Combination Therapy with Local Radiofrequency Ablation and Systemic Vaccine Enhances Antitumor Immunity and Mediates Local and Distal Tumor Regression

Abstract

PurposeRadiofrequency ablation (RFA) is a minimally invasive energy delivery technique increasingly used for focal therapy to eradicate localized disease. RFA-induced tumor-cell necrosis generates an immunogenic source of tumor antigens known to induce antitumor immune responses. However, RFA-induced antitumor immunity is insufficient to control metastatic progression. We sought to characterize (a) the role of RFA dose on immunogenic modulation of tumor and generation of immune responses and (b) the potential synergy between vaccine immunotherapy and RFA aimed at local tumor control and decreased systemic progression.Experimental DesignMurine colon carcinoma cells expressing the tumor-associated (TAA) carcinoembryonic antigen (CEA) (MC38-CEA+) were studied to examine the effect of sublethal hyperthermia in vitro on the cells’ phenotype and sensitivity to CTL-mediated killing. The effect of RFA dose was investigated in vivo impacting (a) the phenotype and growth of MC38-CEA+ tumors and (b) the induction of tumor-specific immune responses. Finally, the molecular signature was evaluated as well as the potential synergy between RFA and poxviral vaccines expressing CEA and a TRIad of COstimulatory Molecules (CEA/TRICOM).Results In vitro, sublethal hyperthermia of MC38-CEA+ cells (a) increased cell-surface expression of CEA, Fas, and MHC class I molecules and (b) rendered tumor cells more susceptible to CTL-mediated lysis. In vivo, RFA induced (a) immunogenic modulation on the surface of tumor cells and (b) increased T-cell responses to CEA and additional TAAs. Combination therapy with RFA and vaccine in CEA-transgenic mice induced a synergistic increase in CD4+ T-cell immune responses to CEA and eradicated both primary CEA+ and distal CEA– s.c. tumors. Sequential administration of low-dose and high-dose RFA with vaccine decreased tumor recurrence compared to RFA alone. These studies suggest a potential clinical benefit in combining RFA with vaccine in cancer patients, and augment support for this novel translational paradigm.

Phase II/III Study of Radiofrequency Ablation Combined with Cytokine-Induced Killer Cells Treating Colorectal Liver Metastases

“…The RFA-induced antitumor immune responses have been shown in animal models and clinical settings [36][37][38], and confirmed again by our ELISPOT assay results. However, the immune reactions elicited by RFA alone are stimulated at a low level and last only a short time [39].…”

“…However, the immune reactions elicited by RFA alone are stimulated at a low level and last only a short time [39]. So the immune reactions requires amplification to control tumor progression subsequent to ablation by immune cells [38] including CIK cells and others such as dendritic cell-based hyperthermic tumor vaccine [40] and CEA-and gp70-specific T cells [36]. Relatively, CIK cell therapy has been studied more often and the transfusion of CIK cells has widely been used clinically.…”

308 Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway

“…The molecular mechanisms of immunogenic modulation include a) changes in the surface phenotype of cancer cells, including exposure of calreticulin on the outer leaflet of the plasma membrane, b) downregulation of antiapoptotic and/or prosurvival genes, and c) modulation of components of the APM [17][18][19][20][21][22][23]. The numerous immunomodulatory effects of standard therapies can be exploited to enhance the antitumor activity induced by immunotherapy.…”

Harnessing the Potential of Radiation-Induced Immune Modulation for Cancer Therapy

“…Finally, the timing of administering a second form of immunotherapy relative to radiotherapy is critical, as surgical excision or rapid ablation of primary tumor by physical means removes the source of the antigen, thereby impeding sustained immune responses. These considerations may apply to several types of physical tumor ablation, including microwave, cryotherapy, laser ablation, high-intensity focused ultrasound, and radiofrequency ablation (23,24).…”