IMMUNOTHERAPY:

1. IMMUNOTHERAPY: The Human Therapeutic Cocaine Vaccine

2. Why Is Cocaine Addiction so Difficult to Treat?

3. 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

4. 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)

5. 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.

6. The Antibody: how it works Cocaine binds in variable region Hinge Cocaine Metabolized (cholinesterases) Antibody free for subsequent binding

7. 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 long-term behavioural effects of cocaine (Zhang et al. 2002).

8. Neurobiology

9. 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.

10. 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).

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 3. Vaccine Pharmacotherapy for the Treatment of Cocaine Dependence (Martell et al. 2005) • 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.

18. 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.

19. 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.

20. Advantages to Approach • 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.

21. 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.

22. 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.