Phase 1 Study in Humans Evaluating the Safety of Rectus Sheath Implantation of Diffusion Chambers Encapsulating Autologous Malignant Glioma Cells Treated With Insulin-Like Growth Factor Receptor-1 Antisense Oligodeoxynucleotide in 12 Patients With Recurrent Malignant Glioma

This trial will be an adaptation and continuation of a previously published trial, reproducing the original study size of 12 patients. Modifications from the previous trial include a modified oligodeoxynucleotide sequence and treatment at initial diagnosis, which would occur with concomitant standard therapy in an additional Phase 1 trial as a continuation if no rate-limiting toxicity is noted in the original Phase 1 arm. For practical purposes, a standard Phase 1 dose-escalation study is not possible with the current paradigm. Although we may have identified a distinct bioactive byproduct of IGF-1R/AS ODN-induced tumor cell apoptosis (exosomes), it is difficult to perform a dose escalation in a typical fashion. Also, antigen concentration can affect immune response in a biphasic manner: too little or too much can dampen an immune response, so even if the antigen or antigens were known, a typical pharmacologic dose escalation would not follow typical pharmacokinetics. For these reasons, we have designed a follow-on Phase 1 arm in which 32 patients will have therapy at initial surgery in 4 cohorts of 8 patients each. We will vary chamber number and implantation duration for each of the four cohorts in the additional Phase 1 arm. When we documented an increase in tumor infiltrating lymphocytes after treatment in our original trial, this observation provided preliminary supporting evidence that this therapeutic vaccine will elicit an adaptive immune response. We have designed the Phase 1 arm to further elucidate an immune response with a quantitative assessment of tumor specific T cells as well as circulating M2 macrophages before and after treatment. The design of the Phase 1 phase of the trial will allow a statistical analysis of both antigen dose (number of chambers) and time of exposure (chamber dwell time) as either variable may relate to any toxicity or treatment response.

A summary of the treatment paradigm includes: Pre-operative plasma leukopheresis, then surgery with tissue harvest and implantation of up to 10 chambers in the rectus sheath with IGF-1R/AS ODN as previously reported within 24 hours of craniotomy plus one chamber containing only phosphate buffered saline. Twelve patients treated for recurrent disease will be assessed for safety of the treatment. If the safety profile is acceptable, the trial will be followed by accrual of 32 patients in an additional Phase 1 trial as a continuation over approximately 3 years prospectively from Thomas Jefferson University Hospital and the Jefferson Hospital for Neuroscience. All patients who meet the eligibility criteria and agree to participate in this study will be potential candidates for therapy.

Pre-Operative Preparation - Patients will consent to a plasma leukopheresis at least 3 days prior to elective craniotomy. The PBMC will be stored for subsequent analysis of T cell responses, the presence of IL-10-producing M2 macrophages, and dendritic cell (DC) preparation. ELISPOT assays will be performed to measure T cell responses to autologous tumor cells and allogeneic tumor cells (U118 tumor lysate) utilizing cross-primed DC to assess both native anti-glioma immunity any acquired immunity after treatment. If U118 allogeneic glioma cells elicit a CTL response, this cell line may serve as an antigen source for future serial vaccination protocols.

A pre-operative PET scan as a baseline against which we can compare post-treatment PET scans as indicated.

Surgery and Tumor Cell Retrieval - Craniotomy and MRI-based image guided tumor resection will be performed on all study patients by an experienced neurosurgeon . All tested malignant gliomas obtained from craniotomies performed at Thomas Jefferson University have expressed the IGF-1R (M. Resnicoff, personal communication). During resection, viable tumor tissue will be confirmed by pathologic examination of frozen sections, and then sent to a BL-2 facility for disaggregation and plating in culture. Permanent section analysis will include an IGF-1R immunostain to determine the presence of IGF-1R. Once the cells are attached, cells will immediately be treated with IGF-1R/AS ODN. Tumor cells will be incubated with IGF-1R/AS ODN for a maximum of 6 hours and 106 cells will be then be loaded into each chamber and a target maximum of 10 chambers prepared. For all combination lot productions, two additional irradiated chambers and 300 ul of treated autologous tumor cells will be sent to microbiology for assessment of sterility according to FDA requirements. Greater than 5 and less than 10 chambers will be scored as a minor protocol violation. Recovery of no viable cells will be grounds for disenrollment from the protocol. Prior to implantation, the chambers will be irradiated with 5 Gy of X-irradiation as previously described. An additional tumor sample will be flash-frozen for exploratory research objectives. At the time of craniotomy the surgeon will create an abdominal acceptor site for subsequent diffusion chamber implantation in the rectus sheath. This implantation site was chosen for the following reasons: (1) it yielded objective favorable biological responses in the prior human Phase 1 trial; (2) this site will easily accommodate multiple chamber implantations; (3) this site should elicit a strong host response due to the extent of the wound, the introduction of a foreign body and its contents, the vasculature of the rectus sheath and muscle, and the favorable inguinal node lymphatic drainage from this site; and (4) exposure of the rectus sheath and muscle is familiar to neurosurgeons all of whom commonly perform ventricular-peritoneal shunts.