Abstract

Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations—such as melanoma, smoking-induced lung cancers and bladder cancer—with little effect in other common epithelial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary1,2,3,4,5,6,7. Adoptive transfer of autologous lymphocytes that specifically target proteins encoded by somatically mutated genes has mediated substantial objective clinical regressions in patients with metastatic bile duct, colon and cervical cancers8,9,10,11. We present a patient with chemorefractory hormone receptor (HR)-positive metastatic breast cancer who was treated with tumor-infiltrating lymphocytes (TILs) reactive against mutant versions of four proteins—SLC3A2, KIAA0368, CADPS2 and CTSB. Adoptive transfer of these mutant-protein-specific TILs in conjunction with interleukin (IL)-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer, which is now ongoing for >22 months, and it represents a new immunotherapy approach for the treatment of these patients.

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Acknowledgements

The authors would like to thank A. Mixon and S. Farid of the Surgery Branch FACS Core for assistance with data acquisition and cell sorting, and J. Yang and E. Tran for their valuable discussions. This work was supported by the Center for Cancer Research at the National Cancer Institute (NCI) at the US National Institutes of Health (NIH).

Author information

Affiliations

  1. Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    • Nikolaos Zacharakis
    • , Harshini Chinnasamy
    • , Mary Black
    • , Hui Xu
    • , Yong-Chen Lu
    • , Zhili Zheng
    • , Anna Pasetto
    • , Michelle Langhan
    • , Thomas Shelton
    • , Todd Prickett
    • , Jared Gartner
    • , Li Jia
    • , Robert P. Somerville
    • , Paul F. Robbins
    • , Steven A. Rosenberg
    • , Stephanie L. Goff
    •  & Steven A. Feldman
  2. Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    • Katarzyna Trebska-McGowan

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Contributions

N.Z. designed and performed the experiments, analyzed and interpreted the data, and co-wrote the manuscript; H.C., M.B. and H.X. performed experiments; Y.-C.L., Z.Z. and A.P. designed and performed experiments for single-cell PCR and sequencing for TCR identification and pairing; R.P.S., M.L. and T.S. maintained and developed clinical-grade lymphocytes for patient infusion; P.F.R., T.P., J.G. and L.J. performed and analyzed WES and RNA-seq data for mutation profiling; K.T.-M. (under the direction of S.L.G. and S.A.R.) was responsible for the clinical care of the patient during protocol treatment; S.A.R. conceived the hypothesis, interpreted the data and co-wrote the manuscript; S.L.G. and S.A.F. coordinated the project, analyzed and interpreted data and co-wrote the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Steven A. Rosenberg.

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https://doi.org/10.1038/s41591-018-0040-8

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