Transcript IMMUNOTHERAPY:

IMMUNOTHERAPY:
The Human Therapeutic
Cocaine Vaccine
Why Is Cocaine
Addiction so Difficult to
Treat?
Approaches to Cocaine
Addiction

The inability to create an effective
pharmacotherapy for the the treatment of
cocaine addiction is, at least in part, due to
the complexities of cocaine pharmacology.
(Fox 1997)
 Most approaches that try to act centrally on
the brain have failed. (Haney and Kosten
2004)
– Multiple neural mechanisms involved.
– A wide range of side effects produced
Cocaine Vaccine
IPC-1010 (TA-CD)

Stimulates production of
cocaine-specific antibodies
that bind cocaine, creating a
complex too large to cross
through the blood-brain
barrier, thus preventing the
substance from entering the
CNS and acting on dopamine
receptor sites in “reward
centers” of the brain (Hall
and Cater 2003)


Acts peripherally before the drug can act
centrally (Haney and Kosten 2004).
TA-CD vaccine is comprised of (Kosten et
al. 2001):
1.Protein conjugate (succinylnorcocaine +
protein carrier)
2. Aluminium hydroxide as an adjuvant.
The Antibody: how it
works
Cocaine
binds in
variable
region
Hinge
Cocaine Metabolized (cholinesterases)
Antibody free for subsequent
binding
Neurobiology
Mesocorticolimbic dopamine
(DA) pathways: DA neurons
that originate in the midbrain
ventral tegmental area and
project to the nucleus
accumbens, amygdala,
olfactory tubercle and frontal
cortex (Zhang et al. 2002)
DA D1 receptors: involved in mediating the longterm behavioural effects of cocaine (Zhang et al.
2002).
Neurobiology
TA-CD: Its Effects

Because cocaine is prevented from entering
the brain, the euphoric rush associated with
the drug is dulled or obliterated entirely
(Martell et al. 2005).
 Cocaine/antibody binding prevents release of
dopamine from the synaptic terminus of brain
neurons (Martell et al. 2005).
 Self-administration behaviour is reduced
through an extinction-like process, as the
effects of cocaine are neutralized.
History of Therapeutic Vaccines
for Substance Abuse

Using antibodies against abused drugs
started in 1974 when Bonese et al.
immunized a monkey against morphine and
demonstrated that the antibodies specifically
altered the animal’s response to heroin (Fox
1997).

The search for a pharmacotherapeutic agent
to treat cocaine dependence began in the
early when clinicians realized standards drug
counseling alone had little impact on addicts
(Fox 1997).
Empirical Evaluations of Treatment
Studies
1. Develop of a therapeutic vaccine for the
treatment of cocaine addiction. Fox (1997)
-IPC-1010 was injected into
8 mice and compared to a
control group (protein
carrier only).
-Immunized mice were
injected with cocaine and
tissue distribution was
measured.
Fox (1997)

Cocaine-immune mice
displayed a significant
reduction of cocaine
levels in the brain
when compared to
control mice 30 s after
injection of the
vaccine.
Fox (1997)

Limitations:
Mice did not undergo repeat dosing with
cocaine to determine if antibody activity could
become oversaturated and thus reduce or
eliminate the effects of the vaccine.
- Small population size.
-
2. Human therapeutic cocaine vaccine: safety
and immunogenicity (Kosten et al. 2002)

Phase I clinical trial assessed the safety and
immunogenicity of TA-CD in 34 former cocaine
abusers.
 Assignment to vaccine or placebo was randomized,
and all injections were double blind.
 Placebo controlled.
 Between-subject design.
Kosten et al (2002)

3 rounds of injection were administered to all
3 cohorts. 15 Subjects were followed followed
for one year.
 Results showed:Antibodies were detectable
after the second injection at day 28 and
increased in all cohorts after the third
vaccination on day 56.
– There was a statistically significant higher
antibody response in cohort 3 (709μg).
– Antibody levels did not persis beyond 1 year for
any groups; booster vaccines are likely to be
needed.
Kosten et al (2002)

Limitations:
- Small population size (out of the 34, only 24
completed the 84 day trial, and only 15
subjects were followed for one year).
- Subjects were not present cocaine users.
- Those with psychiatric disorders (psychotic
disorders, lifetime major depressive disorder)
were excluded.
3. Vaccine Pharmacotherapy for the
Treatment of Cocaine Dependence
(Martell et al. 2005)
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Phase II of Kosten’s study.
18 Subjects, 10 in the 400μg group, 8 in the 200μg,
between subject design.
A more robust response was noted with higher vaccine
dose with more a frequent injection schedule (400 g
with five vaccinations for a total dose of 2000 g).
The peak antibody titers were 2 higher in the high
dose group as compared to the low dose group.
3. Martell et al. 2005

Limitations:
- For medical safety reasons, the assignment
to dosage group was not random; the first ten
subjects received four vaccinations at the
lower dose before the second eight subjects
received five vaccinations at the higher dose.
- Small population size.
Vaccine Administration

Patients typically would
receive three to four
injections over a period of
two to three months.
 Dosage may vary;
injections of 400 μg
presently the optimal
dosage.
 Post vaccination follow-up
to ensure no reaction
occurs.
 Booster vaccinations
between nine and twelve
months after initial
injection.
Advantages to Approach

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Injections are required no more than every two
months, therefore patient compliancy is easier to
attain.
Few to no side effects.
Neither antibodies nor enzyme are able to cross
blood-brain barrier, therefore:
– Neurotransmitter activity necessary for normal
brain functioning will not be effected.
– Vaccine will not interact with other medication
treatments which patients might be simultaneously
taking.
Disadvantages to Approach

Patients may attempt to circumvent the
vaccine by using larger doses of the drug,
thereby increasing its adverse effects.
 Vaccine costly, possibly not a viable option for
many abusers, especially since multiple
injections are required to maintain antibody
levels.
 Most effective on patients who have a healthy
immune system.
Conclusion

While there are few to none other cocaine addiction
treatments to compare this particular vaccination
with, it would seem from the current evidence that
this treatment is extremely effective, requires very
little effort on behalf of the patients and has shown
to produce few to no side effects. While an addict
should look to every possible source to find an
appropriate therapy tailored to his or her needs, one
may find that looking inward and using the body’s
own defenses may be what is required to help the
brain return to a normal state. The recruitment of
natural enzymes and antibodies to help unlearn the
association between cocaine use and feeling “high”
may indeed just prove to be the best way.