Vaccination‐induced functional competence of circulating human tumor‐specific CD8 T‐cells

Abstract

T‐cells specific for foreign (e.g., viral) antigens can give rise to strong protective immune responses, whereas self/tumor antigen‐specific T‐cells are thought to be less powerful. However, synthetic T‐cell vaccines composed of Melan‐A/MART‐1 peptide, CpG and IFA can induce high frequencies of tumor‐specific CD8 T‐cells in PBMC of melanoma patients. Here we analyzed the functionality of these T‐cells directly ex vivo, by multiparameter flow cytometry. The production of multiple cytokines (IFNγ, TNFα, IL‐2) and upregulation of LAMP‐1 (CD107a) by tumor (Melan‐A/MART‐1) specific T‐cells was comparable to virus (EBV‐BMLF1) specific CD8 T‐cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor‐ and virus‐specific T‐cells, demonstrating functional signaling pathways. Interestingly, high frequencies of functionally competent T‐cells were induced irrespective of patient's age or gender. Finally, CD8 T‐cell function correlated with disease‐free survival. However, this result is preliminary since the study was a Phase I clinical trial. We conclude that human tumor‐specific CD8 T‐cells can reach functional competence in vivo, encouraging further development and Phase III trials assessing the clinical efficacy of robust vaccination strategies.

Exploiting the Mutanome for Tumor Vaccination

“…B16 cells express melanoma differentiation antigens and present MHC class I restricted epitopes from gp100, MART1 (35), tyrosinase (36), TRP1 (37) and TRP2 (30). Use of the B16F10 melanoma model has gained momentum in conjunction with vaccine research (38)(39)(40)(41) and is today one of the most widely used cell lines for scientific validation of T cell-based immunotherapies (over 1,700 citations) and general cancer studies (over 13,000 citations). Mutation analyses of B16 cells have focused on prominent candidate genes, showing that Cdkn2a (cyclindependent kinase inhibitor 2A, p19…”

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

“…69 , 70 Briefly, 29 HLA-A2 + patients with histologically proven metastatic melanoma of the skin expressing Melan-A/MART-1 received 1–4 cycles of monthly subcutaneous vaccinations with 100 μg Melan-A/MART-1 A27L analog or native peptide (± a Tyrosinase peptide) and CpG-7909 (500 μg PF-3512676/7909; provided by Pfizer/Coley Pharmaceutical Group) emulsified in incomplete Freund's adjuvant (300–600 μl Montanide ISA-51; provided by Seppic). The patients were evaluated for treatment toxicity, immune response (CD8 + T cell response), tumor response and survival (Table S2).…”

Progression of Lung Cancer Is Associated with Increased Dysfunction of T Cells Defined by Coexpression of Multiple Inhibitory Receptors

“…In contrast with circulating tumor antigen-specific T cells, which have full functional competence (1,2), T cells with the same antigen specificity residing in the tumor are functionally tolerant with severely impaired inflammatory and cytotoxic functions (1,(3)(4)(5). The functional impairment comprising T-cell exhaustion was originally described in the context of murine chronic lymphocytic choriomeningitis virus (LCMV) infection (6,7), but has been observed also in human chronic infections (8).…”