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Therapeutic Vaccination against Murine Lymphoma by Intratumoral Injection of Naive Dendritic Cells

Division of Oncology, Department of Medicine, Stanford University Medical Center, Stanford, California

Requests for reprints: Ronal Levy, Division of Oncology, Department of Medicine, Stanford University Medical Center, Center for Clinical Sciences Research Room 1105, 269 Campus Drive, Stanford, CA 94305-5151. Phone: 650-7256452; Fax: 650-7361454; E-mail: levy{at}stanford.edu.

Dendritic cells are potent antigen-presenting cells that can induce both immune responses and tolerance depending on their state of activation. Immunologic tolerance to established tumors is a major impediment for the development of effective cancer immunotherapy. Dendritic cells may be deficient in number or in function at the tumor site. To address this problem, we evaluated the ability of immature naïve dendritic cells to induce an antitumor immune response when injected directly into a murine B-cell lymphoma. Mice with advanced transplanted syngeneic tumor were given intratumoral injections of bone marrow–derived dendritic cells. Intratumoral dendritic cell injection alone had no antitumor effect. Systemic chemotherapy alone resulted in only transient tumor regression. However, the intratumoral injection of dendritic cells after chemotherapy led to complete, long-term tumor regression in the majority of treated mice. This dendritic cell–mediated antitumor effect was systemic, resulting in simultaneous elimination of the tumor at second uninjected sites. In addition, it resulted in long-term memory with resistance to tumor rechallenge. Both CD4⁺ and CD8⁺ T cells are necessary for the antitumor effect. Furthermore, tumors that occasionally recurred in mice with initial complete tumor regression could be retreated by the same combined chemoimmunotherapy approach. These results show that immunotherapy can succeed in the setting of advanced lymphoma if dendritic cells are restored and loaded with tumor antigens in situ at a single tumor site.

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