August 2018 CANCER DISCOVERY | OF2 abstRactWe evaluated the safety and activity of autologous T cells expressing NY- , an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2-restricted NY-ESO-1/LAGE1a-derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1 c259 T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1 c259 T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1 c259 T cells exhibited an effector memory phenotype following ex vivo expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8+ NY-ESO-1 c259 T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1 c259 T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects.
SIGNIFICANCE:Metastatic synovial sarcoma is incurable with standard therapy. We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen. Cancer Discov;8(8);
BackgroundA wealth of evidence obtained using mouse models indicates that CD4+CD25+FOXP3+ regulatory T cells (Treg) maintain peripheral tolerance to self-antigens and also inhibit anti-tumor immune responses. To date there is limited information about CD4+ T cell responses in patients with colorectal cancer (CRC). We set out to measure T cell responses to a tumor-associated antigen and examine whether Treg impinge on those anti-tumor immune responses in CRC patients.Methodology and Principal FindingsTreg were identified and characterized as CD4+CD25+FOXP3+ using flow cytometry. An increased frequency of Treg was demonstrated in both peripheral blood and mesenteric lymph nodes of patients with colorectal cancer (CRC) compared with either healthy controls or patients with inflammatory bowel disease (IBD). Depletion of Treg from peripheral blood mononuclear cells (PBMC) of CRC patients unmasked CD4+ T cell responses, as observed by IFNγ release, to the tumor associated antigen 5T4, whereas no effect was observed in a healthy age-matched control group.Conclusions/SignificanceCollectively, these data demonstrate that Treg capable of inhibiting tumor associated antigen-specific immune responses are enriched in patients with CRC. These results support a rationale for manipulating Treg to enhance cancer immunotherapy.
BackgroundThere is indirect evidence that T cell responses can control the metastatic spread of colorectal cancer (CRC). However, an enrichment of CD4+Foxp3+ regulatory T cells (Tregs) has also been documented.ObjectiveTo evaluate whether CRC promotes Treg activity and how this influences anti-tumour immune responses and disease progression.MethodsA longitudinal study of Treg activity on a cohort of patients was performed before and after tumour resection. Specific CD4+ T cell responses were also measured to the tumour associated antigens carcinoembryonic antigen (CEA) and 5T4.ResultsTregs from 62 preoperative CRC patients expressed a highly significant increase in levels of Foxp3 compared to healthy age-matched controls (p=0.007), which returned to normal after surgery (p=0.0075). CD4+ T cell responses to one or both of the tumour associated antigens, CEA and 5T4, were observed in approximately two-thirds of patients and one third of these responses were suppressed by Tregs. Strikingly, in all patients with tumour recurrence at 12 months, significant preoperative suppression was observed of tumour-specific (p=0.003) but not control CD4+ T cell responses.ConclusionThese findings demonstrate that the presence of CRC drives the activity of Tregs and accompanying suppression of CD4+ T cell responses to tumour-associated antigens. Suppression is associated with recurrence of tumour at 12 months, implying that Tregs contribute to disease progression. These findings offer a rationale for the manipulation of Tregs for therapeutic intervention.
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