Transcript of Live Chat, from May 14, 2001
Hideho Okada M.D., Ph.D.
Moderator: Al Musella, DPM President, Musella Foundation
Research Assistant Professor of Neurosurgery and Surgery
Co-Director, Vector Core Facility, Pittsburgh Human Gene Therapy Center
University of Pittsburgh Medical Center
208 Center for Biotechnology and Bioengineering
300 Technology Drive
Pittsburgh, PA, 15219
Phone: (412) 383-9759
FAX : (412) 383-9760
Location: Virtualtrials.com Auditorium
MUSELLA: "Our guest is Dr. Hideho Okada, A neurosurgeonand research assistant at the U. Of Pittsburgh Human Gene therapy center"
MUSELLA : "His topic tonight is Gene Therapy for brain tumors"
MUSELLA : "Our first question is:"
MUSELLA : "Can you explain, in plain English, how your treatment works?"
Dr. Okada: "Our approach is more like an immunotherapy. We put genes which stimulates patients' immune system so that patients' immune system can fight against cancers"
MUSELLA : "How do you put the gene in?"
Dr. Okada: "We first operate patients and take tumor cells out, and put genes in the laboratory., we place those cells back to the patients' subcutaneous site as vaccines. We use retrovirus system for this"
MUSELLA : "How does this compare to what Dr. Blacks' groupd does?"
MUSELLA : "with a vaccine?"
Dr. Okada: "but patients themselves NEVER get viruses injected. Virus vectors are used only in the lab."
MUSELLA : "So you put tumor cells back in?"
Dr. Okada: "Dr. Black group uses dendritic cells, We stimulate endogenous dendritic cells in patients body using cytokine genes"
Dr. Okada: "correct"
MUSELLA : "Who would be a good candidate for your treatment? Newly diagnosed / recurrent / what tumor type?"
Dr. Okada: "recurrent glioblastomas or anaplastic astrocytoma"
MUSELLA : "Is it ok if they have tumor all over the place, or just localized to a small area?"
Dr. Okada: "tumor has to be somehow resectable because we make vaccines with cells, also patient s have to be off steroid at the time of the vaccine"
MUSELLA : "How many patients have you treated so far, and how did it go?"
Dr. Okada: "that means, widely diffused tumors are less likely to be our canf=didate"
Dr. Okada: "One patient. We seem to have sustained the tumor growth for half a year."
MUSELLA : "Are you actively looking for more patients,"
MUSELLA : "or waiting to see how that one goes?"
Dr. Okada: "yes we are looking for the next patient"
MUSELLA : "Has this type of gene therapy been done at other facilities?"
Dr. Okada: "UCLA group may have done similar approach using TGF-beta antisense. We have compared several cytokines and found IL_4 is the best for gliomas in animal models"
MUSELLA : "Can this be done on children? Or with low grade tumors, such as PNET / medulloblastoma?"
Dr. Okada: "We are working on the paper work so that we can extend the eligibility to children"
MUSELLA : "I assume this is a far way off from FDA approval?"
Dr. Okada: "however, medulloblastoma/PNET may not be our target, yet."
Dr. Okada: "Well, I don't think it's far away,"
MUSELLA : "How does this compare to say Dr. Hayes trial of using IL-4 + LAK Cells injected into an ommayo reservoir"
Dr. Okada: "LAK is not very specific effector cells, we aim to generate moe specific response by IL-4 transfected tumor cell vaccine"
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MUSELLA : "What is the specific name of the gene and the retrovirus you use?"
Dr. Okada: "a retroviral vector encoding human interleukin-4, herpes simplex thymidine kinase (HSV-TK), and neo resistance,"
Dr. Okada: "HSV-TK is to eliminate vaccine cells from patients' body"
MUSELLA : "Do you use gangcyclovir after injecting the cells?"
Dr. Okada: "neo resistance gene is to select gene transfected cells"
Dr. Okada: "yes, we do"
MUSELLA : "A few people just asked for your contact information."
Dr. Okada: "email@example.com"
Dr. Okada: "phone 412-383-9759"
Dr. Okada: "fax 412-383-9760"
MUSELLA : "Did that first patient have any imediate side effects from the procedure?"
Dr. Okada: "No."
MUSELLA : "Can you use a frozen tumor specimen from a previous surgery, or do you need to do your own surgery?"
Dr. Okada: "we have to do surgery within our institute in order to grow vaccine cells in GMP quality"
MUSELLA : "Then another surgery is needed to put the cells back in? How long after the first surgery?"
Dr. Okada: "No, vaccine cells will be put back i patientts' thigh"
MUSELLA : "that's great!"
