Abstract
Background/Aim: Experimental studies have shown that celecoxib is related to the downregulation of Tregs and an increase in the therapeutic efficacy of PD-1 inhibitors; however, such effect has not been shown in human cancers. Our report confirmed the synergistic effect of celecoxib with a PD-1 inhibitor. Case Report: A 57-year-old male with advanced pulmonary adenocarcinoma was treated with nivolumab monotherapy as 5th line sequential treatment. Although the patient experienced tumor remission, regrowth of the primary tumor was observed and he complained of lumbar pain. Therefore, celecoxib (400 mg/day) was initiated without cessation of nivolumab. Chest radiography revealed a marked shrinkage of the primary site, with a decreasing trend of carcinoma embryonic antigen. Conclusion: This is the report of a case of recovery of sensitivity to nivolumab by additional treatment with celecoxib.
Immune checkpoint inhibitors (ICIs), such as anti-programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) antibodies, have yielded limited efficacy in patients with advanced non-small cell lung cancer (NSCLC). However, some long-term survivors after ICI treatment have been observed. To improve the efficacy of ICIs, the development of additional treatments is necessary.
Celecoxib, 4-[5-(4-methylphenyl)-3-trifluoromethyl1H-pyrazol-1-yl] benzenesulfonamide, is a specific inhibitor of cycloxygenase-2 (COX2) that diminishes inflammation and pain, and is described to be associated with downregulation of regulatory T-cells (T-regs) (1). Reportedly, celecoxib exhibits antitumor activity in various human cancers; moreover, combination therapy of celecoxib and a PD-1 inhibitor increased the efficacy of the PD-1 inhibitor in an experimental model, suggesting that celecoxib treatment can result in the recovery of a negative tumor immune environment (1). Recently, we experienced a case demonstrating the recovery of sensitivity to nivolumab due to celecoxib, in a patient with advanced NSCLC.
Case Report
A 57-year-old male with a history of smoking who harbored epidermal growth factor receptor mutation deletion 19 (cT2aN2M1) was diagnosed with pulmonary adenocarcinoma. In October 2015, gamma-knife therapy was performed owing to cerebral metastases. Subsequently, the patient was administered afatinib. As tumor recurrence with T790M was found, osimertinib was initiated in December 2016. Six months after its initiation, progressive disease was observed and cisplatin plus pemetrexed was administered. He also received erlotinib plus bevacizumab. In September 2017, nivolumab was administered for recurrent disease. Although the patient experienced tumor remission, regrowth of the primary tumor was observed in December 2019 (Figure 1) and he complained of lumbar pain. Therefore, celecoxib (400 mg/day) was initiated without cessation of nivolumab. Despite serological and bacterial investigation, there was no evidence of any disease aside from its regrowth. In January 2020, chest radiography revealed a marked shrinkage of the primary site, with a decreasing trend in the levels of carcinoma embryonic antigen (CEA) (Figure 1). The patient continues to receive nivolumab and celecoxib without any recurrence.
Discussion
To our knowledge, this is the first report of a case of recovery of sensitivity to nivolumab by additional treatment with celecoxib. The efficacy of ICIs has been reported to improve after radiation therapy, however; it remains unclear whether celecoxib could increase the efficacy of anti-PD-1 antibody.
Chest radiography before and after oral celecoxib during nivolumab administration (A, B and C) and transitive graph of CEA (ng/ml) (D). Chest radiography shows almost remission of primary tumor in the left upper lung field (A) (white arrow) during nivolumab administration, but it reveals regrowth of primary site (B) (white arrow). After celecoxib administration, chest radiography reveals obvious shrinkage of primary site (C) (white arrow). Celecoxib (400 mg/day) was initiated in December 2019.
Botti et al. have reported that COX-2 expression significantly correlates with PD-L1 expression in melanoma cells, and the COX2 inhibition by celecoxib downregulates PD-L1 expression in vitro (2).
In lung cancer, PD-L1 expression correlated with that of COX and the majority of lung cancer cells expressing PD-L1 also co-expressed COX2 (3). However, inhibition of COX2 did not affect PD-L1 expression in lung cancer cell lines (3). Likewise, the inhibition of COX2 has been described to reduce the recruitment of myeloid-derived suppressor cells (MDSCs) to the tumor sites and decrease T-regs (1, 4, 5). MDSCs have receptors for prostaglandin E2 (PGE2) and COX inhibitor decreases the production of PGE2 (6). In our case, celecoxib treatment could reestablish sensitivity to nivolumab. The additional administration of celecoxib seemed to act synergistically to ICIs. According to previous studies, any additional therapy to ICIs is expected to improve the efficacy of ICIs; thus, celecoxib is a promising drug to strengthen the immunological effects of PD-1 inhibitors. However, many cases of delayed pseudoprogression have been reported in the literature, especially in melanoma patients. Although we carefully considered whether our patient experienced delayed pseudoprogression, there was no potential of pseudoprogression related to nivolumab treatment because of obvious change in the levels of CEA as tumor marker before and after the administration of celecoxib. Moreover, it remains unclear what kind of patients can obtain the clinical benefit of anti-PD-1 antibody by the administration of celecoxib. Further study is warranted to elucidate the clinical significance of additional treatment of celecoxib to anti-PD-1 antibody for patients with various human cancers. Physicians should be alert to the potential usefulness of celecoxib in addition to PD-1 inhibitors.
Footnotes
Authors' Contributions
Conception and design: Kunihiko Kobayashi. Collection and assembly of data: Kyoichi Kaira. Data analysis and interpretation: Kyoichi Kaira, Kunihiko Kobayashi. Manuscript writing: Kyoichi Kaira. Final approval of the manuscript: All Authors. Accountable for all aspects of the work: All Authors.
Conflicts of Interest
K Kaira and HK have received research grants and a speaker honorarium from Ono Pharmaceutical Company and Bristol-Myers Company. All remaining Authors have declared no conflicts of interest.
- Received June 10, 2020.
- Revision received July 22, 2020.
- Accepted July 23, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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