Therapeutic antitumor immunity induced by combined intratumoral injection of dendritic cells (DCs) and systemic chemotherapy in murine lymphoma

Abstract

2509 Background: DCs are potent antigen presenting cells that can induce both immune responses and self-tolerance. Immune tolerance to tumors and the lack of defined tumor antigens are the two major hurdles for immunotherapy. To overcome this, a novel immunotherapy approach was developed to induce systemic antitumor immunity by combining of intratumoral injection of naïve DCs and systemic chemotherapy in a murine tumor model. Methods: Using a murine A20 B cell lymphoma model, syngeneic mice with established subcutaneous tumors and systemic spread were treated first with chemotherapy (cyclophosphamide or CTX, 50–200mg/kg body wt) and then by direct intratumoral injection of bone marrow-derived DCs (on day 2 and 4 post chemotherapy). The mechanisms of tumor regression was also dissected. Results: Intratumoral DC injection alone had a minimal effect. The systemic chemotherapy alone resulted in only transient tumor regression with prolonged survival, but the majority of treated mice having tumor re-growth and eventually succumbing to systemic lymphoma. Strikingly, the addition of local intratumoral injection of DCs combined with systemic chemotherapy led to complete, long-term regression in the majority of treated mice. Thawed frozen DCs are equally effective as the freshly prepared DCs. This therapeutic effect of intratumoral DC injection was dose dependent and also dependent on injection of the DCs directly into the tumor site rather than a regional or distant site. Furthermore, this DC-mediated antitumor effect was systemic because distant tumor inoculated in the contra-lateral flank of the mice were also made to regress. In vivo T cell depletion studies indicated both CD4+ and CD8+ T cells are involved in the tumor regression. Interestingly, tumor re-challenge in those long term surviving mice revealed broad cross protection which was also mirrored by the in vitro cytotoxic T lymphocyte assay. Conclusion: The combination of chemotherapy induced tumor death and DC loading of tumor antigens in situ may provide a convenient mode of inducing systemic antitumor immunity and may be relevent to the clinical setting. No significant financial relationships to disclose.