Radiation and Cancer Biology

PD 11 - Biology 5 - Poster Discussion

1097 - Anti-PD-1 Immunotherapy Potentiates the Radiation-Induced Lung Injury

Tuesday, October 23
3:27 PM - 3:33 PM
Location: Room 217 A/B

Anti-PD-1 Immunotherapy Potentiates the Radiation-Induced Lung Injury
J. Xue1,2, S. Du1, A. P. Dicker1, Y. Lu2, and B. Lu1; 1Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 2Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China

Purpose/Objective(s): Combination of thoracic radiotherapy and anti-PD1 immunotherapy has been investigated both in the lab and in the clinic. Pneumonitis is a rare but potentially fatal toxicity of ant-programmed death-1 (PD-1) monoclonal antibody (mAb). The purpose of this study is to address whether concurrent anti-PD-1 mAb during thoracic radiation leads to an increase in lung toxicity and mortality using a murine model using Small Animal Radiation Research Platform (SARRP) for lung-targeting irradiation (LIR) and the underlying mechanisms.

Materials/Methods: Both lungs of male C57bl/6 mice were targeted for 20Gy using the SARRP. Mice were stratified into 4 treatment groups receiving IgG, anti-PD1, LIR + IgG, or LIR + anti-PD1. IgG or anti-PD-1 mAb was administrated via i.p. injection, with a dosage of 10mg/kg, twice per week for five doses. The long-term survival was observed. Acute and late lung injuries were assessed at several time points by H&E staining; Masson’s Trichrome staining and hydroxyproline for lung fibrosis, micro CT scan and lung physiological testing. The infiltration of lymphocytes and the expression of cytokines in irradiated lung tissues were measured by immunohistochemistry staining and RT-PCR, respectively. Furthermore, we examined the roles of CD4, CD8, macrophages and TGF-β1 by individual depletion using neutralizing antibody.

Results: LIR+anti-PD-1 led to worse survival with a median survival time of 18 weeks , compared with that of 31 weeks in the LIR+ IgG group (p<0.05). In the acute phase (4 weeks following LIR), LIR+anti-PD-1 treated mice showed more severe inflammation, abnormal alveoli and increased pulmonary resistance compared with LIR+ IgG. In the late phase (22~24 weeks following LIR), LIR+anti-PD-1 treated mice showed more severe fibrosis, increased lung density and resistance, as well as decreased compliance of the lung. LIR+anti-PD-1 mice had increased numbers of CD8+ T cells and macrophages that are strongly positive for TGF-β1 in the lung tissues. Furthermore, depletion of CD8 lymphocytes (median survival 21 weeks), macrophages (median survival 23 weeks) or TGF-β1 (median survival 28 weeks) attenuated the mortality of the LIR+anti-PD-1 treated mice (median survival 17 weeks).

Conclusion: Concurrent anti-PD-1 mAb during thoracic radiation leads to an increase in lung toxicity and the consequent mortality, accompanied by increased CD8+ T lymphocytes and macrophages with strong positivity for TGF-β1. Blocking TGF-β1 significantly attenuates mortality from LIR+anti-PD-1. Lung toxicities should be closely monitored in ongoing clinical trials of concurrent combination of thoracic RT and anti-PD-1 therapy.

Author Disclosure: J. Xue: None. S. Du: None. A.P. Dicker: Research Grant; Radiation Therapy Oncology Group. Travel Expenses; Prostate Cancer Foundation. Chair; Department of Defense.

Jianxin Xue, MD, PhD

Disclosure:
No relationships to disclose.

Presentation(s):

Send Email for Jianxin Xue


Assets

1097 - Anti-PD-1 Immunotherapy Potentiates the Radiation-Induced Lung Injury



Attendees who have favorited this

Please enter your access key

The asset you are trying to access is locked. Please enter your access key to unlock.

Send Email for Anti-PD-1 Immunotherapy Potentiates the Radiation-Induced Lung Injury