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

Abstract

BackgroundMembrane heat shock protein 70 (mHsp70) is indicative of high-risk tumors and serves as a tumor-specific target for natural killer (NK) cells stimulated with Hsp70 peptide (TKD) and Interleukin(IL)-2. Radiochemotherapy (RCT), mHsp70-targeting NK cells, and programmed death(PD)-1 inhibition were combined to improve the efficacy of tumor-specific immune cells in a non-small cell lung carcinoma (NSCLC) patient.PatientFollowing simultaneous RCT (64.8 Gy), a patient with inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated with 4 cycles of autologous ex vivo TKD/IL-2-activated NK cells and the PD-1 antibody nivolumab as a second-line therapy. Blood samples were taken for immunophenotyping during the course of therapy.ResultsAdoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3−/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3−/CD56bright to CD3−/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood.ConclusionA combined therapy consisting of RCT, mHsp70-targeting NK cells, and PD-1 antibody inhibition is well tolerated, induces anti-tumor immunity, and results in long-term tumor control in one patient with advanced NSCLC. Further, randomized studies are necessary to confirm the efficacy of this combination therapy.

HSP70 Multi-Functionality in Cancer

“…In this regard, HSP70 showed to be effective in vitro and in vivo, however, the success of HSP70-based therapies in cancer can only be verified by assessing their efficacy and safety in clinical trials ( Table 2). In that regard it is encouraging that HSP70-based therapies showed to be well tolerated among patients [124,[242][243][244][245][246][247]. However, since most of these clinical trials, except phase II trial of Specht and colleagues, were conducted in 2003-2015 years and have not been progressed through drug development timeline and further pharmacovigilance, assessment of the efficacy and safety of HSP70-based therapies for the treatment of cancer patients still remains a major challenge.…”

“…NSCLC stage IIIb Case study [246] Intratumoral injection of recombinant oncolytic type 2 adenovirus overexpressing HSP70 (H103)…”

Time- and Dose-Dependent Effects of Ionizing Irradiation on the Membrane Expression of Hsp70 on Glioma Cells

“…By its exclusive expression on the plasma membrane of tumor cells [9], mHsp70 provides a tumor-specific target for Hsp70-specific, activated NK cells [10]. Therefore, increasing the density of mHsp70 on tumor cells by irradiation combined with a mHsp70-targeting NK cell-based immunotherapy might provide a novel strategy to improve clinical outcome and extend overall survival of patients with advanced tumors [11][12][13]. Herein, we were interested to identify the optimal radiation dose and time point for an up-regulated mHsp70 density as a target for NK cells on highly aggressive glioblastoma cells.…”

Time- and Dose-Dependent Effects of Ionizing Irradiation on the Membrane Expression of Hsp70 on Glioma Cells

“…By its exclusive expression on the plasma membrane of tumor cells [9], mHsp70 provides a tumor-specific target for Hsp70specific, activated NK cells [10]. Therefore, increasing the density of mHsp70 on tumor cells by irradiation combined with a mHsp70-targeting NK cell-based immunotherapy might provide a novel strategy to improve clinical outcome and extend overall survival of patients with advanced tumors [11][12][13]. Herein, we were interested to identify the optimal radiation dose and time point for an up-regulated mHsp70 density as a target for NK cells.…”