TY - JOUR
T1 - Durable complete response from metastatic melanoma after transfer of autologous T cells recognizing 10 mutated tumor antigens
AU - Prickett, Todd D.
AU - Crystal, Jessica S.
AU - Cohen, Cyrille J.
AU - Pasetto, Anna
AU - Parkhurst, Maria R.
AU - Gartner, Jared J.
AU - Yao, Xin
AU - Wang, Rong
AU - Gros, Alena
AU - Li, Yong F.
AU - El-Gamil, Mona
AU - Trebska-McGowan, Kasia
AU - Rosenberg, Steven A.
AU - Robbins, Paul F.
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
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U2 - 10.1158/2326-6066.CIR-15-0215
DO - 10.1158/2326-6066.CIR-15-0215
M3 - Article
C2 - 27312342
AN - SCOPUS:84985995114
SN - 2326-6066
VL - 4
SP - 669
EP - 678
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 8
ER -