PURPOSE: Cryotherapy of localized
prostate,
renal, and
hepatic primary tumors and
metastases is considered a minimally invasive treatment demonstrating a low complication rate in comparison with conventional
surgery. The main drawback of cryotherapy is that it has no
systemic effect on distant
metastases. We investigated whether intratumoral injections of
dendritic cells following cryotherapy of local
tumors (cryoimmunotherapy) provides an improved approach to cancer treatment, combining local
tumor destruction and systemic
anticancer immunity. EXPERIMENTAL DESIGNS: The 3LL murine Lewis
lung carcinoma clone D122 and the ovalbumin-transfected B16
melanoma clone MO5 served as models for spontaneous
metastasis. The antimetastatic effect of cryoimmunotherapy was assessed in the
lung carcinoma model by monitoring
mouse survival,
lung weight, and induction of tumor-specific CTLs. The mechanism of cryoimmunotherapy was elucidated in the
melanoma model using adoptive transfer of
T cell receptor transgenic OT-I CTLs into the tumor-bearing
mice, and analysis of
Th1/
Th2 responses by
intracellular cytokine staining in
CD4 and
CD8 cells. RESULTS: Cryoimmunotherapy caused robust and tumor-specific CTL responses, increased
Th1 responses, significantly prolonged survival and dramatically reduced
lung metastasis. Although intratumor administration of
dendritic cells alone increased the proliferation rate of
CD8 cells, only cryoimmunotherapy resulted in the generation of effector
memory cells. Furthermore, cryoimmunotherapyprotected
mice that had survived primary MO5
tumors from
rechallenge with parental
tumors. CONCLUSIONS: These results present cryoimmunotherapy as a novel approach for systemic treatment of cancer. We envisage that cryotherapy of
tumors combined with subsequent in situ
immunotherapy by
autologous unmodified immature
dendritic cells can be applied in practice.
