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Rational combinations of in vivo cancer antigen priming and adoptive T-cell therapy mobilize immune and clinical responses in terminal cancers

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Purpose

It is now recognized that solid tumors encroach on the host’s immune microenvironment to favor its own proliferation. Strategies to enhance the specificity of the endogenous T-cell population against tumors have been met with limited clinical success. We aimed to devise a two-tier protocol coupling in vivo whole antigen priming with ex vivo cellular expansion to clinically evaluate survival in patients following re-infusion of primed, autologous T cells, thereby determining treatment efficacy.

Experimental design

Treatment commenced with the acquisition of whole tumor antigens from tumor cell lines corresponding with patients’ primary malignancy. Lysate mixture was inoculated intradermally, while peripheral blood mononuclear cells (PBMCs) were periodically extracted via phlebotomy and expanded in culture ex vivo for re-infusion. Post-treatment tumor-specific T-cell response and cytotoxicity was confirmed via Elispot and real-time cell analyzing (RTCA) assay. Serum cytokine levels and cytotoxicity scores were evaluated for associations with survival status and duration.

Results

There was a significant increase in cytotoxicity exhibited by T cells measured using both Elispot and RTCA following treatment. Correlation analysis determined significant association between higher post-treatment cytotoxicity scores and survival status (R = 0.52, p = 0.0028) as well as longer survival duration in months (R = 0.59, p = 0.005).

Conclusions

Our treatment protocol successfully demonstrated significant correlation between tumor-associated antigen-specific immune response and objective prolongation of survival. Whole-cell cancer antigen priming and adoptive T-cell therapy is, therefore, a highly feasible clinical model which can be easily replicated to positively influence outcome in end-stage malignancy.

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Abbreviations

AIDS:

Acquired immune deficiency syndrome

CI:

Cell index

CTL:

Cytotoxic T cell

DCs:

Dendritic cells

FBS:

Fetal bovine serum

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

IL:

Interleukin

IQR:

Interquartile range

NSCLC:

Non-small cell lung carcinoma

PBMCs:

Blood mononuclear cells

RPMI:

Roswell Park Memorial Institute

RTCA:

Real-time cell analysis

TGF:

Transforming growth factor

Treg :

Regulatory T cell

TIFN−r :

Interferon γ T cell

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Funding

This work was supported by research grants from Xiamen Key Laboratory for Clinical Translation of Cancer Theranostics.

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Authors and Affiliations

  1. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Qing Zhao Ruan

  2. Department of Oncology, Xiamen 5th Hospital, Xiamen, China

    Jian Qian Fu

  3. Xiamen Key Laboratory for Translational Medicine of Cancer Theranostics, School of Pharmaceutical Sciences, Xiamen University, #246-248, Xiangan Nanlu, Xiangan District, Xiamen, China

    Xiao Xuan Wu, Li Ping Huang & Run Sheng Ruan

  4. Zhang Zhou Xing Pu Hospital, Zhang Zhou, China

    Run Sheng Ruan

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  1. Qing Zhao Ruan
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Contributions

Qing Zhao Ruan: study design, data analysis, and drafting and revision of manuscript. Jian Qian Fu: study conduction and data collection. Xiao Xuan Wu: study conduction and data collection. Li Ping Huang: study conduction and data collection. Run Sheng Ruan: study design, study conduction, data collection, and drafting and revision of manuscript.

Corresponding author

Correspondence to Run Sheng Ruan.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The trial was registered to the World Health Organization International Clinical Trials Registry Platform (ChiCTR-OPC-15006703) and was approved by the Xiamen 5th Hospital and Zhang Zhou Xing Pu Hospital Ethics Committee (Project 03/200909).

Informed consent

Written informed consent from study subjects was obtained in accordance with the Declaration of Helsinki. All study subjects were capable of giving informed consent. The participating patients signed printed consent forms after the trial procedure was explained. Care was taken to have patient repeat the procedure in his/ her own words. The attending clinician signed on the consent form after the patient as the responsible physician in this trial. A separate clinician acted as witness and countersigned the document to officially complete it for filing.

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Ruan, Q.Z., Fu, J.Q., Wu, X.X. et al. Rational combinations of in vivo cancer antigen priming and adoptive T-cell therapy mobilize immune and clinical responses in terminal cancers. Cancer Immunol Immunother 67, 907–915 (2018). https://doi.org/10.1007/s00262-018-2142-z

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  • DOI: https://doi.org/10.1007/s00262-018-2142-z

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