Adoptive Transfer of Tumor-Reactive Melan-A-Specific CTL Clones in Melanoma Patients Is Followed by Increased Frequencies of Additional Melan-A-Specific T Cells

Vignard, Virginie; Lemercier, Brigitte; Lim, Annick; Pandolfino, Marie‐Christine; Guilloux, Yannick; Khammari, Amir; Rabu, Catherine; Echasserieau, Klára; Lang, François; Gougeon, Marie‐Lise; Dréno, Brigitte; Jotereau, Francine; Labarrière, Nathalie

doi:10.4049/jimmunol.175.7.4797

Cited by 87 publications

(70 citation statements)

References 36 publications

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“…Our results with adoptive transfer of ovalbumin-targeted T cells are in accord with previous immunotherapy reports, in which epitope spreading and broadened antitumor responses have been detected after targeting a single defined TAA (44)(45)(46)(47). Furthermore, T-cell transfer has been shown to enable repertoire expansion through induction of endogenous antitumor T cells (48). From the clinical perspective, the importance of epitope spreading cannot be overstated.…”

Section: Discussionsupporting

confidence: 79%

Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor

Tähtinen

Grönberg-Vähä-Koskela

Lumén

et al. 2015

Cancer Immunology Research

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Despite the rapid progress in the development of novel adoptive T-cell therapies, the clinical benefits in treatment of established tumors have remained modest. Several immune evasion mechanisms hinder T-cell entry into tumors and their activity within the tumor. Of note, oncolytic adenoviruses are intrinsically immunogenic due to inherent pathogen-associated molecular patterns. Here, we studied the capacity of adenovirus to overcome resistance of chicken ovalbumin-expressing B16.OVA murine melanoma tumors to adoptive ovalbumin-specific CD8 antigens TRP-2 and gp100 was detected in combination-treated mice, indicating epitope spreading. Moreover, the majority of virus/T-cell-treated mice rejected the challenge of parental B16. F10 tumors, suggesting that systemic antitumor immunity was induced. In summary, we provide proof-of-mechanism data on combining adoptive T-cell therapy and adenovirotherapy for the treatment of cancer.

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Section: Discussionsupporting

confidence: 79%

Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor

Tähtinen

Grönberg-Vähä-Koskela

Lumén

et al. 2015

Cancer Immunology Research

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“…In one patient vaccinated with DC pulsed with a MART-1/Melan-A epitope who showed a complete response, they observed in an ELISPOT assay an increase in the frequency of T cells directed against gp100 and tyrosinase, but this increase was Ͻ4-fold. Vignard et al (38) observed that after the adoptive transfer of tumor-reactive Melan-A-specific CTL new expanded clonotypes appeared, suggesting that infused CTL clones may have initiated an anti-tumor response resulting in the expansion of a Melan-A-specific repertoire.…”

Section: Discussionmentioning

confidence: 99%

Vaccination of a Melanoma Patient with Mature Dendritic Cells Pulsed with MAGE-3 Peptides Triggers the Activity of Nonvaccine Anti-Tumor Cells

Carrasco

Pel

Neyns

et al. 2008

The Journal of Immunology

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We previously characterized the CTL response of a melanoma patient who experienced tumor regression following vaccination with an ALVAC virus coding for a MAGE-A3 Ag. Whereas anti-vaccine CTL were rare in the blood and inside metastases of this patient, anti-tumor CTL recognizing other tumor Ags, mainly MAGE-C2, were 100 times more frequent in the blood and considerably enriched in metastases following vaccination. In this study we report the analysis of the CTL response of a second melanoma patient who showed a mixed tumor response after vaccination with dendritic cells pulsed with two MAGE-A3 antigenic peptides presented, respectively, by HLA-A1 and HLA-DP4. Anti-MAGE-3.A1 CD8 and anti-MAGE-3.DP4 CD4 T cells became detectable in the blood after vaccination at a frequency of ∼10−5 among the CD8 or CD4 T cells, respectively, and they were slightly enriched in slowly progressing metastases. Additional anti-tumor CTL were present in the blood at a frequency of 2 × 10−4 among the CD8 T cells and, among these, an anti-MAGE-C2 CTL clone was detected only following vaccination and was enriched by >1,000-fold in metastases relative to the blood. The striking similarity of these results with our previous observations further supports the hypothesis that the induction of a few anti-vaccine T cells may prime or restimulate additional anti-tumor T cell clones that are mainly responsible for the tumor regression.

