αPD-1-mesoCAR-T cells partially inhibit the growth of advanced/refractory ovarian cancer in a patient along with daily apatinib

Juemin Fang, Na Ding, Xinling Guo, Yan Sun, Zhiwei Zhang, Bailu Xie, Zhong Li, Hui Wang, Wei Mao, Zhicai Lin, Fei Qin, Min Yuan, Wenqi Chu, Huanlong Qin, Qijun Qian, Qing Xu, Juemin Fang, Na Ding, Xinling Guo, Yan Sun, Zhiwei Zhang, Bailu Xie, Zhong Li, Hui Wang, Wei Mao, Zhicai Lin, Fei Qin, Min Yuan, Wenqi Chu, Huanlong Qin, Qijun Qian, Qing Xu

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies in China. In particular, advanced/refractory ovarian cancer lacks effective targeted therapies due to the immunosuppressive and proangiogenic tumor microenvironment. Mesothelin (MSLN) has been found to be highly expressive in most EOC. Targeting MSLN by antibodies or chimeric antigen receptor-modified T (CAR-T) cells and immune checkpoint blockades as well as apatinib, an anti-angiogenic drug, have been used in patients with refractory ovarian cancer. Apatinib was reported to promote the infiltration of CD8+ T cells in lung cancer. However, the combination therapy of CAR-T secreting anti-PD-1 antibody with apatinib in EOC has not been reported.

Case presentation: Here we report a case of refractory EOC in a patient who had relapsed after multiline chemotherapy. The patient received autologous T cells that contained sequences encoding single-chain variable fragments specific for MSLN and full-length antibody for PD-1 (αPD-1). The modified T cells were called αPD-1-mesoCAR-T cells. After infusion, the copy number and PD-1 antibody secretion of the CAR-T cells were increased in the blood. By application of multimodality tumor tracking, MRI of the liver showed shrinkage of metastatic nodules from average diameter of 71.3-39.1 mm at month 2. The patient achieved partial response and survived more than 17 months. IL-6 levels in the patient fluctuated from the baseline to 2-4-folds after treatment, but side effects were mild with only grade 1 hypertension and fatigue.

Conclusion: αPD-1-mesoCAR-T cell therapy combined with apatinib demonstrates a potential therapeutic effect on advanced refractory ovarian cancer.

Trial registration number: NCT03615313.

Keywords: Apatinib; CAR-T; PD-1; case reports; chimeric antigen; immunotherapy; ovarian cancer; receptors.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
Clinical response. (A) Detection of plasma CA125 levels by Elecsys (Roche) in hospital medical laboratory. The curve starts from the day first taking apatinib to the end of observation period of immunotherapy and shows a decrease at month 2 and an increase at month 8. The two times of CAR-T cell therapies make it down in 2 months of apatinib treatment. (B) Change of the two metastatic lesions (pink areas) before and after immunotherapy in the right hepatic lobe. Upper panels show nodule 1 (N1), lower panels are nodule 2 (N2). (C) Diameters of two metastatic nodules are determined by the multimodality tumor tracking system. The diameter of N1 reduced from 51.9 to 39.1 mm, while N2 from 19.4 mm to undetectable after the combined immunotherapy. CAR-T, chimeric antigen receptor T cells.
Figure 2
Figure 2
Immunohistochemical analysis of ovarian cancer tissue for MSLN, PD-L1 and CD3 expression. The tissues (5 µm thick) were used for immunohistochemical analysis according to the methods described previously. There were 84% of tumor cells positive for MSLN staining, 46% of infiltrated lymphocytes were CD3 positive, PD-L1 staining was 35.24%. Magnification of the upper panels are 100×, the scale bar is 150 μm. The low panels are 400×, the scale bar is 74 μm. MSLN, mesothelin.
Figure 3
Figure 3
Infusion and expansion of CAR-T cells and levels of PD-1 antibodies and cytokines during treatment. (A) Scheme of apatinib, apheresis, infusion and assessment. (B) Detection of meso-CAR-T and PD-1 antibodies in blood during immunotherapy. Triangles represent PD-1 antibody and circles mean CAR copy number (copies/µg DNA). (C) Cytokine dynamics after two CAR-T infusions (day 0 and day 26). Concentrations of IL-2, 4, 6, tumor necrosis factor (TNF-α) and interferon (IFN-γ) were measured by flow cytometry from day 0 to day 53. Day 0 shows the copy number and PD-1 content of the CAR-T product. CAR-T, chimeric antigen receptor T cells; MSLN, mesothelin.

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