Durable Complete Response from Metastatic Melanoma after Transfer of Autologous T Cells Recognizing 10 Mutated Tumor Antigens.
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. Cancer Immunol Res; 4(8); 669-78. ©2016 AACR.
National Institutes of Health, National Cancer Institute, Surgery Branch, Bethesda, Maryland. prickettt@mail.nih.gov.
Todd D
TD
Prickett
National Institutes of Health, National Cancer Institute, Surgery Branch, Bethesda, Maryland.
Jessica S
JS
Crystal
Laboratory of Tumor Immunology and Immunotherapy, Bar-Ilan University, Ramat Gan, Israel.
Cyrille J
CJ
Cohen
National Institutes of Health, National Cancer Institute, Surgery Branch, Bethesda, Maryland.
Anna
A
Pasetto
National Institutes of Health, National Cancer Institute, Surgery Branch, Bethesda, Maryland.
Maria R
MR
Parkhurst
National Institutes of Health, National Cancer Institute, Surgery Branch, Bethesda, Maryland.
Jared J
JJ
Gartner
National Institutes of Health, National Cancer Institute, Surgery Branch, Bethesda, Maryland.
Xin
X
Yao
U.S. Food and Drug Administration, Bethesda, Maryland.
Rong
R
Wang
National Institutes of Health, National Cancer Institute, Surgery Branch, Bethesda, Maryland.
Alena
A
Gros
National Institutes of Health, National Cancer Institute, Surgery Branch, Bethesda, Maryland.
Yong F
YF
Li
National Institutes of Health, National Cancer Institute, Surgery Branch, Bethesda, Maryland.
Mona
M
El-Gamil
National Institutes of Health, National Cancer Institute, Surgery Branch, Bethesda, Maryland.
Kasia
K
Trebska-McGowan
National Institutes of Health, National Cancer Institute, Surgery Branch, Bethesda, Maryland.
Steven A
SA
Rosenberg
National Institutes of Health, National Cancer Institute, Surgery Branch, Bethesda, Maryland.
Paul F
PF
Robbins
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology*; D002460:Cell Line; D003131:Combined Modality Therapy; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D059472:Exome; D006801:Humans; D016219:Immunotherapy, Adoptive; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000628:therapy*; D008875:Middle Aged; D009154:Mutation; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte