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- [Cancer Res. ] Checkpoint Antibodies but not T Cell-Recruiting Diabodies Effectively Synergize with TIL-Inducing γ-Irradiation.
Medical Center-University of Freiburg / Gabriele Niedermann*
- 출처
- Cancer Res
- 등재일
- 2016 Aug 15
- 저널이슈번호
- 76(16):4673-83. doi: 10.1158/0008-5472.CAN-15-3451. Epub 2016 Jun 14.
- 내용
- AbstractT 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.
Author information
Hettich M1, Lahoti J2, Prasad S1, Niedermann G3.1Department of Radiation Oncology, Medical Center-University of Freiburg, Freiburg, Germany. Faculty of Biology, University of Freiburg, Freiburg, Germany.2Department 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.3Department 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.
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- 다음글 [J Clin Oncol.] Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline.
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편집위원
T cell-recruiting bispecific antibodies(bsAb)는 hematologic malignancies 뿐만 아니라, solid tumors의 치료효율을 높이는 대안으로 주목받고 있다.
2016-09-02 10:00:38
편집위원
본 연구에서는 T cell-recruiting bsAbs와 fractionated tumor radiotherapy (hRT)의 synergistic한 효과를 검증하였다.
2016-09-02 10:00:38
편집위원
기대와 달리 본 연구결과에서는 CD3-engaging bsAbs가 apoptotic TIL depletion, rapid tumor regrowth, reminiscent of tolerance를 유도함으로써 임상 적용에 주의를 요해야 함을 증명하였다.
2016-09-02 10:00:38
편집위원
또한 radiotherapy와 anti-PD-1 치료가 잠정적으로 large tumors 치료의 최선책이 될 수 있음을 제시하였다.
2016-09-02 10:00:38