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Combination therapy with local radiofrequency ablation and systemic vaccine enhances antitumor immunity and mediates local and distal tumor regression.

Gameiro SR, Higgins JP, Dreher MR, Woods DL, Reddy G, Wood BJ, Guha C, Hodge JW - PLoS ONE (2013)

Bottom Line: Murine 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.Sequential administration of low-dose and high-dose RFA with vaccine decreased tumor recurrence compared to RFA alone.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT

Purpose: Radiofrequency 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 design: Murine 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.

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Antitumor efficacy of combination therapy with sequential RFA and recombinant vaccine.MC38-CEA+ cells were transplanted on day 0 on the right flank of CEA-Tg mice (n = 25–29/group). MC38-CEA+ tumors received sham or low-dose RFA (10–30 s at 70°C) on day 12 (dotted line), followed by high-dose ablative RFA (30–300 s at 70°C) on day 15 (solid line). Vaccinated mice received rMVA-CEA/TRICOM s.c. on day 4 and rF-CEA/TRICOM on day 11 and every 7 days thereafter, alone or in combination with sequential RFA. A depicts tumor growth. Data represent tumor volume ± S.E.M. in individual animals. Asterisks denote statistically significant differences among treatment groups (P<0.0001, 1-way ANOVA with Tukey’s multiple comparison test).
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pone-0070417-g006: Antitumor efficacy of combination therapy with sequential RFA and recombinant vaccine.MC38-CEA+ cells were transplanted on day 0 on the right flank of CEA-Tg mice (n = 25–29/group). MC38-CEA+ tumors received sham or low-dose RFA (10–30 s at 70°C) on day 12 (dotted line), followed by high-dose ablative RFA (30–300 s at 70°C) on day 15 (solid line). Vaccinated mice received rMVA-CEA/TRICOM s.c. on day 4 and rF-CEA/TRICOM on day 11 and every 7 days thereafter, alone or in combination with sequential RFA. A depicts tumor growth. Data represent tumor volume ± S.E.M. in individual animals. Asterisks denote statistically significant differences among treatment groups (P<0.0001, 1-way ANOVA with Tukey’s multiple comparison test).

Mentions: We hypothesized that combining vaccine with sequential RFA (low-dose immunogenic RFA followed by high-dose curative-intent RFA) would result in significant antitumor efficacy and improved relapse rates. To test this hypothesis, CEA-Tg mice received MC38-CEA+ cells on day 0. Tumors received sham or low-dose RFA on day 12, followed by ablative high-dose RFA on day 15 (defined as sequential RFA). Mice received vaccine weekly starting on day 4 in combination with sham or sequential RFA. Subsequent analysis of tumor volumes indicated significant differences among treatment groups (P<0.0001). Vaccine alone significantly decreased tumor burden relative to mice receiving RFA sham (Fig. 6) (P<0.05). Tumors exposed to sequential RFA alone or to combination therapy showed the highest decrease in tumor growth relative to controls (P<0.0001). Interestingly, sequential RFA plus vaccine did not decrease tumor volume more effectively than sequential RFA alone, confirming independent observations from two additional studies (data not shown). To better understand the antitumor effects of combination therapy relative to sequential RFA alone, we performed a focused analysis of CRs and durable CRs. In this context, any tumor eradication during the course of the study, regardless of relapse, was considered CR. Any tumor eradication without subsequent relapse during the course of the study was considered a durable CR. No CRs were observed in animals receiving RFA sham or vaccine alone (Table 3). During the course of this study, 34.5% of animals receiving sequential RFA attained a CR; 50% of these subsequently relapsed. However, animals receiving sequential RFA plus vaccine showed a higher CR rate, as well as increased relapse-free durable CR. Specifically, we observed that 52% of all animals receiving combination therapy became tumor-free. Further, 69.2% of all CRs in this cohort did not relapse. Thus, the combination therapy increased durable CRs by 19.2%. These results suggest a trend indicating that low-dose immunomodulatory RFA plus high-dose curative-intent RFA combined with vaccine may reduce the number of tumor relapses and thus prolong survival.


