Reviews on Recent Clinical Trials - Volume 3, Issue 1, 2008

The current hot topics issue of RRCT focuses on immunotherapy of cancer, a field that seems to offer promises as the new, biological dimension in cancer treatment, but it is still in his early days. Immunotherapy involving interferons and monoclonal antibodies has now become part of standard cancer treatments and is considered the fourth pillar of therapy, beyond surgery, chemotherapy, and radiation therapy. Other types of immunotherapy, such as cancer vaccines, still remain experimental. Although quite a few clinical trials of new immunotherapy paradigms are in progress, a large quantity of work remains to be done before the findings and conclusions can be widely applied in the clinical routine. The first article in this hot topic issue by Rainov, Gorbatyuk, and Heidecke reviews treatment of malignant glioma, focusing on ligand-conjugated toxins. The authors discuss the rationale for such approaches, utilization of different ligands, and promising early clinical trials. These therapies offer the ability to target malignant cells in a disease that is almost universally refractory to conventional therapy. The article on dendritic cell (DC) immunotherapy for malignant glioma by Luptrawan, Liu, and Yu discusses the results of DC-based immunotherapy clinical trials and explores the future use of DC vaccines for glioma immunotherapy. The prognosis for patients with malignant gliomas is poor. It has remained almost unchanged in the last decades, despite considerable advances in surgical technology, chemotherapy and radiation therapy. Immunobiological paradigms are thus being increasingly explored as an adjunct to standard therapies. In recent clinical trials, DC have demonstrated an ability to promote an effective anti-tumor immune response and to sensitize glioma cells to chemotherapy. The challenge with such vaccination strategies is to break the immune tolerance, so that the patient's immune system will recognize cancer cells. The success of vaccines depends on the identification of appropriate tumor antigens, establishment of effective immunization strategies, and the ability to circumvent inhibitory immune mechanisms. The authors state in their review that in the future the fundamental knowledge of DC immunobiology, tumor immunology and cancer biology needs to be significantly extended, and that new findings must be implemented in the rational design of DC-based cancer immunotherapy. The review by Rodriguez and Gutierrez focuses on an approved agent in the treatment of lymphoma and highlights specific aspects of the pharmacokinetics and pharmacodynamics of the agent that are not always appreciated or have recently come to light. These factors influence toxicity and efficacy of the agent and should be taken into account when administering the drug and are certainly worthy of further study. In their review on immunotherapy of hepatocellular carcinoma (HCC), Greten, Manns, and Korangy deal with the fifth most common cancer worldwide, which has an increasing incidence in the Western world. A number of experimental trials, many of them immunotherapeutic, have been performed in patients with HCC, mainly because systemic chemotherapy has failed to show substantial benefits. The authors review recent immunotherapy trials in HCC and point at promising strategies to be explored in more detail in the near future. We hope that this “Hot Topic Issue” offers interest to readers in a field of cancer care that is in its early stages therapeutically, but has the potential to truly change the natural history of this disease. There is a plethora of immunologic applications being explored in cancer research and the four review articles in this issue highlight some of the most promising ones.

Currently used targeted toxins are recombinant molecules specifically binding to surface receptors overexpressed on tumor cells. These recombinant proteins consist of a tumor-selective ligand coupled to a truncated peptide toxin. Ligands may bind to tumor-associated molecules with receptor signaling properties, such as epidermal growth factor receptor, transferrin receptor, and interleukin-13 or interleukin-4 receptors. The toxin part of the molecule in all clinically used toxins is a modified bacterial polypeptide fused to one of the above ligands. Targeted toxins are very effective against tumor cells resistant to radiation and chemotherapy. They are far more potent than any known chemotherapy drug. Targeted toxins have shown an acceptable profile of toxicity and safety in early clinical studies and have demonstrated some evidence for tumor response. Currently, phase 3 trials with some targeted toxins are underway and final results are still pending. This review summarizes the study protocols and key findings of the most important clinical studies with targeted toxins in malignant glioma patients. It offers in addition an outlook into future areas of development of targeted toxins, such as improved delivery modes and non-invasive imaging of toxin distribution.

The prognosis for patients with malignant gliomas remains poor despite advances in surgical technique, chemotherapy and radiation therapy. Median survival for glioblastoma multiforme, the most aggressive and deadliest form of brain cancer, remains only fifteen months even after optimal treatment with surgical resection followed by chemoradiation therapy. The grim prognosis can be attributed to the infiltrative nature of the disease, a central nervous system microenvironment that can escape immune surveillance and resistance of the tumor to chemotherapy. In recent trials, dendritic cells have demonstrated an ability to promote an effective anti-tumor immune response and sensitize glioma cells to chemotherapy. This review will discuss the results of dendritic-cell based immunotherapy clinical trials for the treatment of malignant gliomas and explore the future strategies of DC vaccines for glioma immunotherapy.

