Imaging‐guided convection‐enhanced delivery and gene therapy of glioblastoma

Abstract

In a prospective phase I/II clinical study, we treated eight patients suffering from recurrent glioblastoma multiform with stereotactically guided intratumoral convection-enhanced delivery of an HSV-1-tk gene-bearing liposomal vector and systemic ganciclovir. Noninvasive identification of target tissue together with assessment of vector-distribution volume and the effects of gene therapy were achieved using magnetic resonance imaging and positron emission tomography. The treatment was tolerated well without major side effects. In two of eight patients, we observed a greater than 50% reduction of tumor volume and in six of eight patients focal treatment effects. Intracerebral infusion of contrast medium before vector application displayed substantial inhomogeneity of tissue staining indicating the need of test infusions to monitor the mechanical distribution of vectors. Visualization of therapeutic effects on tumor metabolism and documentation of gene expression using positron emission tomography indicated that molecular imaging technology appears to be essential for the further development of biological treatment strategies.

Imaging in neurooncology

“…119 Moreover, metabolic or molecular information derived from PET or SPECT studies is being used in some institutions for the exact planning for radio- 105 and gene therapy. 120,121 This is of special importance because tumor volume as depicted by contrast-enhanced MRI is always smaller than the tumor volume as depicted by [ 11 C]MET-PET. 97 Whether [ 11 C]MET-PET-guided extended fields of radiation have a significant influence on time to progression and overall survival has to be proven in future studies.…”

“…5). 120,121 In trials employing convection-enhanced delivery of local chemotherapeutics, DWI is being used to assess the convective process and routine diagnostic MR imaging to identify the tumor response. 132 …”

“…171,172 Especially the design of small tumor-specific antibody fragments is an attractive way for specific detection of Many of the current experimental protocols investigating new drug and treatment strategies for experimental gliomas include MRI, optical or PET imaging of either the distribution of therapeutic agents, [173][174][175] or therapyinduced tumor-changes, 171,176 -184 with the overall attempt of designing image-guided treatments. 120,121 Most intriguing for potential clinical application is the design of multifunctional nanoparticles that can be detected both by MRI and fluorescence imaging, allowing for the noninvasive preoperative assessment of the tumor and for the intraoperative visualization of tumor margins by optical imaging. 185 …”

Transposon-based interferon gamma gene transfer overcomes limitations of episomal plasmid for immunogene therapy of glioblastoma

“…3 Despite advances in surgery, radiation and chemotherapy, the prognosis for GBM patients remains dismal with a median survival of 15 months and 2-year survival rate below 27%. 8 Gene therapy has shown modest efficacy in GBM patients, 3,9,10 but curative therapy remains an elusive goal.…”

Gene Directed Enzyme-Prodrug Therapy

“…The encouraging results obtained in the preclinical studies led to its application in a number of clinical trials against different types of cancers (20)(21)(22)(23)(24)(25). Positive results have been obtained in these clinical trials; however, it is far from a perfect system because gene targeting and drug delivery to the tumor cells remains challenging.…”