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4 Translation into Clinical Trials: Humans Are Not Large Mice
9.5 CONVECTION-ENHANCED DELIVERY OF
TARGETED TOXINS AND OTHER AGENTS
Delivery of therapeutic agents to HGGs is a difficult task that has perplexed neurosurgeons and brain tumor researchers for several decades. The effectiveness of some
chemotherapeutic agents against gliomas in vitro has been recognized for many
years, but the BBB minimizes the amount of drug that penetrates tumors when
administered systemically, even with highly lipophilic nitrosureas.124
Toxicity limits how high a systemic dose can be given and prevents satisfactory
levels of agents from reaching tumors in the brain. This circumstance led to many
attempts to treat brain tumors with intratumoral or local injections of methotrexate
or nitrosureas in the 1960s and 1970s, all with minimal beneficial responses.125–129
Despite the lack of therapeutic benefit, these early investigations were encouraging
because they found that intratumoral injections of chemotherapeutic agents resulted
in lower systemic toxicity.129,130
The revolution in molecular biology techniques and other scientific advances
are leading to a dramatic increase in discoveries of potential therapeutic agents for
the treatment of cancer. These agents include traditional chemotherapies, molecular
therapies, targeted toxins, viruses, liposomal–DNA complexes, viral packaging cells,
stem cells, and others.131–133 Although few of the new therapeutic modalities have
achieved mainstream use in cancer therapy as yet, it is likely that some will do so
soon. To allow brain tumor patients to benefit from these exciting new developments,
a method to deliver therapeutic agents to the brain in a safe and effective manner
must be developed. It is possible that this stumbling block to progress in the treatment
of HGGs will be overcome by promising developments in CED.
9.5.2 CONVECTION-ENHANCED DELIVERY
Traditional means of delivering agents to the brain have involved direct injection
into the parenchyma or cerebrospinal fluid. These injections rely on diffusion of the
delivered agent to reach brain tissue away from the injected site. Unfortunately,
multiple studies demonstrated that diffusion of agents in the brain is extremely
limited, particularly with high molecular weight or polar molecules.134–136
Attempts have been made to overcome this limitation with use of multiple
intraparenchymal catheters.137 One study involving cisplatin infusion via 68 catheters
still did not produce a significant impact on the patient’s prognosis. This suggests
that far too many catheters would be required to treat gliomas in this fashion. A
more feasible approach is to use fewer catheters and increase the volume of diffusion
through each catheter using CED.
CED uses sustained intracerebral infusion to induce a convective interstitial fluid
current that has the potential to homogeneously distribute even large molecules great
distances within the brain by displacing interstitial fluid.138 In animal models, CED
achieved high homogeneous concentrations of various macromolecular therapeutic
agents throughout large regions of the brain that were several orders of magnitude
greater than those obtainable by systemic delivery.139 The potential benefit of CED
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in the treatment of brain tumors in animal models has been demonstrated in several
A significant limitation to interpreting data from CED experiments comes from
the fact that human brains are much larger than those of the animal models routinely
used. Although a few studies have been conducted using CED in humans,142 no data
are available on the actual distribution of agents delivered in the human brain via
this method. Data recently submitted for publication demonstrate distribution of at
least 10% of the injected concentration of a macromolecule within a nearly spherical
radius over 4 cm from the catheter tip throughout the gray and white matter surrounding a tumor resection cavity (D. Bigner, personal communication, 2004).
In addition to this encouraging data on distribution of agents in the human brain
using CED, two clinical trials demonstrated the efficacy of CED in treating human
brain tumor patients. In a clinical trial by Laske et al., 9 of 15 malignant brain tumor
patients had greater than 50% reductions in tumor volume after receiving therapeutic
agents via CED.142 Although local toxicity was seen at the highest dose administered,
no systemic toxicity was observed, suggesting CED is an effective way to deliver
therapeutic toxins to the human brain. In a trial by Rand et al., 7 of 9 patients treated
with CED had increased tumor necrosis as evidenced by reduced gadolinium
enhancement on MRI following therapy.143 One patient survived more than 18
months after therapy.
