Brain Tumour Survivor

A site dedicated to leading edge treatment for brain tumours
It is currently Mon Dec 17, 2018 1:27 pm

All times are UTC + 10 hours




Post new topic Reply to topic  [ 7 posts ] 
Author Message
PostPosted: Mon Oct 20, 2008 8:53 pm 
Offline
Registered User

Joined: Sat Nov 04, 2006 10:18 pm
Posts: 360
Location: Australia
Interleukin-13 receptor as a unique target for anti-glioblastoma therapy
http://cat.inist.fr/?aModele=afficheN&cpsidt=1027259
Résumé / Abstract
Surgery, radiotherapy and chemotherapy have minimally altered survival of glioblastoma patients. We explored a specific approach for glioblastoma therapy in which cellular interleukin-13 (IL-13) receptors were targeted by an IL-13 cytotoxin. A wide array of human glioblastoma cell lines expressing the receptor for IL-13 were effectively killed by an IL-13 cytotoxin, a chimeric protein composed of human IL-13 and a mutated form of Pseudomonas exotoxin (termed IL13-PE38QQR or IL-13 toxin). Daily (qd) intratumoral injections of IL-13 toxin (50 and 100 μg/kg/day) for 5 consecutive days into subcutaneous human U251 glioblastoma tumors (approx. 30 mm2) in nude mice resulted in complete regression of tumors in 4/5 and 5/5 mice, respectively. Tumor regression persisted for at least 221 days postimplantation. Three alternate day injections (qod) of IL-13 toxin (250 μg/kg/day) into other subcutaneous U87 glioblastoma tumors also produced durable complete responses (CR) in all 5 mice. Twice daily (bid) intraperitoneal injections of IL-13 toxin at 25 or 50 μg/kg/dose for 5 days (total doses = 10) regressed U251 tumors by 45% and 58% with 1/5 and 2/5 CRs, respectively, on day 54. Intraperitoneal administration of IL-13 toxin with an identical schedule at a dose of 50 μg/kg injected into mice bearing U87 xenografts reduced tumor burden by one-half on day 36. Similar doses (25 or 50 μg/kg) with a daily schedule (qd x 5) by the intravenous route also suppressed growth of U251 subcutaneous tumors by 75% and 81% with 1/6 CR in either group by day 34. All mice tolerated therapy well without any visible signs of toxicity. On the basis of these studies, we have initiated a Phase I clinical trial using IL13-PE38QQR in patients with recurrent glioblastoma.

Immunotoxins for Glioma Therapy
http://www.springerlink.com/content/q3t0gr7r3x1w5788/
Targeting cancer cells with an immunotoxin represents a novel therapeutic approach. Several immunotoxins composed of a ligand or antibody and truncated bacterial toxins are in clinical development to treat various cancers including glioblastoma multiforme (GBM). GBM is an infiltrative tumor that defies a “ecomplete surgical resection”e invariably recurring most often at the site of resection. A number of local therapies are being explored. One approach is to identify unique or over-expressed cell surface receptors on GBM cells and targeting them with a receptor-specific immunotoxin. We have identified over-expression of a receptor for an immune regulatory cytokine, interleukin-13 (IL-13) on human malignant glioma cell lines, primary brain tumor cell cultures, and tumor tissues. The targeting of IL-13 receptors (IL-13R) with a recombinant fusion protein composed of IL-13 and a mutated form of Pseudomonas exotoxin (IL 13-PE3 8QQR or IL-13-PE38, referred to here as IL 13-PE) demonstrated apotent and specific cell-killing of GBM cells in vitro. Normal brain cells, immune cells, and endothelial cells devoid of the unique IL-13R chain were not susceptible to immunotoxin cell killing activity. Direct injection of IL13-PE into subcutaneous (sc) or intracranial human GBM tumors in nude mice resulted in complete and durable regression of tumors. IL13-PE delivered through intravenous (iv) and intraperitoneal (ip) routes of administration also reduced sc tumor burden with fewer complete responses (CR). High doses of systemic (up to 50 μg/kg) or intracerebral (up to 100 μg/mL) IL13-PE were well tolerated in mice and rats, respectively without evidence of gross or microscopic necrosis.
Based on these encouraging preclinical results, four phase I and II clinical trials were initiated to investigate the safety, toxicity, and optimal convection-enhanced delivery (CED) of IL13-PE to patients with recurrent malignant gliomas; patients had already undergone standard therapy including surgery, radiation, and chemotherapy. CED uses a positive pressure to generate a pressure gradient that optimizes distribution of the macromolecule within tumor and peritumoral regions. A total of 97 patients were treated with IL13-PE in these studies. CED of IL13-PE into solid tumor component as well as the surrounding brain tissues felt to be at risk for residual infiltrating tumor before and after tumor resection, respectively was fairly well tolerated in terms of safety profile. Histological antitumor effects have been observed at drug concentrations of 0.5, 1.0 and 2.0 μg/mL without apparent increased antitumor activity at higher concentrations. Duration of infusions up to 7 d was fairly well tolerated. A randomized worldwide phase III clinical trial (PRECISE, phase III Randomized Evaluation of Convection Enhanced Delivery of IL 13-PE3 8QQR with Survival Endpoint) is currently recruiting patients with recurrent supratentorial GBM at first recurrence to evaluate overall survival duration, safety, and quality-of-life of patients treated by tumor resection followed by peritumoral IL13-PE infusion vs Gliadel® Wafer placement.

