Clinical Trial Finder

Inclusion Criteria:

1. Histopathologically proved WHO grade-4 malignant glioma. 2. Age: 13 years (physically mature) to 70 years. 3. Karnofsky performance score before surgery: ≧70 [Karnofsky 1951] . 4. Adequate liver functions, including serum alanine aminotransferase (ALT or SGPT), serum aspartate aminotransferase (AST or SGOT), and alkaline phosphatase at ≤3.0 times upper limits of normal levels (ULN), total bilirubin ≤1.5mg/dl), total serum bilirubin <3 mg/dl. 5. Adequate renal function (BUN ≤25 mg/ml; creatinine≤1.8 mg/dl，creatinine clearance >50 ml/min prior to starting therapy. 6. Hemoblobin≧8 g/dl，platelet ≧100,000/μl，WBC>2,000/μl; absolute neutrophil count >1,000/μl. 7. Prothrombin time and partial thromboplastin time≦1.5x the normal upper limit.

Exclusion Criteria:

1. Pregnant or breast feeding. 2. With radioactive implant. 3. Acute infection, fever. 4. Active collagen diseases. 5. Acute cardiovascular diseases. 6. Acute viral hepatitis. 7. Syphilis. 8. Human immunodeficiency virus (HIV) infection. 9. Carrier of other transmissible infection. 10. Immune deficiency due to chronic disease

Rationale and Background : Glioblastoma multiforme (GBM) and other WHO grade IV malignant gliomas of the brain are among the most lethal of human cancers. Despite current intensive multimodal regimen including the use of temozolomide (TMZ) for combined chemo-radiotherapy (CCRT) and for subsequent adjuvant chemotherapy, the medium survival period of GBM patients is still 8-16 months after diagnosis and surgery, with prognosis varied according to demographic features such as age, radiotherapy types and chemotherapy measures.These fatal brain cancers in general contain cancer cells with mutation in certain genes. Also, the mutated GBM cancer cells are usually heterogenous; and different GBM patients may have individual sets of heterogenous glioma cancer cells in which the mutant genes would generate altered antigens that can be recognized by the patient's adaptive immune system to mount immuno-targeting responses to reject or kill the GBM tumor cells. However, GBM is still fatal because it is highly immunosuppressive, i.e. able to anergize the immune effector cells in the body. Although surgical resection of rapidly expanding tumor bulk will prevent further physical damages to the brain and curtail the immunosuppression, the already anergized effector T lymphocytes still require functional restoration. On the other hand, post-surgical TMZ CCRT and adjuvant chemotherapy may weaken the residual tumor cells, but TMZ will also impair if not kill the active T lymphocytes in general, including anti-GBM lymphocytes. It is therefore important to exploit the adaptive immunity system for effective therapy of GBM. To apply the adaptive immunotherapy, it is best to use each patient's surgical tumor specimen to prepare the own individual "tumor regression antigens" for loading onto the patient's own dendritic cells (the "professional" antigen processing and presenting cells of the immune system). Dendritic cells loaded with tumor-specific antigens, upon maturation and inoculation ("vaccination"), would migrate/home to the T cell area of lymph nodes and stimulate proliferation of tumor-specific cytotoxic T lymphocyte that would move out of lymph node to find the brain tumor lesion to attack and eradicate the residual GBM tumor cells, resulting in prevention of GBM recurrence. With fore-mentioned working hypotheses, the investigators carried out translational research from 1997 to 2002. A special method has been developed for production of an immunotherapeutic, which is named "autologous dendritic cell/autologous tumor cell antigens of GBM" (ADCTA-G). For clinical trial purpose, the investigators have established standard operational procedures (SOP) of the method with the use of clinical Good Manufacturing Practice (cGMP)-grade cytokines and pharmaceutical reagents. Individual ADCTA-G lots of all participant GBM patients are manufactured in high efficiency particle arresting (HEPA) air-filtered, germ-free bio-safety barrier clinical Good Laboratory Practice (cGLP) facilities. The phase I/II clinical trial was officially approved by Taiwan Department of Health and performed in a clinical center to demonstrate that ADCTA-G adjuvant immunotherapy was safe and apparently could prolong the survival for GBM patients.

Arms

Experimental: Single arm, open-label

Experimental: ADCTA-G total 10 doses, each dose (30+/-5 millions autologous dendritic cells plus 6+/-0.5 millions 100Gy-irradiated short-term cultured autologous GBM tumor cells) divided in 2 halves for subcutaneous injection into both axillar areas, in a course of 6 months (sequential series of weekly injections 4 times, bi-weekly injections twice; then monthly injections 4 times. Experimental: ADCTA-G total 10 doses, each dose (similar fore-mentioned numbers of 5:1 ratio of autologous dendritic cells and irradiated short-term cultured autologous GBM tumor cells) divided into 2 injections administered subcutaneously in both axillar areas, in a course of 8 months (sequential series of bi-weekly injections 4 times, then monthly injections 6 times).

Interventions

Biological: - Single arm, open-label

Biological: ADCTA-G. Biological: autologous DC loaded with irradiated autologous tumor cells. Biological: dendritic cell "vaccine". Drug: 180mg/m2•per day temozolomide prior and concomitant with radiotherapy. Radiotherapy: Local ionizing radiation 200 centigray(cGy)/day, 5 successive days per week for 6 weeks, total dose of 6000 cGy. Drug: Adjuvant chemotherapy-temozolomide (TMZ) monthly cycle, 200mg/m2•per day continued for 5 days in the beginning of every month, 6 cycles of TMZ.