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“…Although the immunogenicity of a number of TAA has been documented in clinical trials, their therapeutic potential has not been clearly assessed, with the exception of the Melan-A/MART-1 antigen. Indeed, the therapeutic usefulness of the Melan-A antigen in melanoma is supported by the analysis of several active [2,3] and passive [4][5][6][7][8][9] immunotherapy protocols targeting this antigen.…”

Section: Introductionmentioning

confidence: 99%

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

et al. 2010

Self Cite

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We recently showed that the infusion of tumor infiltrating lymphocytes specific for the MELOE-1 antigen was associated with a prolonged relapse-free survival for HLA-A2 1 melanoma patients who received tumor infiltrating lymphocytes therapy. Here, we characterized the MELOE-1/A2-specific T-cell repertoire in healthy donors and melanoma patients to further support an immunotherapy targeting this epitope. Using tetramer enrichment followed by multicolor staining, we found that MELOE-1-specific T cells were present in the blood of healthy donors and patients at similar frequencies (around 1 in 1 Â 10 5 CD8 1 cells). These cells mainly displayed a naïve phenotype in 4/6 healthy donors and 3/6 patients, whereas high proportions of memory cells were observed in the remaining individuals of both groups. There was a recurrent usage of the Va12.1 chain for 17/18 MELOE-1-specific T-cell clones derived from healthy donors or patients, associated with diverse Vb chains and V(D)J junctional sequences. All clones derived from melanoma patients (9/9) were reactive against the MELOE-1 36-44 peptide and against HLA-A2 1 melanoma cell lines. This study documents the existence of a large TCR repertoire specific for the MELOE-1/A2 epitope and its capacity to give rise to antitumor CTL that supports the development of immunotherapies targeting this epitope.Key words: Immunotherapy . Melanoma . MELOE-1 . T-cell repertoire . TCR Introduction A key advance in tumor immunology in the past 15 years has been the elucidation of the antigenic basis of tumor cell recognition and destruction, which has opened the way to development of antigen-based immunotherapy in cancer patients. Tumor-associated antigens (TAA) have been grouped into categories according to their expression pattern in neoplastic and normal tissues. TAA can be roughly subdivided into two main classes: proteins expressed specifically by tumor cells, and proteins that are expressed by both tumor cells and by normal cells to a significant level. The first category includes cancergermline antigens, proteins expressed by unconventional gene expression and mutated antigens (see [1] for review). TAA belonging to the second category are the differentiation antigens, mainly expressed in the melanocytic lineage, and the antigens overexpressed by various tumor tissues. Although the immunogenicity of a number of TAA has been documented in clinical Ã These authors contributed equally to this work. We recently showed a correlation between the infusion of T cells reactive against an HLA-A2 epitope derived from another melanoma antigen, MELOE-1, and time to progression of patients treated with autologous tumor infiltrating lymphocytes (TIL) [10]. This antigen is encoded by the meloe gene, overexpressed in human melanoma cell lines, when compared to normal melanocytes, and dramatically underexpressed in other cancer cell lines (colon, renal, breast and lung carcinoma cell lines) and in a variety of normal tissues [10]. This expression profile and the potential involvement of MELOE-1-specific...

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Adoptive Transfer of Tumor-Reactive Melan-A-Specific CTL Clones in Melanoma Patients Is Followed by Increased Frequencies of Additional Melan-A-Specific T Cells

Cited by 87 publications

References 36 publications

Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor

Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor

Vaccination of a Melanoma Patient with Mature Dendritic Cells Pulsed with MAGE-3 Peptides Triggers the Activity of Nonvaccine Anti-Tumor Cells

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

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