Malignant Brain Tumor Treatment Protocol
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Hoag Memorial Hospital Presbyterian (Newport Beach, CA)
Good Samaritan Hospital (Los Angeles, CA)

Christopher M. Duma, MD
Neurological Surgery
Originally submitted: Feb. 10, 1999
Last time verified: 12/5/2005



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 my opinion, is only possible using a combination of our conventional therapies and various biological techniques. Surgery, radiation and chemotherapy alone are not the answer. Our protocol for a newly-diagnosed tumor is as follows, of course any patient may enter the protocol at any point depending upon their previous treatment strategies.

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 is grown in tissue culture for enrollment in our Phase I, FDA-approved tumor vaccine protocol.

3) Gamma Knife Radiosurgery Boost to all abnormal tissue seen on post-operative scans. One day procedure. This alone has been shown to improve the median survival by 1 full year, over and above the current survival statistics.

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. Furthermore, the dismal results of adding chemotherapy to a patient's regimen compounded with its immunosuppressive effects makes us unlikely to use chemotherapy in a patient's regimen.

6) At the first sign of recurrence of tumor one or all of the following may be instituted at some point depending on the location, and size of the recurrence:

6A) Mixed lymphocyte immunotherapy. Described in our website and below:
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.
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 cancer may well lie in the breakdown of this wall, or indeed the overwhelming of this wall.
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.

Approximately 4 years ago, my colleagues Drs. Deane (Skip) Jacques and Gale (Morrie) Granger experimented with Interleukin-2 (IL-2) activated lymphocytes and their in vivo effect on human brain tumors.
The results were excellent in some 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.
If these are placed in the tumor bed at the time of a repeat 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.

Results: A "Phase 1" study is performed to detect toxicity of a new experimental model.
Of the 19 patients in the Phase I trial at Good Samaritan, there was no toxicity within a certain dose range of activated white blood cells, and 25% of the patients enrolled (4 patients with glioblastoma multiforme and 1 with anaplastic astrocytoma) are currently in complete remission with no evidence of active disease up to 3 years from implantation.
Another 19 patients are able to be enrolled in Phase 2, and results expect to surpass those of the Phase 1 due to better patient selection.

Basic inclusion criteria are:

  1. Ages 18-70
  2. Recurrent disease, GBM or Anaplastic astrocytoma
  3. At least 8 weeks out from last chemotherapy
  4. Unifocal disease (disease present in only one area of the brain)


6B) IL-2 activated autologous lymphocytes. Our longest survivors had enrolled in this protocol. Some have been alive now for 10 years or more. We have resurrected this protocol at Hoag Memorial Hospital, and intend to use it in a series of 19 patients.
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. The action is much like protocol "6A" above.

6C) Immunotherapy: OKT-3 (Anti-CD 3) Phase I, FDA approved protocol. This is the same agent used to suppress the immune response in patients who have undergone kidney and liver transplants. However, in low doses this antibody actually upgrades the immune response. The antibody is injected into the patient systemically to mount an internal immune response. We have performed this on 8 Brain tumor patients with a 75% response rate. Two of the patients (50%) are still in remission at 2 years follow-up. Good for patients in which the tumor is diffuse and truly unresectable.

6D) Tumor cell-directed vaccine. The original tumor cells from #2 above, are grown in tissue culture, exposed to an agent which upgrades the antigens on the tumor cells (makes them more recognizable and more visible to the immune system) and then killed. The inactive tumor cells are then injected into the lymphatic system of the leg of the patient directly in order to set up a cell-directed immune response.

7) Re-operation for a radiographically complete resection and return to step #2 above.

I have been using the above protocols for all of my patients with anaplastic astrocytoma and glioblastoma multiforme and other malignant gliomas (oligodendrogliomas, mixed tumors, etc.) I am following some patients who have completed only up to step 3 for more than 1 1/2 years 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 either my Orange County office in Newport Beach, California or my Los Angeles office whichever is more convenient for you. 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 one of my two offices to discuss these options in person.

Regardless of your treatment decisions, I wish you the best of luck.

Sincerely,
Christopher M. Duma, MD
 
Good Samaritan Hospital  Hoag Memorial Presbyterian Hospital
Medical Office Building  Gamma Knife and Brain Tumor Center
1245 Wilshire Blvd., Suite 305  One Hoag Drive, Building 41
Los Angeles, CA 90017  Newport Beach, CA 92663
213-977-0494  714-760-5938




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