Preclinical efficacy of dendritic cell immunotherapy for CNS tumors

A. B. Heimberger M.D., L. E. Crotty B.S., G. E. Archer Ph.D., R. E. McLendon M.D., D. D. Bigner M.D., Ph.D., and J. H. Sampson M.D., Ph.D.

Duke University Medical Center, Durham, NC United States

Aim: Dendritic cells (DCs) are specialized cells of the immune system that are capable of generating potent immune responses that are active even within the immunologically privileged central nervous system. We evaluate the in vivo efficacy of DC immunotherapy against syngeneic astrocytomas that mirror human gliomas phenotypically and morphologically and to a tumor-specific antigen, epidermal growth factor variant III (EGFRvIII). Methods: In the first model system, VM/Dk mice were systemically vaccinated with DCs pulsed with tumor homogenate followed by intracerebral tumor challenge with syngeneic astrocytoma (560). In our second model system, C3H mice were systemically vaccinated with DCs pulsed a tumor-specific peptide and challenged intracerebrally by melanoma cells (K1735) expressing EGFRvIII. Results: Systemic vaccination of mice with DCs pulsed either with a tumor homogenate or tumor-specific peptide followed by intracerebral tumor challenge resulted in a 160% (p=0.016) and 600% (p<0.0016) increase in median survival, respectively. Immunologically memory was demonstrated by 100% of mice surviving rechallenge with intracerebral tumor. Cell-mediated and antigen-specific IgG2a humoral immunity was induced. We did not observe the induction of autoimmunity. Conclusions: DCs pulsed with either a tumor homogenate or a tumor-specific peptide results in potent in vivo antitumor efficacy against intracerebral tumors. The in vivo mechanism resulting from DC immunotherapy may be a combination of cytotoxic responses and antigen-specific humoral immunity. A tumor-specific antigen approach for DC immunotherapy may be preferable since the inherent risk of autoimmunity is eliminated; we are currently proceeding with a phase I clinical trial for glioma patients.

KEY WORDS: melanoma, astrocytoma, epidermal growth factor receptor variant III (EGFRvIII), autoimmunity, cytotoxic response, humoral response.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Immunotherapy.