MUSELLA : "is this a one time procedure,"
Dr. Okada: "there is no need for another surgery, injection is about 6 weeks after craniotomy"
MUSELLA : "or do you do it multiple times?"
Dr. Okada: "we give two cyces of vaccines with two weeks interval"
MUSELLA : "Is this covered by insurance?"
Dr. Okada: "Experimental part (i.e. vaccine) is covered by funding (NIH), surgery by insurance"
MUSELLA : "Can the patient have prior chemotherapy? One person asks about her sister, being treated at your hospital already,"
MUSELLA : "she has a GBM, but is now on cpt-11 and temodar"
MUSELLA : "already had surgery, radiation and bcnu"
Dr. Okada: "Patients have to have gone through all the conventional therapies incl. chemo and RT"
MUSELLA : "do they have to stop the temodar + CPT-11, for how long?"
MUSELLA : "Would it make sense to do it when they need the next surgery?"
Dr. Okada: "if temodar/CPT-11 is effective, pt should continue with current therapy"
MUSELLA : "Can you tell us about the other gene therapy trials going on around the USA?"
Dr. Okada: "for the previous question, we shall consult the case before the next surgery if hte patient wishes"
Dr. Okada: "I am unable to update all the gene thrapy trials in this country"
MUSELLA : "OK. Another questions:"
MUSELLA : "If only part of the tumor is resectable, is that ok?"
Dr. Okada: "as far as we can drive patients steroid free, that's OK."
MUSELLA : "What happens if there is swelling from the procedure - are steroids absolutely forbidden?"
Dr. Okada: "we do use steroid if needed. Safety first!! use of steroid after vaccine does not necessarily mean failure"
MUSELLA : "Is your type of gene therapy being done anywhere else in the world?"
Dr. Okada: "In terms of immune gene therapy in a vaccine form, UCLA group."
MUSELLA : "How many patients do you need before getting approval, assuming things go well?"
Dr. Okada: "Back in 80's vaccines with tumor cells without cytokines were"
Dr. Okada: "we plan to recruit 20 patients for Phase I/II trial"
MUSELLA : "what were you saying about the '80s?"
Dr. Okada: "There was a trial using irradiated allogeneic glioma cell vaccine in 1980's"
MUSELLA : "How did it turn out?"
Dr. Okada: "there seem to be some response, but our preclinical data clearly indicates use of cytokine gene provides more benefits"
MUSELLA : "If a patient entered this trial, would that prevent you from inserting gliadel wafers at the time of surgery"
Dr. Okada: "Unfortunately, yes."
MUSELLA : "have you heard of ""specific targetting therapy"" by Dr. Sako in Japan, 10 years ago - reported unbelievable results,"
MUSELLA : "with a bispecifc antibody injected into the tumor"
Dr. Okada: "I know of bispecific antibody stories. I am not sure if they still keep the same approach open in clinic"
MUSELLA : "What are you thoughts on the use of Gliadel wafers - (in general - when not considering your trial)"
Dr. Okada: "Interesting approach, although I am not sure how far the wafers can convey the effect to the invading edge of the tumors"
MUSELLA : "Are the tumor cells that you inject into the thigh alive or dead?"
Dr. Okada: "They are actually alive. Our preclinical data indicate non-irradiated live cells works much better, we have HSV-TK CGV system to eliminate themC"
MUSELLA : "Would a patient with a pilocytic astrocytoma or a medulloblastoma be eligable for your trial (2 seperate questions:)"
Dr. Okada: "Unfortunately, none of those tumor types are eligible at this point"
MUSELLA : "So when you give gangcyclovir, these injected tumor cells will all die - right?"
Dr. Okada: "That's correct."
MUSELLA : "What would be your ideal treatment plan for a newly diagnosed patient with a gbm?"
MUSELLA : "Assume a healthy 30 year old"
Dr. Okada: "If it is resectable, resection, followed by irradiation. As soon as we complete the first few patients, we will make our IL-4 vaccine available for newly diagnosed cases because our lab data indicates irradiation and immmuno gene therapy may work in a synergistic fashion"
MUSELLA : "A few people are apprehensive about being only the second person to try your treatment... but this is just a variation on a treatment that has been done on hundreds of patients, correct?"
Dr. Okada: "I think you are right."
MUSELLA : "Do you know of any research papers that explain your treatment in depth?"
MUSELLA : "can you get us the references (later - and I will add them to the transcript)"
Dr. Okada: "If you ask about our own publications, we have several papers published. I am happy to give you references"
MUSELLA : "Do you see this treatment as an attempt at a cure, or just to buy some time?"
