Subcutaneous injection allows for administration outside the clinic.

Epigenetic factors such as DNA methylation and histone deacetylation are known to contribute to the malignant transformation of cells by silencing critical genes. Drugs that inhibit DNA methyltransferases or histone deacetylases were shown to have the potential to reactivate silenced genes and induce differentiation or apoptosis of malignant cells. The most intensively studied class of such agents is DNA methyltransferase inhibitors, including 5-azacytidine (azacitidine) and 5-aza-2'-deoxycytidine (decitabine). In 2004, azacitidine was approved for the treatment of myelodysplastic syndrome on the basis of phase II and III studies that showed a response rate (complete and partial responses) of 15%. Azacitidine is also being evaluated in clinical trials for other malignant diseases. Decitabine has response rates of 17-49% in myelodysplastic syndrome in multiple phase II and III studies and also activity in acute and chronic myelogenous leukemia. Histone deacetylase inhibitors belong to another class of epigenetic modifying agents that include depsipeptide, butyrate derivatives, suberoylanilide hydroxamic acid and valproic acid. No agent in this class has been studied in a phase III trial, but several agents have been or are being studied in phase II trials. Further research is needed to determine the appropriate patient selection and dosing schedules.