Although these results are encouraging, several limiting factors remain as obstacles to the use of CED in the treatment of HGG patients. First, although a distribution
of agent 4 cm from the catheter tip is encouraging, the technique still requires
infusion via multiple catheters and careful optimization and planning to deliver
therapeutic agent to the region surrounding a tumor or its resection cavity. Second,
tumors clearly alter the fluid dynamics in the brain and the effect of this alteration
on CED is poorly understood. Despite these limitations, further studies aimed at
optimizing catheter design and infusion parameters should identify modifications
capable of effectively addressing these issues now that the potential utility of this
approach has been established in humans.
9.5.3 TARGETED TOXINS
Although CED could be used to deliver any of a number of therapeutic agents to
treat brain tumors, the majority of work to date has utilized targeted toxins. A
targeted toxin is attached to a receptor ligand; an immunotoxin consists of a toxin
attached to an antibody that recognizes a receptor. In both cases, receptors selected
for targeting are over-expressed on tumor cells (for simplicity, this chapter will
use the term “targeted toxin” in reference to both moieties). Targeted toxins allow
targeted delivery of potent toxins to tumors with relative sparing of normal tissue.133 The specificity of these agents is enhanced and systemic toxicity reduced
by delivery to an anatomically isolated compartment, such as the intracranial or
Bacterial and plant toxins are potent cytotoxic agents that have been exploited
in targeted toxin therapy. Such toxins have at least two important advantages over
most chemotherapeutic agents: (1) they are far more potent, while most
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chemotherapies require >104 molecules to kill a single tumor cell, many toxins
require only one,133 and (2) they are active against hypoxic and nondividing cells,
making them potentially effective against tumors that are resistant to chemotherapy
The powerful potential of targeted toxins derives from a combination of the high
potency and toxicity of the toxin with the highly selective binding of a receptor
ligand or antibody. Critical to the success of targeted toxin therapy is the identification of a receptor that is ubiquitously highly expressed on the tumor but not on
surrounding tissue. This has been accomplished in tumors outside the CNS. Clinical
trials using targeted toxin therapy have targeted interleukin-2 receptors in hematologic malignancies146 and interleukin-13 receptors in squamous cell carcinomas.147
Other trials have used tumor-specific antibodies to target ovarian, breast, and colon
In order for targeted toxin therapy to be effective against HGGs, a receptor that
is commonly over-expressed on the tumors must be identified and targeted. It has
been known for several years that HGGs frequently over-express EGFR.150 Overexpression is often associated with amplification of the EGFR gene. A simultaneous
examination of GBM samples for EGFR gene amplification, mRNA, and protein
found approximately one-third had gene amplification, all had mRNA, and 85% had
detectable EGFR protein151 (McLendon et al., personal communication, 2004). By
contrast, EGFR was found in only very low levels in surrounding brain — a circumstance that lends it to targeted toxin treatment with minimal unwanted toxicity.152
EGFR has two natural ligands, epidermal growth factor and transforming growth
factor alpha (TGF-α). A targeted toxin for the EGFR was designated TP-38. It is a
recombinant chimeric protein composed of TGF-α and a genetically engineered
form of the pseudomonas exotoxin PE-38. Encouraging results of a Phase I clinical
trial examining treatment of patients with recurrent HGGs using CED of TP-38 have
recently been submitted for publication.153
Other receptors over-expressed on HGGs have been identified. Targeted toxins
for interleukin-4 and interleukin-13 receptors showed therapeutic efficacy against
HGGs.154,155 Further work using sophisticated molecular biology techniques will
undoubtedly identify other potential receptors for toxin targeting and enhance the
potential of this novel therapy for HGG patients.
The relatively recent revolution in molecular biology techniques has in fact led to
many significant discoveries of underlying mechanisms of the development of
HGGs, only a few of which were covered here. Even more importantly, a variety
of scientific advances led to the development and rapid translation to clinical trials
of many novel forms of cancer therapy, broadly increasing the landscape of
potential therapies far beyond the traditional modes of surgery, chemotherapy, and
Although we have not yet discovered the combination of novel therapy and better
understanding of underlying tumor mechanisms that will lead to an efficacious new
© 2005 by CRC Press LLC
treatment of HGGs, many promising new therapies are on the horizon. In this
environment of rapid new discovery, it remains of utmost importance that neurosurgeons are involved in and informed of the development of these exciting new
therapies that may soon allow us to better serve our sickest patients.
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