Dr. Okada: "Since we are at Phase I stage, the primary goal has to be to prove safety. But it was a pleasant surprize to see some clinical response in the first patient. Well, in phase I, in which we treat recurrent huge tumors, it may not be easy to dream of melting tumors with immune system, but in future, if tis therapy is applied to primary cases, we may be able to cure"
MUSELLA : "Would this be specific to brain tumors? Or would a patient with metastatic colon (or breast) tumors which spread to the brain be helped both in the brain and systemic tumors?"
Dr. Okada: "At this point, the clinical trial is NT available to metastatic brain tumors, but we plan to apply our approach to those in near future"
MUSELLA : "IF you tried it on a metastatic tumor - do you think it would help the systemic tumors also?"
Dr. Okada: "Yes, in fact, there are trials with very similar approach for metastatic melanomas and renal cancers"
MUSELLA : "A patient who has an anaplastic astrocytoma, who had had surgery and radiation only - and doesn't want to do chemo - could she be eligable? You mention they had to fail chemo first?"
Dr. Okada: "She might be eligible. ,"
MUSELLA : "Since this is a phase 1 trial, are you going to be dose escalating over the next few patients?"
Dr. Okada: "In our current design, we have intra patient dose escalation; which means that we give five shots of vaccine with grading doses at the same time and see reactions. We are not planning more usual type dose escalation"
MUSELLA : "We have about 4 minutes left, and 100 questions left on non-gene therapy questions:).. about 30 of them deal with the new drug, Gleevec. Do you know anything about the use of Gleevec for brain tumor"
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Dr. Okada: "We have an open study in our institute."
MUSELLA : "See any results yet?"
Dr. Okada: "not yet. I am curious how it works if it works, it was designed specifically for the fusion gene product thymidine kinase in CML cells"
MUSELLA : "As a neurosurgeon, what are your thoughts about the importance of the new high tech gadgets, like intra-operative MRI? Is it just a gimmick, or is it very important?"
Dr. Okada: "It is important. It would allow us to know more exact loation of brain structure intraoperally. Pre-ope brain mapping always loose precision as soon as the brain is opened"
MUSELLA : "That concludes our chat.. Thank you very much for your time! Everyone can now chat.."
The following references were added after the chat was over:
- Okada H., Giezeman-Smits KM., Tahara H., Attanucci J., Fellows WK., Lotze MT., Chambers WH., and Bozik ME. Effective cytokine gene therapy against an intracranial glioma using a retrovirally transduced IL-4 plus HSV-TK tumor vaccine Gene Therapy 6, 219-226, 1999
- Okada H., Attanucci J., Tahara H., Pollack IF, Bozik ME., Chambers WH., and Lotze MT. Characterization and transduction of a retroviral vector encoding human interleukin-4 and the Herpes simplex-thymidine kinase for glioma tumor vaccine therapy. Cancer Gene Ther;7(3):486-494 March 1, 2000
- Okada H., Attanucci J., Giezeman-Smits KM., Brissette-Storkus C., Fellows WK., Pollack IF., Bozik ME., Lotze MT., and Chambers WH. An antigen identified by cytokine tumor vaccine-assisted SEREX (CAS) suppressed growth of a rat 9L glioma in vivo. Cancer Research 61, 2625-2631, March 15, 2001
- Okada H., Lotze MT., Pollack IF., Kondziolka D., Lunsford L.D., Lieberman F., Shiff D., Attanucci J., Edington H., Chambers WH. Robbins P., Baar J., Kinzler D., Whiteside T., Elder E., Potter D. Gene therapy of malignant gliomas: a phase I study of IL-4-HSV-tk gene-modified autologous tumor to elicit an immune response (Clinical Protocol) Human Gene Ther 11:637-653, March 1, 2000
- Giezeman-Smits KM, Okada H.,, Brissette-Storkus C., Villa LA, Attanucci J., Lotze MT., Pollack IF, Bozik ME, Chambers WH. Cytokine gene therapy of gliomas: Induction of Reactive CD4+ T cells by interleukin-4-transfected 9L gliosarcoma is essential for protective immunity. Cancer Research 60 (9) 2449-2457, May 1, 2000
- Okada, H., Villa L., Attanucci J., Erff M., Fellows W.K., Lotze M.T., Pollack I.F., and Chambers W.H.. Cytokine gene therapy of gliomas: Effective induction of therapeutic immunity to intracranial tumors by peripheral immunization with IL-4-transduced gliomas cells. (Gene Therapy in press).