Combination therapy with local radiofrequency ablation and systemic vaccine enhances antitumor immunity and mediates local and distal tumor regression.

Gameiro SR, Higgins JP, Dreher MR, Woods DL, Reddy G, Wood BJ, Guha C, Hodge JW - PLoS ONE (2013)

Antitumor efficacy of combination therapy with sequential RFA and recombinant vaccine.MC38-CEA+ cells were transplanted on day 0 on the right flank of CEA-Tg mice (n = 25–29/group). MC38-CEA+ tumors received sham or low-dose RFA (10–30 s at 70°C) on day 12 (dotted line), followed by high-dose ablative RFA (30–300 s at 70°C) on day 15 (solid line). Vaccinated mice received rMVA-CEA/TRICOM s.c. on day 4 and rF-CEA/TRICOM on day 11 and every 7 days thereafter, alone or in combination with sequential RFA. A depicts tumor growth. Data represent tumor volume ± S.E.M. in individual animals. Asterisks denote statistically significant differences among treatment groups (P<0.0001, 1-way ANOVA with Tukey’s multiple comparison test).
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Related In: Results  -  Collection

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pone-0070417-g006: Antitumor efficacy of combination therapy with sequential RFA and recombinant vaccine.MC38-CEA+ cells were transplanted on day 0 on the right flank of CEA-Tg mice (n = 25–29/group). MC38-CEA+ tumors received sham or low-dose RFA (10–30 s at 70°C) on day 12 (dotted line), followed by high-dose ablative RFA (30–300 s at 70°C) on day 15 (solid line). Vaccinated mice received rMVA-CEA/TRICOM s.c. on day 4 and rF-CEA/TRICOM on day 11 and every 7 days thereafter, alone or in combination with sequential RFA. A depicts tumor growth. Data represent tumor volume ± S.E.M. in individual animals. Asterisks denote statistically significant differences among treatment groups (P<0.0001, 1-way ANOVA with Tukey’s multiple comparison test).
Mentions: We hypothesized that combining vaccine with sequential RFA (low-dose immunogenic RFA followed by high-dose curative-intent RFA) would result in significant antitumor efficacy and improved relapse rates. To test this hypothesis, CEA-Tg mice received MC38-CEA+ cells on day 0. Tumors received sham or low-dose RFA on day 12, followed by ablative high-dose RFA on day 15 (defined as sequential RFA). Mice received vaccine weekly starting on day 4 in combination with sham or sequential RFA. Subsequent analysis of tumor volumes indicated significant differences among treatment groups (P<0.0001). Vaccine alone significantly decreased tumor burden relative to mice receiving RFA sham (Fig. 6) (P<0.05). Tumors exposed to sequential RFA alone or to combination therapy showed the highest decrease in tumor growth relative to controls (P<0.0001). Interestingly, sequential RFA plus vaccine did not decrease tumor volume more effectively than sequential RFA alone, confirming independent observations from two additional studies (data not shown). To better understand the antitumor effects of combination therapy relative to sequential RFA alone, we performed a focused analysis of CRs and durable CRs. In this context, any tumor eradication during the course of the study, regardless of relapse, was considered CR. Any tumor eradication without subsequent relapse during the course of the study was considered a durable CR. No CRs were observed in animals receiving RFA sham or vaccine alone (Table 3). During the course of this study, 34.5% of animals receiving sequential RFA attained a CR; 50% of these subsequently relapsed. However, animals receiving sequential RFA plus vaccine showed a higher CR rate, as well as increased relapse-free durable CR. Specifically, we observed that 52% of all animals receiving combination therapy became tumor-free. Further, 69.2% of all CRs in this cohort did not relapse. Thus, the combination therapy increased durable CRs by 19.2%. These results suggest a trend indicating that low-dose immunomodulatory RFA plus high-dose curative-intent RFA combined with vaccine may reduce the number of tumor relapses and thus prolong survival.

Bottom Line: Murine 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.Sequential administration of low-dose and high-dose RFA with vaccine decreased tumor recurrence compared to RFA alone.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT

Purpose: Radiofrequency 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 design: Murine 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.

Show MeSH
Related in: MedlinePlus