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Potential clinical application of tumor-infiltrating lymphocyte therapy for ovarian epithelial cancer prior or post-resistance to chemotherapy

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Abstract

Background

Immunotherapy has become a powerful treatment option for several solid tumor types. The presence of tumor-infiltrating lymphocytes (TIL) is correlated with better prognosis in ovarian cancer, pointing at the possibility to benefit from harnessing their anti-tumor activity. This preclinical study explores the feasibility of adoptive cell therapy (ACT) with TIL using an improved culture method.

Methods

TIL from high-grade serous ovarian cancer were cultured using a combination of IL-2 with agonistic antibodies targeting 4-1BB and CD3. The cells were phenotyped using flow cytometry in the fresh tissue and after expansion. Tumor reactivity was assessed against HLA-matched ovarian cancer cell lines via IFN-γ ELISPOT.

Results

Ovarian cancer is highly infiltrated with CD8+ TIL that are preferentially and robustly expanded with the addition of the agonistic antibodies. With a 95% success rate, the TIL are grown to ≥ 100 × 106 cells in 2–3 weeks without over differentiation. In addition, the CD8+ TIL grown with this method showed HLA-restricted tumor recognition.

Conclusions

These results indicate the viability of TIL ACT for refractory ovarian cancer by allowing for the large expansion of anti-tumor TIL in a short time and consistent manner.

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Abbreviations

BTLA:

B- and T-lymphocyte attenuator

OvCa:

Epithelial ovarian cancer

MDACC:

MD Anderson Cancer Center

ORR:

Overall response rate

TIL-CM:

Tumor-infiltrating lymphocyte complete medium

T RM :

Tissue-resident memory T cell

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Acknowledgements

The authors wish to acknowledge the patients who consented to tissue procurement for research and their caregivers. Thank you to Bristol-Myers Squibb for providing Urelumab and Prometheus for the IL-2. The authors would like to thank René J. Tavera for his early contributions to culturing OvCa TIL.

Funding

This research was supported in part by the MD Anderson Cancer Center Support Grant (P30 CA016672), a T32 training grant for gynecologic oncology (CA101642), the MD Anderson Ovarian Cancer Moon Shot program, and an MD Anderson Institutional Research Grant (Amir A. Jazaeri). We also acknowledge the support of the Flow Cytometry and Cellular Imaging, Research Histology, and Characterized Cell Line cores which are also supported by the support grant (P30 CA016672).

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Authors and Affiliations

  1. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center (UT MDACC), Unit 904, 7455 Fannin, Houston, TX, 77054, USA

    Donastas Sakellariou-Thompson, Marie-Andrée Forget, Patrick Hwu & Chantale Bernatchez

  2. Department of Gynecologic Oncology and Reproductive Medicine, UTMDACC, Houston, TX, USA

    Emily Hinchcliff, Joseph Celestino & Amir A. Jazaeri

  3. Department of Translational Molecular Pathology, UT MDACC, Unit 2951, 2130 W. Holcombe Blvd., Houston, TX, 77030, USA

    Cara Haymaker & Chantale Bernatchez

Authors
  1. Donastas Sakellariou-Thompson
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  2. Marie-Andrée Forget
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  3. Emily Hinchcliff
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  4. Joseph Celestino
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  5. Patrick Hwu
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  6. Amir A. Jazaeri
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  7. Cara Haymaker
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  8. Chantale Bernatchez
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Contributions

DST conducted all the experiments and data analysis. DST and MAF generated the TIL lines and prepared the figures. DST, MAF, CH, and CB were responsible for writing the manuscript, while all authors contributed to manuscript editing and approved the final manuscript version. JC oversaw the consent and collection of human samples. MAF, CH, and CB helped with interpretation of the data. JC, EH, and AAJ helped with patients’ clinical information. PH and AAJ provided support and guidance for the study. DST, MAF, CH, and CB designed the experiments and the conceptual design of the study.

Corresponding authors

Correspondence to Cara Haymaker or Chantale Bernatchez.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed were in accordance with the 1975 Helsinki declaration. Ethical approval and tissue from surgical resections used to expand TIL were both obtained under protocols (PA16-0912 and LAB02-188) approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center.

Informed consent

Written informed consent was obtained from all individual participants included in the study for their specimens and data to be used in research and for publication.

Cell line authentication

COV318 and COV362 were originally purchased from Sigma–Aldrich (now Millipore-Sigma, St. Louis, MO) and SKOV3 from the American Type Culture Collection (ATCC, Manassas, VA). All OvCa cell lines were HLA-typed, STR fingerprinted, and confirmed mycoplasma-free at MDACC.

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Sakellariou-Thompson, D., Forget, MA., Hinchcliff, E. et al. Potential clinical application of tumor-infiltrating lymphocyte therapy for ovarian epithelial cancer prior or post-resistance to chemotherapy. Cancer Immunol Immunother 68, 1747–1757 (2019). https://doi.org/10.1007/s00262-019-02402-z

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