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Kokowski, K.* ; Stangl, S.* ; Seier, S.* ; Hildebrandt, M.A.* ; Vaupel, P.* ; Multhoff, G.

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

Strahlenther. Onkol. 195, 352-361 (2019)

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BackgroundMembrane heat shock protein 70 (mHsp70) is indicative of high-risk tumors and serves as atumor-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 anon-small cell lung carcinoma (NSCLC) patient.PatientFollowing simultaneous RCT (64.8Gy), apatient with inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated with 4cycles of autologous ex vivo TKD/IL-2-activated NK cells and the PD-1 antibody nivolumab as asecond-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 amassive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33months after diagnosis. Therapy response was associated with significantly increased CD3(-)/NKG2D(+)/CD94(+) NK cell counts, elevated CD8(+) to CD4(+) Tcell and CD3(-)/CD56(bright) to CD3(-)/CD56(dim) NK cell ratios, and significantly reduced regulatory Tcells (Tregs) in the peripheral blood.ConclusionAcombined 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.

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