There has been no change in the management of primary malignant tumors of the brain (Glioblastoma Multiforme and anaplastic astrocytomas – astrocytomas Grades 3 and 4) for 20 years. Immunotherapy results show that radiation therapy can double life expectancy, and chemotherapy may add a few more months to median survival.
The modern use of Gamma Knife radiosurgery has pushed further the survival curve with its high response rate, but still there is no cure for this dreaded disease. Survival may be only 1 year from the time of diagnosis, with fewer than 5% living 5 years. Thus, a new approach had to be undertaken.
Brain tumor cells, being foreign to the body, should be able to be managed by our normal immunologic defenses as they would if a bacterial or viral infection occurred. Furthermore, there should be a “memory” of the foreign pathogen such that if the immune system came in contact with a tumor cell again, it could recognize and destroy it much like a second exposure to chicken pox.
Because of the infiltrative nature of Grade 4 astrocytomas versus the compact nature of Grade 1 astrocytomas, and the presence of their hypothetical “immunosuppressive barrier”, the cure for this tumor must be a biological one such as immunotherapy.
Why doesn’t this occur with primary malignant tumors of the brain? We think that brain tumors have evolved a way to evade our own defenses and produce a “wall” of immunosuppression. The cure for this brain tumor may well lie in the breakdown of this wall, or indeed the overwhelming of this wall with immunotherapy procedures.
In the early 1990s, researchers experimented with Interleukin-2 (IL-2) -activated lymphocytes and their in vivo effect on human brain tumors. Some immunotherapy results were excellent, but toxicities could be high. IL-2 is a “cytokine” – a type of chemical messenger which can enhance the immune response toward a foreign antigen (such as a tumor cell).
It was discovered that many cytokines may be automatically produced when two unlike, foreign, white blood cells come in contact. Thus, mixing the patients white blood cells with those of an unrelated donor, and allowing them to incubate in the lab for three days causes enhanced production of at least 7 different cytokines.
Mixture of host and donor lymphocytes causing the production of cytokines and the targeting of a tumor cell.
If these are placed in the tumor bed at the time of a tumor resection, presumably this “angry” white cell mixture can break the immunosuppressive barrier that Glioblastoma Multiforme and Anaplastic Astrocytomas inherently have, and enable the hosts own immune system to “seek and destroy” the abnormal tumor cells. This is called a Mixed Lymphocyte Culture or MLC.
The mixed Lymphocyte Culture three days after incubation, and their instillation into the tumor bed at the time of surgery.
RESULTS OF THE PHASE 1 MLC IMMUNOTHERAPY TRIAL 1996 – 1998
A “Phase 1″ study is performed to detect toxicity of a new experimental model. Of the 19 patients in the Phase I trial, there was no toxicity within a certain dose range of activated white blood cells, and 25% of the patients enrolled (1 patients with glioblastoma multiforme and 2 with anaplastic astrocytoma) are currently in complete remission with no evidence of active disease since their implantation in 1996.
Glioblastoma Multiforme (Grade 4 astrocytoma)
Before and 3 1/2 years post immunotherapy. Biopsies of the residual mass on the right showed only dead, necrotic tissue.
CURRENT TRIAL – HOAG MEMORIAL HOSPITAL PRESBYTERIAN
Malignant Brain Tumor Treatment Protocol
Hoag Memorial Hospital Presbyterian (Newport Beach, CA)
Christopher M. Duma, MD
Neurological Surgery, Gamma Knife Radiosurgery
The goal of the program is long-term survival, and attempts at a “cure” of perhaps one of the most difficult tumors to treat. This, in our opinion, is only possible using a combination of conventional therapies and various biological techniques. Surgery, radiation and chemotherapy alone are not the answer. Our protocol for a newly diagnosed brain tumor is as follows:
1A) Gross total (radiographically complete) tumor resection using specialized stereotactic neuronavigational techniques. It has been shown that when this is possible it markedly extends the patient’s chance of survival. Unfortunately it is not always possible for all tumors. Or,
1B) Stereotactic, MRI-guided biopsy (for tumors difficult to fully resect or tumors in eloquent locations in the brain).
2) Tissue from 1A and 1B above is sent for chemosensitivity assay and/or vaccine production.
3) Gamma Knife radiosurgery Boost to all abnormal tissue and if possible treatment of “the leading edge” of the tumor tracts (fingers) seen on post-operative scans. One day procedure. This alone has been shown to double the median survival. It is often directed by MR Spectroscopy, a technique which requires only a MRI scan, but the scan shows spectroscopic patterns which show live tumor molecules or dead tumor molecules.
4) Involved-field, conventional radiation therapy. (5-6 weeks) This has been shown to double life expectancy.
5) Chemotherapy. This is directed by the results of #2 above. The original tumor is grown in tissue culture and then exposed to different chemotherapy agents. Then selective sensitivity is then determined. In some cases tumor is only sensitive to certain agents and in others not at all. There is no sense in giving chemotherapy and compromising the immune system if the tumor will not respond.
6) IL-2 activated autologous lymphocytes. Our longest survivors had enrolled in this protocol. We have resumed this protocol at Hoag Memorial Hospital, and intend to use it in a series of 30 up-front patients. This means that only patients with newly diagnosed glioblasotomaglioblastoma multiforme are eligible. The lymphocyte portion of a peripheral blood draw is extracted and exposed to the cytokine IL-2 in vitro. This exposure activates the patients’ autologous cells over a 3-day incubation period. They are then implanted into the tumor bed after a thorough resection to debulk the residual/recurrent tumor.
7) Re-operation for a radiographically complete resection, possible implantation of Gliadel chemotherapy wafers, and return to step #2 above.
Of course any patient of the immunotherapy for brain tumor may enter the protocol at any point depending upon their previous treatment strategies.
We have been using the above protocols for all of our patients with anaplastic astrocytoma and glioblastoma multiforme and other malignant gliomas (oligodendrogliomas, mixed tumors, etc.) We are following some patients who have completed only up to step 3 since 1997 without a recurrence. Thus some of my patients are in complete remission with only the initial phases of this regimen.
Please send your films and a short history to my Orange County office in Newport Beach, California. We will enter you into our data base, present your films free of charge at our weekly Gamma Knife, multidisciplinary Tumor Board, and get back to you by telephone or by mail with our recommendations. Otherwise, preferentially, please make an appointment at my office to discuss these options in person.