T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma

Hopkins, Alexander C.; Yarchoan, Mark; Durham, Jennifer N.; Yusko, Erik; Rytlewski, Julie; Robins, Harlan; Laheru, Daniel A.; Le, Dung T.; Lutz, Eric R.; Jaffee, Elizabeth M.

doi:10.1172/jci.insight.122092

Cited by 191 publications

(176 citation statements)

References 22 publications

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“…The TCR clonality of both CD4 + and CD8 + T cells is more restricted than in healthy people, and broader T cell responses with greater diversity of CD4 + blood T cell clones may predict the longer survival of patients with melanoma treated with anti‐CTLA4 or PD‐1 antibodies . Many studies have shown that peripheral blood TCR diversity can be used to predict the efficacy of immunotherapy . Therefore, PEG‐rhG‐CSF may improve the efficacy of immunotherapy by increasing peripheral blood TCR diversity; however, further clinical studies are needed to confirm this.…”

Section: Discussionmentioning

confidence: 99%

“…19 Many studies have shown that peripheral blood TCR diversity can be used to predict the efficacy of immunotherapy. 17,21,33,34 Therefore, PEG-rhG-CSF may improve the efficacy of immunotherapy by increasing peripheral blood TCR diversity; however, further clinical studies are needed to confirm this. We found no MH overlap on day 3, and day 8-10 showed a significant difference between groups.…”

Section: Discussionmentioning

confidence: 99%

“…TCR diversity is predominantly derived from the highly variable complementarity‐determining region 3 (CDR3) and is generated by random rearrangement and junction region mutation of the V‐D‐J regions, which are three fragments located in TCR‐coding genes. Many studies have shown that lymphocytes recognize the patient's unique mutations in the peripheral blood; TCR repertoire in peripheral blood could be a biomarker of clinical outcomes for chemotherapy and immunotherapy . We predicted that the peripheral blood TCR repertoire and lymphocyte subsets reflect the immune status of patients with SCLC, and its dynamic changes can reflect immune status changes.…”

Section: Introductionmentioning

confidence: 99%

“…Many studies have shown that lymphocytes recognize the patient's unique mutations in the peripheral blood 15,16 ; TCR repertoire in peripheral blood could be a biomarker of clinical outcomes for chemotherapy and immunotherapy. [17][18][19] We predicted that the peripheral blood TCR repertoire and lymphocyte subsets reflect the immune status of patients with SCLC, and its dynamic changes can reflect immune status changes.…”

Section: Introductionmentioning

confidence: 99%

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Pegylated recombinant human granulocyte colony‐stimulating factor regulates the immune status of patients with small cell lung cancer

et al. 2020

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Background Small cell lung cancer (SCLC) is an aggressive disease involving immunodeficiency for which chemotherapy is the standard treatment. Pegylated recombinant human granulocyte colony‐stimulating factor (PEG‐rhG‐CSF) is widely used for primary or secondary prophylaxis of febrile neutropenia (FN) in chemotherapy. However, whether PEG‐rhG‐CSF influences immune cells, such as lymphocytes, remains unclear. Methods A total of 17 treatment‐naïve SCLC patients were prospectively enrolled and divided into the PEG‐rhG‐CSF and control groups according to their FN risk. Longitudinal sampling of peripheral blood was performed before, after and 4–6 days after the first cycle of chemotherapy. Flow cytometry was used to assess lymphocyte subsets, including CD3+ T, CD4+ T, CD8+ T, NK, and B cells. The diversity and clonality of the T‐cell receptor (TCR) repertoire was analyzed by next‐generation sequencing. Results In the PEG‐rhG‐CSF group, the proportions of CD3+ T and CD4+ T cells had increased significantly (P = 0.002, P = 0.020, respectively), whereas there was no increase in CD8+ T cells. Further, TCR diversity increased (P = 0.009) and clonality decreased (P = 0.004) significantly after PEG‐rhG‐CSF treatment. However, these factors showed opposite trends before and after chemotherapy. Vβ and Jβ gene fragment types, which determine TCR diversity, were significantly amplified in the PEG‐rhG‐CSF group. The change in TCR diversity was significantly correlated with changes in the CD3+ T or CD4+ T cell proportions, but not the CD8+ T cell proportion. Conclusions PEG‐rhG‐CSF regulates the immune status of SCLC patients; CD4+ T cells may be the main effector cells involved in this process. These findings may optimize the treatment of SCLC. Key points PEG‐rhG‐CSF regulates SCLC immunity. PEG‐rhG‐CSF increased CD3+ T and CD4+T cell proportions. PEG‐rhG‐CSF increased TCR diversity and decreased clonality in peripheral blood. Change in TCR diversity were correlated with CD3+ T or CD4+ T changes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pegylated recombinant human granulocyte colony‐stimulating factor regulates the immune status of patients with small cell lung cancer

et al. 2020

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“…183,185-187 In several instances, vaccination is further combined with standard treatment regimens including conventional chemotherapy, 117,188-191 radiation therapy, 52,192-195 and targeted anticancer agents, 196-199 or with various immunotherapeutic interventions. 200-205 The latter include (1) immune checkpoint blockers such as the anti-PD-1 mAbs pembrolizumab and nivolumab, 206-208 the anti-PD-L1 mAbs durvalumab and atezolizumab, 209-211 and the anti-CTLA4 mAb ipilimumab; 137,186,212-215 (2) immunostimulatory antibodies such as utomilumab, which stimulates TNF receptor superfamily member 9 (TNFRSF9; best known as 4-1BB or CD137) signaling, 28,216-218 or the CD27 agonist varlilumab; 28,216,219,220 and immunomodulatory agents such as lenalidomide. 221-224 In line with preclinical and clinical data demonstrating that multi-epitope vaccines are generally more powerful than their single-epitope counterparts, 117,225 the most common vaccination strategy employed by these studies consists in targeting simultaneously multiple TAAs (20 studies).…”

Section: Ongoing Clinical Trialsmentioning

confidence: 99%

Trial watch: Peptide-based vaccines in anticancer therapy

et al. 2018

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Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant or synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in the clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations that minimize antigenicity and/or changes in the tumor microenvironment that foster immunosuppression. Several strategies have been developed to overcome such limitations, including the use of immunostimulatory adjuvants, the co-treatment with cytotoxic anticancer therapies that enable the coordinated release of damage-associated molecular patterns, and the concomitant blockade of immune checkpoints. Personalized peptide-based vaccines are also being explored for therapeutic activity in the clinic. Here, we review recent preclinical and clinical progress in the use of peptide-based vaccines as anticancer therapeutics.Abbreviations: CMP: carbohydrate-mimetic peptide; CMV: cytomegalovirus; DC: dendritic cell; FDA: Food and Drug Administration; HPV: human papillomavirus; MDS: myelodysplastic syndrome; MHP: melanoma helper vaccine; NSCLC: non-small cell lung carcinoma; ODD: orphan drug designation; PPV: personalized peptide vaccination; SLP: synthetic long peptide; TAA: tumor-associated antigen; TNA: tumor neoantigen

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