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Safety and efficacy of PD-1 blockade-activated multiple antigen-specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: a pooled analysis of two prospective trials

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Abstract

Background

The lethal effects of multiple antigen-specific cellular therapy (MASCT) may be enhanced by blocking PD-1 in vitro and vascular endothelial growth factor receptor 2 inhibitor (apatinib). We analyzed the pooled data from our phase I/II trials to determine the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in advanced solid tumors.

Methods

Patients with advanced solid tumors received aMASCT alone (n = 32) or aMASCT plus apatinib (500 mg q.d., n = 38) after standard treatment. The safety profile was the primary end point. The secondary end points were antitumor response, progression-free survival (PFS), and overall survival (OS). The circulating T cells were quantified before and after aMASCT infusion.

Results

Treatment-related adverse events (AEs) occurred in 18/32 (56.3%) and 25/38 (65.8%) patients in the aMASCT and aMASCT plus apatinib groups, respectively. No serious AEs were reported, and apatinib did not increase immunotherapy-related toxicity. The objective response rate (34.2% and 18.8%) and PFS (median 6.0 and 4.5 months, P = 0.002) were improved in the aMASCT plus apatinib group compared with the aMASCT group; however, the OS was not improved (median 10.0 and 8.2 months, P = 0.098). Multivariate analyses indicated that two or more cycles of aMASCT treatment was an independent and favorable prognostic factor of PFS and OS. The circulating T cells increased and Tregs decreased in both groups after one cycle of aMASCT treatment.

Conclusions

Treatment with aMASCT plus apatinib was safe and effective for the management of advanced solid tumors.

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Abbreviations

ACT:

Adoptive cellular therapy

AEs:

Adverse events

CI:

Confidence intervals

CR:

Complete response

CTL:

Cytotoxic T lymphocytes

DCs:

Dendritic cells

DCR:

Disease control rate

PD:

Disease progression

ELISPOT:

Enzyme-linked immunospot assay

HFSR:

Hand–foot syndrome

HR:

Hazard ratios

MASCT:

Multiple antigen-specific cellular therapy

MDSC:

Myeloid-derived suppression cells

ORR:

Objective response rate

OS:

Overall survival

PR:

Partial response

aMASCT:

PD-1 blockade (SHR-1210)-activated MASCT

PBMCs:

Peripheral blood mononuclear cells

PD-1:

Programmed cell death-1

PD-L1:

Programmed cell death ligand-1

PFS:

Progression-free survival

Tregs:

Regulatory T cells

RECIST:

Response Evaluation Criteria in Solid Tumors version 1.1

SD:

Stable disease

VEGF:

Vascular endothelial growth factor

VEGFR2:

Vascular endothelial growth factor receptor 2

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Acknowledgements

We thank the patients enrolled in our clinical trials.

Funding

This work was supported by the Jiangsu Province Key Research and Development Plan (Social Development) Project (BE2017684), Scientific Research Project of Jiangsu Health and Family Planning Commission (H2017039), National Natural Science Foundation of China grants 81472792 and 81702813, Postgraduate Research & Practice Innovation Program of Jiangsu Province grants SJCX18_0707 and SJCX19_0766, the Technology Office Foundation of Lianyungang City (No. SH1613), and Beijing Medical and Health Foundation grants YWJKJJHKYJJ-13185016 and 13185014.

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Author notes

  1. Lijun Liang, Yixuan Wen and Rong Hu contributed equally to this article.

Authors and Affiliations

  1. Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, No. 182 Tongguan North Road, Lianyungang, 222002, China

    Lijun Liang, Yixuan Wen, Lei Wang, Youyou Xia, Chenxi Hu, Yun Qiao, Ting Chen, Jiayan Fei, Kaiyuan Hui & Xiaodong Jiang

  2. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Rong Hu

  3. Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, Jiangsu, China

    Xiaowei Geng

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Contributions

XJ, LL, YW, and KH participated in the conception and design of this study. LW, YX, YQ, TC, JF, and XJ contributed to the recruitment of patients and acquisition and analysis and review of the data. LL, YW, RH, and XG conducted the in vitro experiments, analyzed the data, and wrote the manuscript. XJ and KH supervised the drafting of the manuscript. All authors critically reviewed each draft and approved the version to be published.

Corresponding authors

Correspondence to Kaiyuan Hui or Xiaodong Jiang.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

The two single-center, open-label, phase I/II studies were conducted using a protocol approved by the medical ethics committee of the Affiliated Lianyungang Hospital of Xuzhou Medical University (2016016 and 2016018). All methods and procedures associated with this study were conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, the Declaration of Helsinki, and the Chinese law. These trials were registered with the Clinical Trials Registry (NCT02844881, NCT02858232).

Informed consent

Informed consent for protocol therapy, the analysis of blood samples for research purposes, and the use of generated data for publication was obtained from all patients enrolled in this study.

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Parts of this paper were published as abstract no. e14014 at the American Society of Clinical Oncology (ASCO) Annual Meeting, 31 May–4 June 2019, Chicago, IL, USA [1].

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Liang, L., Wen, Y., Hu, R. et al. Safety and efficacy of PD-1 blockade-activated multiple antigen-specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: a pooled analysis of two prospective trials. Cancer Immunol Immunother 68, 1467–1477 (2019). https://doi.org/10.1007/s00262-019-02375-z

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