Rituximab is a mouse/human chimeric IgG1κ monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal B-lymphocytes. The mechanisms of action of rituximab involve complement-dependent cytotoxicity (CDC), complement-dependent cellular cytotoxicity (CDCC), antibody dependent cellular cytotoxicity (ADCC) and induction of apoptosis. Pharmacokinetic issues, tumor and molecular related factors mediate resistance to rituximab. Optimizing rituximab treatment requires a therapeutic project that might ideally be individualized and that includes enhancing of ADCC and CDC mechanisms, acting over apoptosis-regulating proteins and using synergistic conventional chemotherapeutic agents. Pharmacokinetic favourable schedules in specific diseases alone or associated to chemotherapeutic agents are not well known, therefore studies focusing on these issues are warranted. New information regarding targeting the lymphoma microenvironment and rituximab effects is the focus of current research.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with increasing incidence in the Western World. In contrast to most other malignancies, only surgical and local ablative therapeutic options have shown efficacy in patients with HCC. Systemic chemotherapy has failed to show a substantial benefit for these patients. Therefore, a number of immunotherapeutic trials have been performed to evaluate the efficacy of immunotherapy for the treatment of HCC. Although only a limited number of patients have been enrolled in most trials so far, results from these studies clearly suggest that immunotherapy is safe in HCC patients. Here, we review recent immunotherapy trials in HCC.

SCLC represents 13% of all lung cancer cases and is the most aggressive form of lung cancer with an overall 5- year survival less than 5%. The combination of cisplatin or carboplatin with etoposide remains the standard treatment for SCLC. Despite a good initial response to therapy, most SCLC patients suffer from the development of chemotherapy resistance and relapse. Second-line chemotherapy should then be applied, which however frequently results in only a low survival increase. To improve the outcome of SCLC, new drugs such as topotecan, irinotecan, amrubicin, paclitaxel or gemcitabin have recently been added to chemotherapeutic regimens. In combination with etoposide or platinum-based agents, some of these drugs could be able to offer a significant survival benefit. Moreover, recent progress in the understanding of SCLC biology has led to the identification of critical signaling pathways, which allowed the development of specific targeted therapies for the disease. A number of new molecules are currently under clinical evaluation in SCLC. These inhibitors target the proteasome, receptors tyrosine kinases, farnesyltransferase, Bcl-2, or angiogenic pathways. Some studies have demonstrated that these new strategies can be associated with chemotherapy and show positive results. This review summarizes recent clinical trials performed with new chemotherapeutic regimens and the current status of specific targeted approaches in SCLC patients.

Most of the conventional immunosuppressive drugs act by inhibiting the activation of enzymes, production of cytokines or proliferation of immune cells. Recently much attention is given to a new class of inhibitors that act by counteracting the functions of the lysophospholid sphingosine-1-phosphate (S1P). S1P is emerging as a potent stimulator of several immune cells and is critical for lymphocyte migration. The sphingosine analogue, FTY720 (fingolimod), a high affinity agonist of sphingosine-1-phosphate type-1 receptor (S1P-1), acts primarily by sequestering lymphocytes within peripheral lymphoid organs rendering them incapable of migrating to the sites of inflammation. Phase I, II and III, clinical trials comparing the efficacy of FTY720 containing regimens to conventional immunosuppressive regimens in de novo renal transplant patients, have been conducted. Moreover, clinical trials are also on-going in patients with relapsingremitting multiple sclerosis showing obvious benefit for patients receiving FTY720. In this review, we focus on the transition of this novel compound from bench to clinical trials, and discuss the clinical potential of this drug in autoimmune diseases and in transplantation immunology.

Background: Biliary tract carcinoma is infrequent; usually majority of cases are detected in an advanced phase of the disease, thus surgical resection is not feasible and prognosis is poor, mean survival is 6 months and, chemotherapy is the main therapeutic option. Objective: An overall review of all clinical trials published regarding gemcitabine, alone or in combination, as a treatment in advanced biliary tract carcinoma. Results: Gemcitabine has been reported as a single drug, in 12 trials and as a combination in 21 studies. As a single agent it has been evaluated in a 30 minute infusion, biweekly administration, fixed infusion [10 mg/m2/min] or as a prolonged infusion [24 hours]. Objective response has been reported between 0 and 36%, stable disease 13 to 15%, time to progression 2 - 10.7 months, overall survival 4 to 14 months. Chemotherapy combinations based on gemcitabine have been evaluated with several agents, among them were 5-FU, mitomycin oxaliplatin, capecitabine, cisplatin, docetaxel and irinotecan; the objective response seen: 9.3% to 64%, stable disease 9.3% to 53%, time to progression 3 - 10 months and overall survival 4.7 to 18 months. Conclusion: Gemcitabine is an effective drug in advanced biliary tract carcinoma with a low toxicity profile. It should be considered as the standard treatment for unresectable or metastatic disease while awaiting phase III results.