Endogenous Heat-Shock Protein Induction with or Without Radiofrequency Ablation or Cryoablation in Patients with Stage IV Melanoma

Evidio Domingo-Musibay, James M Heun, Wendy K Nevala, Matthew Callstrom, Thomas Atwell, Evanthia Galanis, Lori A Erickson, Svetomir N Markovic, Evidio Domingo-Musibay, James M Heun, Wendy K Nevala, Matthew Callstrom, Thomas Atwell, Evanthia Galanis, Lori A Erickson, Svetomir N Markovic

Abstract

Lessons learned: Percutaneous thermal ablation combined with in situ granulocyte-macrophage colony-stimulating factor cytokine therapy was technically feasible and well tolerated.No significant clinical or immunologic responses were seen.

Background: Melanoma tumor-derived heat-shock proteins (HSPs) and HSP-peptide complexes can elicit protective antitumor responses. The granulocyte-macrophage colony-stimulating factor (GM-CSF) chemokine can also promote uptake and processing by professional antigen presenting cells (APCs). On this basis, we designed a pilot study of percutaneous thermal ablation as a means to induce heat-shock protein vaccination plus GM-CSF to determine safety and preliminary antitumor activity of this combination.

Materials and methods: This study was designed to assess overall safety of percutaneous ablation combined with GM-CSF for unresectable, metastatic melanoma including uveal and mucosal types. All patients received heat-shock therapy (42°C for 30 minutes), then received one of three treatments: (a) intralesional GM-CSF (500 mcg standard dose); (b) radiofrequency ablation (RFA) + GM-CSF; or (c) cryoablation plus GM-CSF. The primary endpoint of the study was the induction of endogenous HSP70 and melanoma-specific cytotoxic T lymphocytes (CTL).

Results: Nine patients (three per study arm) were enrolled. No dose-limiting toxicity was observed as specified per protocol. All patients developed progressive disease and went on to receive alternative therapy. Median overall survival (OS) was 8.2 months (95% confidence interval [CI] 2-17.2). The study was not powered to detect a difference in clinical outcome among treatment groups.

Conclusion: Percutaneous thermal ablation plus GM-CSF was well tolerated, technically feasible, and demonstrated an acceptable adverse event profile comparable to conventional RFA and cryoablation. While HSP70 was induced following therapy, the degree of HSP70 elevation was not associated with clinical outcome or induced CTL responses. While percutaneous thermal ablation plus GM-CSF combinations including checkpoint inhibitors could be considered in future studies, the use of GM-CSF remains experimental and for use in the context of clinical trials.

Trial registration: ClinicalTrials.gov NCT00568763.

© AlphaMedPress; the data published online to support this summary is the property of the authors.

Figures

Figure 1.
Figure 1.
Plasma HSP70 levels. Baseline circulating HSP70 was detectable in all patients. (A): Individual patient levels of plasma HSP70 over 24 hours shown for heat shock therapy (HST), RFA, and cryoablation cohorts. (B): HSP70 fold‐change above baseline level measurements for patients receiving cryoablation (top, arm C), RFA (middle, arm B), and HST (lower, arm A), with sustained elevations of HSP70 seen in patients receiving cryoablation therapy. Abbreviations: HSP70, 70 kilodalton heat‐shock protein; RFA, radiofrequency ablation.
Figure 2.
Figure 2.
Major histocompatibility complex‐tetramer testing identified cluster of differentiation 8 positive (CD8+) cytotoxic T lymphocytes (CTLs) for each tumor antigen. Pre‐specified criteria for positive tetramer results was >0.02% tetramer positive CD8+ CTLs if baseline negative, or >2‐fold increase in the baseline detectable number. We detected low baseline levels of peripheral CD8+ CTLs against known melanoma antigens MART‐1, GP100, and Tyrosinase (7 of 8 evaluable patients). There was no significant induction of CD8+ CTL responses to melanoma antigens following treatment. Abbreviations: GP100, glycoprotein 100; MART‐1, melanoma antigen recognized by T cells 1.

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Source: PubMed

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