Complete regression of established human glioblastoma tumor xenograft by interleukin-4 toxin therapy.http://www.ncbi.nlm.nih.gov/pubmed/9721874
No curative therapy is available for malignant gliomas. We have discovered that human glioblastoma cells express high affinity interleukin-4 receptor (IL-4R), which is an attractive target for receptor-directed IL-4 toxin therapy. The IL-4 toxin, IL-4(38-37)-PE38KDEL, is a fusion protein containing translocation and enzymatic domains of Pseudomonas exotoxin and a circularly permuted human IL-4. The IL-4 toxin binds specifically to the IL-4R and is highly cytotoxic to glioblastoma cells, as determined by clonogenic and protein synthesis inhibition assays. Intratumoral administration of the IL-4 toxin given on alternate days for 3-4 doses into U251 glioblastoma flank tumors in nude mice, showed a complete remission of small (approximately 13 mm3) and large (approximately 60 mm3) tumors in all animals, without any evidence of toxicity. A significant antitumor activity was also observed when the IL-4 toxin was administered via i.p. and i.v. routes. These results demonstrate that the IL-4 toxin may be a new therapeutic drug for the treatment of human glioblastoma. Therefore, we have begun a Phase I clinical trial with IL-4(38-37)-PE38KDEL for treatment of human glioblastoma.

Intratumoral injection of lipopolysaccharide causes regression of subcutaneously implanted mouse glioblastoma multiforme.
http://cat.inist.fr/?aModele=afficheN&cpsidt=971724
Résumé / Abstract
OBJECTIVE: Anecdotal reports documented extended survival times for patients who developed infections at the site of resection of malignant gliomas. Hypothesized mechanisms for this phenomenon include immune responses triggered by lipopolysaccharide (LPS). This investigation assessed whether LPS could produce tumor regression in an in vivo model of malignant glioma. METHODS: Delayed brain tumor cells (2 x 106) were injected subcutaneously into female BALB/c mice. LPS (300-500 μg) was injected intratumorally or subcutaneously at a contralateral site on Days 10, 17, and 24. Control animals received phosphate-buffered saline intratumorally or subcutaneously. Mice were killed on Day 28, and tumors were removed. Mean tumor masses for control animals and the two LPS-treated groups (intratumoral or contralateral subcutaneous treatment) were compared. Histological assessments of treated and control tumors were performed. RESULTS: Complete or nearly total tumor regression was achieved in all 20 mice with subcutaneous delayed brain tumor cell tumors treated intratumorally with 400 μg of LPS (mean tumor mass of 0.09 ± 0.38 g versus 2.42 ± 2.46 g for control animals, P < 0.0001). Intratumoral administration of 300 μg of LPS or subcutaneous injection of 300 or 400 μg of LPS at a contralateral site resulted in less consistent regression of subcutaneous tumors. Administration of 500 μg of LPS resulted in tumor regression similar to that observed with lower doses but was limited by treatment-related deaths in 40% of animals. Histological assessment revealed lymphocytic infiltration of LPS-treated tumors. CONCLUSION: Intratumoral injections of LPS caused dramatic regression of subcutaneously implanted delayed brain tumor cell mouse gliomas. Investigation of this antitumoral effect may improve treatment responses for patients with malignant gliomas.


