Durable complete response from metastatic melanoma after transfer of autologous T cells recognizing 10 mutated tumor antigens

Todd D. Prickett, Jessica S. Crystal, Cyrille J. Cohen, Anna Pasetto, Maria R. Parkhurst, Jared J. Gartner, Xin Yao, Rong Wang, Alena Gros, Yong F. Li, Mona El-Gamil, Kasia Trebska-McGowan, Steven A. Rosenberg, Paul F. Robbins

Research output: Contribution to journalArticle

Abstract

Immunotherapy treatment of patients with metastatic cancer has assumed a prominent role in the clinic. Durable complete response rates of 20% to 25% are achieved in patients with metastatic melanoma following adoptive cell transfer of T cells derived from metastatic lesions, responses that appear in some patients to be mediated by T cells that predominantly recognize mutated antigens. Here, we provide a detailed analysis of the reactivity of T cells administered to a patient with metastatic melanoma who exhibited a complete response for over 3 years after treatment. Over 4,000 nonsynonymous somatic mutations were identified by whole-exome sequence analysis of the patient's autologous normal and tumor cell DNA. Autologous B cells transfected with 720 mutated minigenes corresponding to the most highly expressed tumor cell transcripts were then analyzed for their ability to stimulate the administered T cells. Autologous tumor-infiltrating lymphocytes recognized 10 distinct mutated gene products, but not the corresponding wild-type products, each of which was recognized in the context of one of three different MHC class I restriction elements expressed by the patient. Detailed clonal analysis revealed that 9 of the top 20 most prevalent clones present in the infused T cells, comprising approximately 24% of the total cells, recognized mutated antigens. Thus, we have identified and enriched mutation-reactive T cells and suggest that such analyses may lead to the development of more effective therapies for the treatment of patients with metastatic cancer.

Original languageEnglish (US)
Pages (from-to)669-678
Number of pages10
JournalCancer immunology research
Volume4
Issue number8
DOIs
StatePublished - 2016
Externally publishedYes

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Neoplasm Antigens
Melanoma
T-Lymphocytes
Neoplasms
Exome
Tumor-Infiltrating Lymphocytes
Antigens
Mutation
Adoptive Transfer
Therapeutics
Immunotherapy
Sequence Analysis
B-Lymphocytes
Clone Cells
DNA
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Immunology

Cite this

Prickett, T. D., Crystal, J. S., Cohen, C. J., Pasetto, A., Parkhurst, M. R., Gartner, J. J., ... Robbins, P. F. (2016). Durable complete response from metastatic melanoma after transfer of autologous T cells recognizing 10 mutated tumor antigens. Cancer immunology research, 4(8), 669-678. https://doi.org/10.1158/2326-6066.CIR-15-0215

Durable complete response from metastatic melanoma after transfer of autologous T cells recognizing 10 mutated tumor antigens. / Prickett, Todd D.; Crystal, Jessica S.; Cohen, Cyrille J.; Pasetto, Anna; Parkhurst, Maria R.; Gartner, Jared J.; Yao, Xin; Wang, Rong; Gros, Alena; Li, Yong F.; El-Gamil, Mona; Trebska-McGowan, Kasia; Rosenberg, Steven A.; Robbins, Paul F.

In: Cancer immunology research, Vol. 4, No. 8, 2016, p. 669-678.

Research output: Contribution to journalArticle

Prickett, TD, Crystal, JS, Cohen, CJ, Pasetto, A, Parkhurst, MR, Gartner, JJ, Yao, X, Wang, R, Gros, A, Li, YF, El-Gamil, M, Trebska-McGowan, K, Rosenberg, SA & Robbins, PF 2016, 'Durable complete response from metastatic melanoma after transfer of autologous T cells recognizing 10 mutated tumor antigens', Cancer immunology research, vol. 4, no. 8, pp. 669-678. https://doi.org/10.1158/2326-6066.CIR-15-0215
Prickett, Todd D. ; Crystal, Jessica S. ; Cohen, Cyrille J. ; Pasetto, Anna ; Parkhurst, Maria R. ; Gartner, Jared J. ; Yao, Xin ; Wang, Rong ; Gros, Alena ; Li, Yong F. ; El-Gamil, Mona ; Trebska-McGowan, Kasia ; Rosenberg, Steven A. ; Robbins, Paul F. / Durable complete response from metastatic melanoma after transfer of autologous T cells recognizing 10 mutated tumor antigens. In: Cancer immunology research. 2016 ; Vol. 4, No. 8. pp. 669-678.
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