In April this year, Neurotech SA (Evry, France)

announced they have started Phase I/II trials of

a novel treatment for high-grade glioma, one of

the most aggressive human brain cancers.

‘High-grade gliomas, often called glioblastomas,

do not respond well to any available treatments

and the oncology community has been keen to

encourage new approaches for some time,’ says

Tom Shepherd, CEO at Neurotech.

A typical glioblastoma grows rapidly. By the

time it causes symptoms, the volume of the

tumour is already life threatening. Treatment

involves radical surgery, but the tumour has in-

distinct margins and cannot be completely re-

moved. It always returns, often reaching its

pre-surgery size within months. Follow-up

surgery is sometimes performed in the USA but,

says Shepherd, some European specialists ask

whether the trauma of a second operation is

justified in light of the very poor prognosis. The

only new therapy to be approved in recent

years is the Gliadel wafer developed by Rhone-

Poulenc Rorer (Collegeville, PA, USA) and

Guilford Pharmaceuticals (Baltimore, MD, USA).

The wafer is a biodegradable mesh impregnated

with carmustine, a potent anti-cancer drug,

and is implanted in the brain cavity after

surgery. However, it only extends life ex-

pectancy by approximately two months,

according to the Phase III study on which USA

approval was based (http://www.rpr.rpna.com).

Neurotech’s novel approach‘About three years ago, we decided to try to at-

tack glioblastomas in a completely different

way. Our main idea was to “light up” the tu-

mour so that the immune system could see it

as a foreign entity that should be attacked and

destroyed,’ says Shepherd. He and colleagues at

Neurotech developed an endothelial cell line

that could be genetically engineered to express

interleukin-2 (IL-2). Endothelial cells migrate

naturally to any sites where active blood-vessel

growth is taking place and are attracted to a

glioblastoma because of the tumour’s excessive

angiogenic activity. Preclinical studies in vitroand in a rat model of a glioblastoma showed

that NTC-121 cells did indeed home in on

tumour cells and they grew actively, expressing

high levels of IL-2 (Ref. 1). This stimulated the

immune system by overwhelming the immuno-

suppressive factors secreted by the tumour

itself, and by recruiting immune cells to the

tumour site.

In the rat model used, cells from a human

glioblastoma cell line are injected into the rat’s

brain to set up aggressive tumours that are

usually fatal within 19 days. Treatment with

NTC-121 cells at the time of the tumour cell in-

jection was found to double the average sur-

vival time. Most significantly, approximately

25% of the treated rats survived for several

months. The results of the animal studies are to

be submitted for publication later this year. ‘We

were pleased with the animal results but we are

still very cautious,’ says Shepherd. Central to the

team’s concerns is the fact that the rat model

involves co-injection or treatment and tumour

cells, whereas in patients, treatment is given

after an established tumour is removed surgi-

cally. Also, the rat mounts no xenogenic im-

mune response, a response that Shepherd be-

lieves will contribute greatly to the efficacy of

the treatment. ‘Only human studies can reveal

whether this treatment has the potential we

are hoping for,’ he says.

A Phase I/II human trial that aims to treat a

total of 16 patients began in mid-March this

year. To further enhance the immune response

generated, the team decided to implant rat

endothelial cells, rather than human cells. ‘This

is also a safety factor,’ says Shepherd, ‘The endo-

thelial cells will themselves be destroyed by the

immune system of the patients and so will be

removed after the period of treatment is over.’

Shepherd stresses that this preliminary human

trial has been designed to assess safety only. ‘If

some of the patients in the trial show longer-

term survival, that would be an added bonus,’

he says, ‘but this is not our primary

objective.’

Multiple strategies might be importantPaul Zeltzer, Clinical Professor of Pediatrics and

a neurooncologist at the Maxine Dunitz

Neurosurgical Institute (Cedars Sinai Medical

Center, Los Angeles, CA, USA), regards

Neurotech’s trial as ‘novel and exciting’ and he

predicts that the endothelial cell delivery sys-

tem will have great potential. He is less con-

vinced about using IL-2. ‘Stimulating the im-

mune response to tumour cells is difficult;

many interleukins and other factors act in con-

cert to bring this about and I question whether

using just one interleukin is the best approach,’

he says. ‘If IL-2 fails to show efficacy’, he adds,

‘it might be worth trying to express other fac-

tors in the same system’. Zeltzer is currently col-

laborating with the Immune Response

Corporation (Carlsbad, CA, USA) on a Phase I

trial of an allovaccine against glioblastoma. The

vaccine contains human embryogenic fibro-

blasts that express granulocyte macrophage

colony-stimulating factor (GM-CSF), a cytokine

that helps CD4 T-helper cells to initiate CD4

and CD8 cytotoxic T-lymphocyte expansion.