Last edited by Mary on Fri Oct 31, 2008 2:04 am, edited 1 time in total.

Top
 Profile  
 
 Post subject:
PostPosted: Thu Oct 30, 2008 9:41 pm 
Offline
Registered User

Joined: Thu Oct 30, 2008 9:21 am
Posts: 1
Location: Australia
A Message for Mary (or any person with relevent information),
My sister has just (2 days ago) been diagnosed with a glioblastoma with an extremely poor prognosis. The tumor is inoperable with then radio and chemo the other options.
We (my brother) found this sight with the articles you posted last monday and it gave us some hope that perhaps there was an extremely viable option potentially available.
We would like to know more (so much more) about the interleukin therapy, specifically whether any similar trials are operating, or planned, in Australia in the immediate future. Or if not then whether the overseas trial that is requesting volunteers would accept someone from Australia.
Can you please reply as soon as possible as my sister meets with neuro team tomorrow to be presented with options and will need to decide within the week what course she wishes to follow.
Thank you
Tim Harrison


Top
 Profile  
 
 Post subject:
PostPosted: Thu Oct 30, 2008 10:19 pm 
Offline
Registered User
User avatar

Joined: Mon Mar 10, 2008 4:03 pm
Posts: 18130
Location: Australia
The first thing that I would do in your situation is get a second opinion. Especially if the first did not come from a specialist cancer center in a large city.

The second thing is to find out whether a sample is possible at all if labelled inoperable. Tests on this sample could help determine which treatments are likely to be most effective.

My advice is to stay away from treatments that have not at least made it to human trials yet. It may seem like anything is worth a try in this situation, but you could waste a lot of time, and incur many side effects, on treatments that don't work. Out of the dozens available you want to select the best, right?

There are disadvantages to jumping right into trials. For one you may catch the wrong boat. Another is that due to scientific methods you are usually excluded from using multiple treatments. Have a think about this before automatically signing up.

There are a number of treatments aside from the standard, that are available now or arriving soon. The Ben Williams article listed in this section is about the best that I have seen. The next 'gold star' treatment arriving is DCVax, it should arrive in Sydney early next year. Keep an eye on http://virtualtrials.com/news.cfm for the latest treatments internationally.

The best treatment protocols for radiotherapy and chemotherapy are now shown to be low dose. When I started on chemo I was 5 days on/ 20 off. By taking less than 1/3 daily for 20 day of 28 now, I am now getting 150mg a month more, don't have a large break and have less tiredness & nausia.

I feel for your situation, which was 18 months ago for me. I was told mine was inoperable and prognosis very bad, but they were wrong in my case. I hope they are in your sister's too :o).


Top
 Profile  
 
 Post subject: Good question!
PostPosted: Thu Oct 30, 2008 10:24 pm 
Offline
Registered User

Joined: Sat Nov 04, 2006 10:18 pm
Posts: 360
Location: Australia
Hi Tim,

Welcome and sorry to hear about your sister. No doubt you're all still reeling with the sudden news. The words "brain tumour" are not something anyone anticipates they'd ever hear for either themselves or a loved one.

Re: the trials on this treatment:

It looks to me like they’re still gathering info about the results of these trials being done overseas re: survival, recurrence etc. I’ve included some extra links and the best you can probably do here in Australia is talk to your sister’s oncologist about these more “innovative new treatments” as a possible “Plan B”.

They’ve generally got their standard protocols but after standard treatments, there is no reason that Plan B couldn’t be put into action and you have a little time to work out what Plan B could be with her oncologist. Given the prognosis for these tumours is not fabulous they should be receptive to the idea of trialing something else on a compassionate use basis (even if not an approved treatment). Means signing you agree to an investigational drug/treatment etc but oncologists usually have specific paperwork for that. Maybe access the articles you're interested in and print them off and show them to her neuro team and put out some feelers to see if they're receptive to trialing anything more innovative for starters and get some feedback.

