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

• Published in: The oncologist (Dayton, Ohio) Vol. 22; no. 9; pp. 1026 - e93
• Main Authors: Domingo‐Musibay, Evidio, Heun, James M., Nevala, Wendy K., Callstrom, Matthew, Atwell, Thomas, Galanis, Evanthia, Erickson, Lori A., Markovic, Svetomir N.
• Format: Journal Article
• Language: English
• Published: United States AlphaMed Press 01.09.2017
• Subjects: Aged; Aged, 80 and over; Clinical Trial Results; Combined Modality Therapy; Cryosurgery - adverse effects; Cryosurgery - methods; Feasibility Studies; Female; Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use; HSP70 Heat-Shock Proteins - metabolism; Humans; Hyperthermia, Induced - adverse effects; Hyperthermia, Induced - methods; Immunotherapy - adverse effects; Immunotherapy - methods; Injections, Intralesional; Kaplan-Meier Estimate; Male; Melanoma - immunology; Melanoma - mortality; Melanoma - pathology; Melanoma - therapy; Middle Aged; Neoplasm Staging; Pilot Projects; Skin Neoplasms - immunology; Skin Neoplasms - mortality; Skin Neoplasms - pathology; Skin Neoplasms - therapy; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - radiation effects; Treatment Outcome
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2017-0060

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. 经验总结 • 经皮热消融联合原位粒细胞‐巨噬细胞集落刺激因子细胞因子疗法在技术上可行、耐受性良好。 • 没有观察到明显的临床或免疫应答。 摘要 背景.黑色素瘤衍生的热休克蛋白（HSP）和HSP‐肽复合物可以引发保护性抗肿瘤反应。粒细胞‐巨噬细胞集落刺激因子（GM‐CSF）趋化因子也可促进专职抗原呈递细胞（APC）的摄取和加工处理。在此基础上, 我们设计了一项经皮热消融初步研究, 据此诱导热休克蛋白疫苗与GM‐CSF, 以确定这种联合的安全性和初步抗肿瘤效果。 材料和方法.本研究旨在评估经皮消融联合GM‐CSF用于不可切除的转移性黑色素瘤（包括葡萄膜和粘膜型）的总体安全性。所有患者首先接受热休克治疗（42°C, 30分钟）, 然后接受以下三种治疗方法之一：（a）病灶内GM‐CSF（500 mcg标准剂量）；（b）射频消融（RFA）+GM‐CSF；或（c）冷冻消融联合GM‐CSF。研究的主要终点是诱导内源性HSP70和黑色素瘤特异性细胞毒性T淋巴细胞（CTL）。 结果.入组了九名患者（每个研究组三名）。按照方案规定, 未观察到剂量限制性毒性。所有患者均发生了疾病进展, 并继续接受替代治疗。中位总生存期（OS）为8.2个月[95％置信区间（CI）2‐17.2]。该研究的把握度不足以检出治疗组间临床结局的差异。 结论.经皮热消融联合GM‐CSF具有良好的耐受性且在技术上可行, 其不良事件特征被证实可接受并且与常规RFA和冷冻消融相似。HSP70在治疗后被诱导, HSP70升高程度与临床结局或诱导的CTL应答无关。虽然在未来的研究中可以考虑联合使用经皮热消融与GM‐CSF（包括检查点抑制剂）, 但GM‐CSF的使用仍然是实验性的, 并且是在临床试验范围内使用。