Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: TIL populations from patient 4136 recognize autologous mutant SLC3A2 and KIAA0368 antigens.
Fig. 2: Adoptive transfer of autologous TILs targeting immunogenic tumor mutations mediated tumor regression.
Fig. 3: Persistence of known mutant-reactive TCR clonotypes at time of infusion and identification of new dominant clonotypes of unknown reactivity present in an apheresis product obtained 6 weeks after treatment.
Fig. 4: Persistence of the 11 mutant-reactive TCR clonotypes from cell infusion to 17 months after cell transfer.

References

  1. Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).

    Article  PubMed  CAS  Google Scholar 

  2. Robert, C. et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-comparison cohort of a phase 1 trial. Lancet 384, 1109–1117 (2014).

    Article  PubMed  CAS  Google Scholar 

  3. Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).

    Article  PubMed  CAS  Google Scholar 

  4. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Dawood, S. et al. Trends in survival over the past two decades among white and black patients with newly diagnosed stage IV breast cancer. J. Clin. Oncol. 26, 4891–4898 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Hamanishi, J. et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J. Clin. Oncol. 33, 4015–4022 (2015).

    Article  PubMed  CAS  Google Scholar 

  8. Tran, E. et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 350, 1387–1390 (2015).

    Article  PubMed  CAS  Google Scholar 

  9. Tran, E. et al. T cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375, 2255–2262 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).

    Article  PubMed  CAS  Google Scholar 

  11. Stevanović, S. et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 356, 200–205 (2017).

    Article  PubMed  CAS  Google Scholar 

  12. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

    Article  PubMed  Google Scholar 

  13. Lefebvre, C. et al. Mutational profile of metastatic breast cancers: a retrospective analysis. PLoS Med. 13, e1002201 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors. Nature 490, 61–70 (2012).

    Article  PubMed Central  CAS  Google Scholar 

  15. Dudley, M. E. et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J. Clin. Oncol. 26, 5233–5239 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Abate-Daga, D. et al. Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes. Blood 122, 1399–1410 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Assadipour, Y. et al. Characterization of an immunogenic mutation in a patient with metastatic triple-negative breast cancer. Clin. Cancer Res. 23, 4347–4353 (2017).

    Article  PubMed  CAS  Google Scholar 

  18. Jin, J. et al. Simplified method of the growth of human tumor-infiltrating lymphocytes (TIL) in gas-permeable flasks to numbers needed for patient treatment. J. Immunother. 35, 283–292 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Pasetto, A. et al. Tumor- and neoantigen-reactive T cell receptors can be identified based on their frequency in fresh tumor. Cancer Immunol. Res. 4, 734–743 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Cohen, C. J., Zhao, Y., Zheng, Z., Rosenberg, S. A. & Morgan, R. A. Enhanced antitumor activity of murine–human hybrid T cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR–CD3 stability. Cancer Res. 66, 8878–8886 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Haga-Friedman, A., Horovitz-Fried, M. & Cohen, C. J. Incorporation of transmembrane hydrophobic mutations in the TCR enhance its surface expression and T cell functional avidity. J. Immunol. 188, 5538–5546 (2012).

    Article  PubMed  CAS  Google Scholar 

  22. Aldrich, J. R. A. Fisher and the making of maximum likelihood. 1912–1922. Stat. Sci. 12, 162–176 (1997).

    Article  Google Scholar 

Download references

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

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Steven A. Rosenberg.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–5 and Supplementary Figures 1–4

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zacharakis, N., Chinnasamy, H., Black, M. et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat Med 24, 724–730 (2018). https://doi.org/10.1038/s41591-018-0040-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer