Update on cancer therapeutics最新文献

This article reviews recent preclinical and clinical advances in the use of pretargeting methods for the radioimmunodetection and radioimmunotherapy of cancer. Whereas directly labeled antibodies, fragments, and subfragments (minibodies and other constructs) have shown promise in both imaging and therapy applications over the past 25 years, their clinical adoption has not fulfilled the original expectations due to either poor image resolution and contrast in scanning or insufficient radiation doses delivered selectively to tumors for therapy. Pretargeting involves the separation of the localization of tumor with an anticancer antibody from the subsequent delivery of the imaging or therapeutic radionuclide. This has shown improvements in both imaging and therapy by overcoming the limitations of conventional, or one-step, radioimmunodetection or radioimmunotherapy. We focus herein on the use of bispecific antibodies followed by radiolabeled peptide haptens as a new modality of selective delivery of radionuclides for the imaging and therapy of cancer. Our particular emphasis in pretargeting is the use of bispecific trimeric (three Fab′s) recombinant constructs made by a modular method of antibody and protein engineering of fusion molecules called dock and lock (DNL).

Preclinical and clinical investigations currently underway are employing novel strategies for combining vaccines with conventional and experimental anticancer therapies. To date, the FDA has not approved a therapeutic cancer vaccine. However, the results of recent investigations suggest an increasing role for vaccines in new models of combination therapy for many types of cancer. This article reviews and discusses therapeutic cancer strategies that employ vaccines in combination with local radiation, chemotherapy, hormone therapy, and anti-CTLA-4 mAb. Preclinical studies have shown that certain anticancer agents have immune modulatory effects that result in up-regulation of surface expression of MHC molecules, tumor-associated antigens, or Fas on malignant cells, rendering them more susceptible to immune destruction. Preliminary results of clinical studies using combination strategies have demonstrated a postvaccination antigen cascade, prolonged time to disease progression, and improved overall survival. Several larger randomized trials are ongoing, and more are required to support these findings.

Neuroendocrine tumours can be divided into endocrine neoplasms occurring in the lungs, thymus, gastrointestinal tract and pancreas. Most neuroendocrine tumours are slowly growing neoplasms, but some of them are highly malignant and show an aggressive behaviour. A special feature of neuroendocrine tumours is the ability to produce peptides or hormones, for example, serotonin, histamine, ACTH, VIP, insulin, proinsulin, glucagon or calcitonin, thereby giving rise to disabling endocrine syndromes such as the carcinoid syndrome, an atypical carcinoid syndrome, ectopic Cushing's syndrome, the WDHA-syndrome, the insulinoma syndrome or the glucagonoma syndrome. The treatment of patients with neuroendocrine tumours consists of surgery, radiotherapy, biotherapy, chemotherapy and local ablative treatments such as liver embolization and radiofrequency ablation. Nearly all patients should be considered for surgery, which is the only curative treatment but may also be used for debulking of metastases. Radiotherapy may either be given as conventional radiotherapy, usually against bone or brain metastases, or as targeted irradiation therapy with ¹¹¹Indium-, ⁹⁰Yttrium- or ¹⁷⁷Lutetium-labelled somatostatin analogues. Biotherapy traditionally consists of alpha-interferon and somatostatin analogues, which may show antitumoural activity and relieve endocrine symptoms. Today, several new biological agents have been introduced such as tyrosine kinase inhibitors, mTOR inhibitors and antiangiogenic agents. Various chemotherapy combinations are used in patients with endocrine pancreatic tumours, lung and thymic carcinoids and in patients with highly aggressive neuroendocrine tumours. Most patients with neuroendocrine tumours have a relatively good prognosis with long expected survival, but the prognosis in patients with poorly differentiated neuroendocrine tumours is poor.

Drugs that target tubulin, including the vinca alkaloids and taxanes, represent some of the most effective anticancer medications. Both natural-product and semisynthetic compounds show a remarkable spectrum of anticancer activity. In this chapter, we review new developments in cancer biology and pharmacology that shed light on the effectiveness of tubulin binding agents. In addition, we highlight newer agents and several drugs in preclinical development that hold considerable promise for the future. Finally, we comment on the rational selection of patients for chemotherapy and a more mechanistic approach to using these drugs in combinations.

Introduction

Chemotherapy, immunotherapy, and biological response modifiers were tested in clinical trials for brain tumors. Results of these studies published in 2003 and 2004 are reviewed.

Materials and methods

Major peer-reviewed journals in the disciplines of neurosurgery, neurology, medical oncology, and radiation oncology were surveyed. Results of phase II and phase III clinical trials testing chemotherapy, gene therapy, immunotherapy, and radiosensitizers for adults and children with malignant and low-grade glioma, primary central nervous system lymphoma (PCNSL), brain metastasis, medulloblastoma/primitive neuroectodermal tumor (PNET), and germ cell tumors were reviewed.

Results

Nitrosourea and temozolomide were tested as monotherapy or in combination with other agents as neoadjuvant, concurrent, and adjuvant treatment with radiotherapy for newly diagnosed malignant glioma in adults, including high-risk treatment groups, such as the elderly. Trials for recurrent malignant glioma included novel therapies, dendritic vaccine therapy, gene therapy and immunotherapy. High-dose chemotherapy with bone marrow rescue was tested in anaplastic oligodendroglioma (AO). Seven additional studies were performed to treat recurrent oligodendroglioma (O). Nine clinical trials for PCNSL emphasized the use of high-dose systemic methotrexate, temozolomide, and rituxin. Chemotherapy and immunotherapy were used to treat low-grade glioma in 7 studies. Intra-arterial and (IT) chemotherapy were used for metastatic disease. Treatment protocols for children were compared using multi-agent chemotherapy for malignant glioma, brainstem glioma, medulloblastoma, and germ cell tumors.

Conclusion

Multi-agent chemotherapy is successful for some pediatric brain tumors and PCNSL in adults. Vaccine, immunotherapy, and other gene therapies are still under investigation. Temozolomide and nitrosourea, specifically degradable polymer wafers, had the best results for malignant gliomas in adults. Treatment standards have been established for medulloblastoma/PNET. Treating malignant glioma in children remains problematic.