Heat Shock Protein 70 (Hsp70) Peptide Activated Natural Killer (NK) Cells for the Treatment of Patients with Non-Small Cell Lung Cancer (NSCLC) after Radiochemotherapy (RCTx) – From Preclinical Studies to a Clinical Phase II Trial

Abstract

Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and non-small cell lung cancer (NSCLC) in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2014. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum-based radiochemotherapy (RCTx) with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with RCTx alone. As secondary endpoints overall survival, toxicity, quality-of-life, and biological responses will be determined in both study groups.

Radiochemotherapy combined with NK cell transfer followed by second-line PD-1 inhibition in a patient with NSCLC stage IIIb inducing long-term tumor control: a case study

“…Membrane Hsp70 serves as a tumor target for activated NK cells [1, 16–18, 21], whereas cytosolic Hsp70 impairs apoptosis [25]. Previously, exHsp70 has been shown to predict the mHsp70 status of primary tumors and viable tumor mass in tumor-bearing mice [26] and NSCLC patients [27].…”

Modulation of inflammation by low and high doses of ionizing radiation: Implications for benign and malign diseases

“…However, the combined treatment with immunotherapeutic agents as adjuvants to RT has shown promising effects in inducing NK and cluster of differentiation (CD)8 T cell toxicity in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer using a Toll-like receptor (TLR)7/8 agonist in combination with 5 × 2 Gy fractionated irradiation [53]. A newsworthy clinical phase II trial is running examining Hsp70-peptide activated NK cells for the treatment of patients with non-small cell lung cancer (NSCLC) after radiochemotherapy (RCT) [54].…”

Targeting Hsp70: A possible therapy for cancer

“…In a mouse model, peripheral blood lymphocytes incubated with TKD-peptide and IL-2 induce migration of NK cells towards Hsp70 membrane-positive tumor cells [208]. An Hsp70-based vaccine is in phase-I clinical trials; an advantage of this approach is the excellent safety and the bioavailability of the synthetic Hsp70 peptide that stimulates NK-cells [209]. …”