Drugs that are not approved for use here yet, can still be imported for individual use (patient pays cost though) through the Personal Access Scheme or Special Access Scheme via the drug regulators the TGA. I can’t give you any specific details about possible suppliers or whether there are any in Australia or overseas as that info is not readily available unfortunately, so that might take a bit of research. All challenging stuff.

Convection-enhanced delivery of interleukin-13 receptor-directed cytotoxin for malignant glioma therapy
http://cat.inist.fr/?aModele=afficheN&cpsidt=17849741

Interleukin-13 receptor-directed cytotoxin for malignant glioma therapy: from bench to bedside
http://cat.inist.fr/?aModele=afficheN&cpsidt=15288388


Personal Import Scheme:
http://www.tga.gov.au/impexp/personal.htm

Special Access Scheme:
http://www.tga.gov.au/hp/sas.htm


Here’s some info about formal registered clinical trials being done in Australia/New Zealand:
(Just type in eg. type of tumour in a search and see what comes up – if any but they all need to be registered these days (except if you’re doing something as an individual with agreement of your oncologists).

http://www.anzctr.org.au/default.aspx


Top
 Profile  
 
PostPosted: Fri Oct 31, 2008 9:26 am 
Offline
Registered User

Joined: Thu Oct 30, 2008 10:22 pm
Posts: 5
Location: Canberra
Now that I look more deeply into this, those trial reports are from 2003 and 2006. I've Googled the subject but only seem to come up with heaps of references to the respective journal reports, and nothing that looks like a result or anything like that. Should we be looking somewhere or for something more specific? Or does it just take this long for 'follow-up' reports to appear?

As you can guess, at this point we're all just in (frantic) information gathering mode before our sister decides on a course of treatment. She says that she was actually at Basser College at the same time as Charlie Teo, but that she doubts that he'd remember her. Nonetheless, we have another GP friend who is gathering all the details to forward to Charlie for a second opinion.

Our sister lives in Adelaide and is just coming up to her 51st birthday. The tumour, apparently, is an aggressive GBM IV, about the size of a golf ball, between the two frontal lobes. The prognosis after yesterday's biopsy report is not good.

This is all a little more poignant for us because our eldest brother was diagnosed with what turned out to be an untreatable brain tumour 5 years ago, almost to the very day, when he was just 52. Our brother was living in Sweden and his wife was a nurse, so we didn't really have much to do with anything but the personal side of his battle. But our sister's case is all very much closer to home, in more ways than one.


Top
 Profile  
 
 Post subject: Can take ages.
PostPosted: Fri Oct 31, 2008 11:49 am 
Offline
Registered User

Joined: Sat Nov 04, 2006 10:18 pm
Posts: 360
Location: Australia
OMG, two in one family is more than anyone should have to cope with.

Re: clinical trial results, well if the end-point of the trial is to establish increased survival rate, increased length of time to recurrence and improved overall survival rate (as compared with a standard treatment) and reduction of toxicity of treatment protocol then it takes a few years of follow up after treatment to gather that data to report on because at least 2-3 years would need to lapse before it would be known and can be published as a credible finding.


Top
 Profile  
 
 Post subject: Trials
PostPosted: Fri Apr 08, 2011 2:24 pm 
Offline
Registered User

Joined: Fri Apr 08, 2011 2:07 pm
Posts: 1
Location: Australia
Mary, can you tell me where clinical trials are up to for IL-4 toxin for malignant gliomas which you mentioned in your post on this subject which was quite some time ago.


Top
 Profile  
 
Display posts from previous:  Sort by  
Post new topic Reply to topic  [ 7 posts ] 

All times are UTC + 10 hours


Who is online

Users browsing this forum: No registered users and 2 guests


You cannot post new topics in this forum
You cannot reply to topics in this forum
You cannot edit your posts in this forum
You cannot delete your posts in this forum
You cannot post attachments in this forum

Search for:
Jump to:  
cron
Powered by phpBB® Forum Software © phpBB Group
[ Time : 0.121s | 11 Queries | GZIP : Off ]