Intratumoral Dendritic Cells and Chemoradiation for the Treatment of Murine Squamous Cell Carcinoma

Abstract

Dendritic cells are potent antigen presenting cells that have been shown to have significant antitumor effects in vitro and in vivo. However, the therapeutic efficacy of dendritic cells as an immunotherapeutic treatment has been limited by both immunologic tolerance and active immunosuppression in the tumor microenvironment. To address this problem, we examined the ability of concurrent systemic chemotherapy and local, fractionated radiation to augment intratumoral dendritic cell injections in a mouse model of squamous cell carcinoma. Intratumoral injections of dendritic cells alone did not have a significant antitumor effect in mice with squamous cell carcinoma flank tumors, but the addition of chemoradiation resulted in significant tumor regression. Concurrent chemoradiation alone resulted in slower tumor growth, but no complete tumor regressions. The combination of chemoradiation and intratumoral dendritic cell injections resulted in improved survival and complete tumor regression in 30% of mice. Mice with complete tumor regression were partially resistant to the repeat challenge with relevant tumor sixty days after treatment. These findings were partially dependent on the presence of CD4+ T cells, CD8+ T cells, and NK cells. Chemoradiation may augment intratumoral dendritic cell injections through increased intratumoral apoptosis as well as decreased intratumoral regulatory T cells. This work suggests a possible role for the use of intratumoral dendritic cell therapy with more traditional chemoradiation strategies.

Cancer Stem Cell Vaccination Confers Significant Antitumor Immunity

“…SCC7 is a spontaneously arising squamous cell cancer syngeneic to C3H mice also described in our previous report (29). …”

Combination of External Beam Radiotherapy (EBRT) With Intratumoral Injection of Dendritic Cells as Neo-Adjuvant Treatment of High-Risk Soft Tissue Sarcoma Patients

“…Only after treatment the development of tumor-specific immune responses was observed in 52.9% of patients. This trial was not designed to test what the individual components of therapy would induce immune responses in vivo in human; however murine data from our and other groups 7–12 suggest that individually either DC or radiation is not sufficient to generate curative tumor-specific immune response or infiltration of tumor site with T-lymphocytes. We believe that these results are promising enough to warrant further trials.…”

“…In a number of pre-clinical studies we and others have demonstrated that local tumor irradiation in combination with intratumoral DC administration but not irradiation alone resulted in potent antitumor immune responses that translated into an antitumor effect 7–12 . These preclinical studies provided a compelling rationale for testing this approach in the clinic.…”

Using chemo-drugs or irradiation to break immune tolerance and facilitate immunotherapy in solid cancer

“…Preclinical studies show that local tumor irradiation in combination with immunotherapy can be used as an effective therapeutic strategy to improve treatment outcome [54]. It was reported that an intratumor injection of DC vaccination could synergize with radiation and then increase tumor-specific Tcell priming [55], and also extend survival in murine models [56]. Local irradiation combining with a cancer vaccine expressing human papilloma virus E6/E7 oncoproteins, made an 85-fold increase in the ratio of antitumoral CD8 + T cells to immune MDSC at the tumor site in mice [50].…”