Persistence of CTL clones targeting melanocyte differentiation antigens was insufficient to mediate significant melanoma regression in humans

Adoptive transfer of autologous tumor infiltrating lymphocytes (TIL) can mediate durable cancer regression in selected patients with metastatic melanoma. However, the tumor antigens associated with these favorable responses remain unclear. We hypothesized that a clinical strategy involving the itera...

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Bibliographic Details
Published in:Clinical cancer research 2015-02, Vol.21 (3), p.534-543
Main Authors: Chandran, Smita S, Paria, Biman C, Srivastava, Abhishek K, Rothermel, Luke D, Stephens, Daniel J, Dudley, Mark E, Somerville, Robert, Wunderlich, John R, Sherry, Richard M, Yang, James C, Rosenberg, Steven A, Kammula, Udai S
Format: Article
Language:English
Subjects:
Adult
Aged
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - metabolism
Cytotoxicity, Immunologic
Dermatitis - etiology
Female
gp100 Melanoma Antigen - immunology
HLA-A2 Antigen - immunology
Humans
Immunotherapy, Adoptive - adverse effects
Lymphocytes, Tumor-Infiltrating - immunology
Lymphocytes, Tumor-Infiltrating - metabolism
Male
MART-1 Antigen - immunology
Melanoma - immunology
Melanoma - pathology
Melanoma - therapy
Melanoma-Specific Antigens - immunology
Middle Aged
T-Cell Antigen Receptor Specificity - genetics
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Cytotoxic - metabolism
Treatment Outcome
Tumor Burden
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Summary:Adoptive transfer of autologous tumor infiltrating lymphocytes (TIL) can mediate durable cancer regression in selected patients with metastatic melanoma. However, the tumor antigens associated with these favorable responses remain unclear. We hypothesized that a clinical strategy involving the iterative adoptive transfer of selected autologous antigen-specific T-cell clones could help systematically define immunologic targets associated with successful cancer therapy, without the interpretative ambiguity of transferring polyclonal populations. Here, we evaluated the clinical efficacy of CD8(+) T-cell clones specific for the melanocyte differentiation antigens (MDA), gp100 and MART-1, respectively. We conducted two consecutive phase II clinical trials involving the adoptive transfer of highly selected autologous antigen-specific CD8(+) T-cell clones against gp100 and MART-1, respectively. Fifteen patients with HLA-A2(+) treatment-refractory metastatic melanoma received highly avid MDA-specific CD8(+) T-cell clones specific for either gp100 (n = 10) or MART-1 (n = 5) with or without intravenous interleukin-2 (IL2) after a lymphodepleting myeloablative preparative regimen. Of the 15 treated patients, we observed immune-mediated targeting of skin melanocytes in 11 patients (73%) and clonal engraftment in eight patients (53%) after cell transfer. There were only transient minor tumor regressions observed, but no objective tumor responses based on Response Evaluation Criteria in Solid Tumor (RECIST) criteria. Despite successful clonal repopulation and evidence of in vivo antigen targeting, the poor therapeutic efficacy after the adoptive transfer of autologous MDA-specific T cells raises significant concerns regarding future immunotherapy efforts targeting this class of tumor antigens.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-14-2208