Preliminary studies in rats have shown that the

vaccine can cause necrosis in established

tumours and a small safety study in 12 patients

began at the beginning of April, 2000. Once

PSTT Vol. 3, No. 6 June 2000 update news

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Glioblastoma: encouraging thebody to fight backKathryn Senior, tel: 144 118 9421639, e-mail: ksenior@dircon.co.uk

An immune-system boost that could augment

cancer vaccines has, for the first time, been

shown to trigger an immunological response to

cancer cells in humans, rather than just in vivo,

according to researchers in the USA1.

Michael Roth and Robert Figlin (Jonsson

Comprehensive Cancer Center, University of

California at Los Angeles, Los Angeles, CA, USA)

have carried out a promising early clinical

trial into the effects of injecting two immune-

system hormones once daily into patients.

Dendritic cell boostThe team found that granulocyte macrophage

colony-stimulating factor (GM-CSF) and inter-

leukin-4 (IL-4) induced a 100-fold increase in

the number of dendritic cells, which are

specialized blood cells that recognize foreign

substances and trigger lymphocytes to fight

pathogens. The Roth and Figlin team hope that

their immune-system booster might be coupled

with vaccine treatments as a novel approach to

treating metastatic solid malignancies

Dendritic cells are believed to be the cells

that play a crucial role in identifying and pro-

cessing abnormal proteins and other molecules

from bacteria, viruses and allergens. As such,

they are the critical component required for an

immunization against disease. The clinical im-

pact of dendritic cells in the treatment of

human cancer, however, depends on their

role as potent antigen-presenting cells for

priming an antitumour T-cell response. Roth

and Figlin have spent the past decade in-

vestigating this basic concept and in 1999

they successfully demonstrated that functional

dendritic cells could be generated in culture

from blood taken from patients with metastatic

renal cell carcinoma using GM-CSF and IL-4

(Ref. 2).

Exploiting hormonesThe strategy of boosting dendritic cells in

humans brings the concept of cancer im-

munotherapy closer. ‘I think this is a major step

towards making vaccine therapies more patient

friendly and less costly,’ said Figlin.

A patient’s dendritic cells do not normally

produce an immune response to cancer, even

though tumour cells are expressing antigens.

The team believe that the cancer cells deceive

the immune system, and prevent the dendritic

cells from responding to such an invasion.

Indeed, dendritic cells removed from cancer pa-

tients do not function as stimulators of the im-

mune system against pathogens.

Roth and Figlin believe that the main prob-

lem is that dendritic cells are also rare – ac-

counting for approximately 0.1% of white

blood cells in the body – which is where their

idea of boosting differentiation into dendritic

cells comes into play. Combining a technique

for increasing dendritic-cell numbers with a

way to activate them might produce an im-

mune response against cancer without the

toxic effects of chemotherapy and radio-

therapy.

In 1996, Roth first reported that the more

common monocytes could be stimulated to

mature into dendritic cells using GM-CSF and

IL-4 (Ref. 3). Monocytes comprise approxi-

mately 5–10% of white blood cells, which ac-

cording to Roth means they represent abun-

dant raw material from which dendritic cells

might be produced.

Initially, the team found that they could

generate dendritic cells outside the human

body (in vitro) from monocytes. Then, by stimu-

lating these newly developed cells with an anti-

gen from a patient’s tumour, they could pro-

duce active dendritic cells. When these

activated dendritic cells were injected, once

daily, into the patient, their immune system

was stimulated to attack the tumour cells ex-

pressing that particular antigen. This approach,

however, was highly labour intensive and

costly; here the researchers have devised a

more direct approach. Roth’s idea was that in-

stead of culturing monocytes from extracted

blood in the laboratory, a patient’s own

safety profiles are confirmed, Phase II efficacy

studies could begin within two years and, if re-

sults from these are encouraging, both treat-

ments could move to fast-track development.

The therapeutic use of genetically engi-

neered endothelial cells might also have other

applications. Brain metastases of systemic

tumours are an obvious target, but Neurotech is

also considering the technique as a treatment

for stroke. Current drug therapy tackles the

problems that occur within 48 h of a stroke, but

an ischaemic zone can persist in the brain for a

further 2–3 weeks, causing further neuronal

death. ‘The idea of using endothelial cells engi-

neered to secrete neurotrophic factors seems

very attractive,’ says Shepherd. However, he

confirms that Neurotech will not consider

moving beyond the preclinical Phase in stroke

until much more data on the safety of the gen-

eral approach has been gathered. ‘We also need

to prove the concept of endothelial cell therapy

with glioblastoma first,’ he concludes.

Reference1 Quinonero, J. et al. (1997) Gene transfer to the

central nervous system by transplantation of

cerebral endothelial cells. Gene Ther. 4, 111–119

update news PSTT Vol. 3, No. 6 June 2000

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Augmenting cancer vaccine strategies with dendritic cell boostsDavid Bradley, tel/fax: 144 1954 202218, Web: http://www.sciencebase.com