Abstract 546P
Background
Malignant pleural mesothelioma (MPM) is an asbestos-related fatal malignant neoplasm. Although combination therapy of ipilimumab plus nivolumab has proven to bring about a better outcome in patients with MPM, long-term survival remains unsatisfactory. To further improve the prognosis, developing a novel treatment strategy to maximize the antitumor effect of ICI is a pressing issue. We examined whether nintedanib, an antiangiogenic agent, could augment the antitumor effect of anti-PD-1 antibody (Ab).
Methods
We established subcutaneous mice mesothelioma allograft model. Mice were treated either with vehicle, anti-PD-1 Ab, nintedanib or anti-PD-1 Ab plus nintedanib. Tumor size was routinely measured with a caliper. Mice were euthanized before they became moribund, and allografts were collected for histological analyses. Angiogenesis and infiltrating immune cells were assessed by immunohistochemistry (IHC). We further performed ex vivo study using bone marrow-derived macrophages (BMDMs) to elucidate the antitumor mechanism of the combination therapy of anti-PD-1 Ab plus nintedanib.
Results
Nintedanib significantly suppressed the growth of mesothelioma allografts. Combination therapy with anti-PD-1 Ab plus nintedanib reduced tumor burden more dramatically compared with nintedanib monotherapy. IHC analyses revealed that nintedanib not only inhibited angiogenesis but also decreased the infiltration of tumor-associated macrophages (TAMs). Moreover, ex vivo study using BMDMs showed that nintedanib could polarize TAMs from M2 to M1 phenotype. Thus, nintedanib could suppress protumor activity of TAMs both numerically and functionally. On the other hand, nintedanib upregulated the expression of PD-1 and PD-L1 in BMDMs and mesothelioma cells, respectively, and impaired the phagocytic activity of BMDMs against mesothelioma cells. Co-administration of anti-PD-1 Ab may reactivate phagocytic activity of BMDMs by disrupting nintedanib-induced immunosuppressive signal.
Conclusions
Combination therapy of anti-PD-1 Ab plus nintedanib exerts synergistic antitumor activity and can become a novel therapeutic option for patients with MPM.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
T. Minami: Financial Interests, Institutional, Research Grant: Nippon Boehringer Ingelheim. All other authors have declared no conflicts of interest.
Resources from the same session
87TiP - Phase I expansion study of the tissue factor (TF)–targeting antibody-drug conjugate (ADC) XB002 as a single-agent and combination therapy in patients with advanced solid tumors (JEWEL-101)
Presenter: Mustafa Syed
Session: Poster Display
Resources:
Abstract
88TiP - A phase Ib study of HMBD-001, a monoclonal antibody targeting HER3, with or without chemotherapy in patients with genetic aberrations in HER3 signaling
Presenter: Nick Pavlakis
Session: Poster Display
Resources:
Abstract
93P - Efficacy and safety of fruquintinib (F) + best supportive care (BSC) vs placebo (P) + BSC in refractory metastatic colorectal cancer (mCRC): Asian vs non-Asian outcomes in FRESCO-2
Presenter: Daisuke Kotani
Session: Poster Display
Resources:
Abstract
94P - Sidedness-dependent prognostic impact of gene alterations in metastatic colorectal cancer in the nationwide cancer genome screening project in Japan (SCRUM-Japan GI-SCREEN)
Presenter: Takeshi Kajiwara
Session: Poster Display
Resources:
Abstract
95P - Interim results of a prospective randomized controlled study to compare the clinical outcomes of total neoadjuvant therapy vs long course chemoradiotherapy in locally advanced carcinoma rectum
Presenter: Sandip Barik
Session: Poster Display
Resources:
Abstract
96P - Tyrosine kinase inhibitor (TKI) plus PD-1 blockade in TKI-responsive MSS/pMMR metastatic colorectal adenocarcinoma (mCRC): Updated results of TRAP study
Presenter: Jingdong Zhang
Session: Poster Display
Resources:
Abstract
97P - Asian subgroup analysis of the phase III LEAP-017 trial of lenvatinib plus pembrolizumab vs standard-of-care in previously treated metastatic colorectal cancer (mCRC)
Presenter: Rui-Hua Xu
Session: Poster Display
Resources:
Abstract
98P - Real clinical impact of postoperative surgical complications after colon cancer surgery
Presenter: Toru Aoyama
Session: Poster Display
Resources:
Abstract
99P - Extended lymphadenectomy may not be necessary for MSI-H colon cancer patients after immunotherapy
Presenter: Rongxin Zhang
Session: Poster Display
Resources:
Abstract
100P - Identification of phenomic data in the pathogenesis of colorectal cancer: A UK biobank data analysis
Presenter: Shirin Hui Tan
Session: Poster Display
Resources:
Abstract