Checkpoint Antibodies but not T Cell-Recruiting Diabodies Effectively Synergize with TIL-Inducing γ-Irradiation.
T cell-recruiting bispecific antibodies (bsAb) show promise in hematologic malignancies and are also being evaluated in solid tumors. In this study, we investigated whether T cell-recruiting bsAbs synergize with hypofractionated tumor radiotherapy (hRT) and/or blockade of the programmed death-1 (PD-1) immune checkpoint, both of which can increase tumor-infiltrating lymphocyte (TIL) numbers. Unexpectedly, large melanomas treated with hRT plus bsAb (AC133×CD3) relapsed faster than those treated with hRT alone, accompanied by massive TIL apoptosis. This fast relapse was delayed by the further addition of anti-PD-1. Mechanistic investigations revealed restimulation-induced cell death mediated by BIM and FAS as an additional cause of bsAb-mediated TIL depletion. In contrast, the double combination of hRT and anti-PD-1 strongly increased TIL numbers, and even very large tumors were completely eradicated. Our study reveals the risk that CD3-engaging bsAbs can induce apoptotic TIL depletion followed by rapid tumor regrowth, reminiscent of tolerance induction by CD3 mAb-mediated T-cell depletion, warranting caution in their use for the treatment of solid tumors. Our findings also argue that combining radiotherapy and anti-PD-1 can be quite potent, including against very large tumors. Cancer Res; 76(16); 4673-83. ©2016 AACR.
Department of Radiation Oncology, Medical Center-University of Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany.
Michael
M
Hettich
Department of Radiation Oncology, Medical Center-University of Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany. German Cancer Consortium (DKTK), Freiburg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jayashree
J
Lahoti
Department of Radiation Oncology, Medical Center-University of Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany.
Shruthi
S
Prasad
Department of Radiation Oncology, Medical Center-University of Freiburg, Freiburg, Germany. German Cancer Consortium (DKTK), Freiburg, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. gabriele.niedermann@uniklinik-freiburg.de.
Gabriele
G
Niedermann
D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000528:radiation effects; D059248:Chemoradiotherapy / Q000379:methods; D005434:Flow Cytometry; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000528:radiation effects; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D011878:Radiotherapy
D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor