Autologous Dendritic Cell Therapy in Mesothelioma Patients Enhances Frequencies of Peripheral CD4 T Cells Expressing HLA-DR, PD-1, or ICOS

Our plain-English summary of Autologous Dendritic Cell Therapy in Mesothelioma Patients Enhances Frequencies of Peripheral CD4 T Cells Expressing HLA-DR, PD-1, or ICOS, by P.L. de Goeje, Y. Klaver, M.E.H. Kaijen-Lambers, et al (Frontiers in Immunology, 2018).

The study

• Authors: P.L. de Goeje, Y. Klaver, M.E.H. Kaijen-Lambers, A.W. Langerak, H. Vroman, A. Kunert, C.H.J. Lamers, J.G.J.V. Aerts, R. Debets, R.W. Hendriks
• Journal: Frontiers in Immunology
• Published: 2018;9:2034
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a malignancy with a very poor prognosis for which new treatment options are urgently needed. We have previously shown that dendritic cell (DC) immunotherapy provides a clinically feasible treatment option. In the current study, we set out to assess the immunological changes induced by DC immunotherapy in peripheral blood of MPM patients. Methods: Peripheral blood was collected from nine patients enrolled in a phase I dose escalation study, before and after treatment with DCs that were pulsed with an allogeneic tumor lysate preparation consisting of a mixture of five cultured mesothelioma cell lines. We used immune profiling by multiplex flow cytometry to characterize different populations of immune cells. In particular, we determined frequencies of T cell subsets that showed single and combinatorial expression of multiple markers that signify T cell activation, maturation and inhibition. Therapy-induced T cell reactivity was assessed in peptide/MHC multimer stainings using mesothelin as a prototypic target antigen with confirmed expression in the clinical tumor lysate preparation. T cell receptor (TCR) diversity was evaluated by TCRB gene PCR assays. Results: We observed an increase in the numbers of B cells, CD4 and CD8 T cells, but not NK cells at 6 weeks post-treatment. The increases in B and T lymphocytes were not accompanied by major changes in T cell reactivity toward mesothelin nor in TCRB diversity. Notably, we did observe enhanced proportions of CD4 T cells expressing HLA-DR, PD-1 (at 2 weeks after onset of treatment) and ICOS (6 weeks) and a CD8 T cell population expressing LAG3 (2 weeks). Discussion: DC immunotherapy using allogeneic tumor lysate resulted in enhanced frequencies of B cells and T cells in blood. We did not detect a skewed antigen-reactivity of peripheral CD8 T cells. Interestingly, frequencies of CD4 T cells expressing activation markers and PD-1 were increased. These findings indicate a systemic activation of the adaptive immune response and may guide future immune monitoring studies of DC therapies.

In plain English

This laboratory study examined blood from nine patients with malignant pleural mesothelioma (MPM) in a first-in-human, phase I dose-escalation trial. They received their own dendritic cells (immune cells) loaded with a lysate of five cultured mesothelioma cell lines, at 10, 25 or 50 million cells per vaccination. Asbestos exposure was not studied. In the six patients on the two higher doses, median counts rose significantly from baseline to week 6: CD4 T cells from 522 to 634 cells/µl, CD8 T cells from 256 to 304, and B cells from 162 to 199. NK cell numbers did not increase significantly. Among 8 HLA-A2-positive patients, mesothelin-binding CD8 T cells, detected after four rounds of laboratory expansion, were present before treatment in 5 and did not change significantly. T cell receptor patterns stayed generally similar. The share of CD4 T cells with HLA-DR or PD-1 rose by week 2, and with ICOS by week 6. LAG3-positive CD8 T cells also rose. The authors concluded the therapy raised T and B cell numbers and proposed these markers for monitoring future trials. They noted that patient numbers were too low to link results to clinical outcome.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Immune-monitoring (laboratory) study of blood samples taken before and after treatment from patients in a phase I dose-escalation clinical trial of dendritic cell therapy; no control group
• Who was studied: Nine patients with pathologically proven malignant pleural mesothelioma in a first-in-human trial (three cohorts of three). Flow cytometry counts were done only for the six patients in cohorts 2 and 3. The article does not give enrolment dates.
• Exposure: No asbestos exposure was studied. The treatment studied was autologous dendritic cells pulsed with an allogeneic tumor lysate made from five cultured mesothelioma cell lines. It was given every 2 weeks for three vaccinations, with boosters at 3 and 6 months, at 10, 25 or 50 million cells per vaccination.
• Main results:
  • Absolute cell counts were measured only in the six patients from the second and third dose cohorts (25 and 50 million cells per vaccination).
  • In these six patients, median counts rose significantly from baseline to week 6: CD4 T cells from 522 to 634 cells/µl, CD8 T cells from 256 to 304 cells/µl, and B cells from 162 to 199 cells/µl. NK cells did not show a significant increase.
  • Three patients had lysate-pulsed dendritic cells available. In their co-cultures, activated (CD69- and CD137-positive) CD4 and CD8 T cells and IFNγ secretion increased after therapy.
  • T cells were first expanded in the laboratory through four culture cycles with mesothelin peptides. Mesothelin-binding CD8 T cells were then found before treatment in 5 of 8 HLA-A2 positive patients, and their frequency did not change significantly with treatment.
  • T cell receptor (TCRB) patterns were generally similar before and after treatment. The authors read this as showing no clonal T cell expansion.
  • CD4 T cells showed a significant gain in HLA-DR-positive and PD-1-positive cells after the first vaccination (week 2).
  • After three vaccinations (week 6), ICOS (CD278)-positive CD4 T cells were significantly increased compared with baseline.
  • CD8 T cells showed a significant enrichment of LAG-3 (CD223)-positive cells. The abstract dates this at 2 weeks.
  • No significant changes were seen in CD25, CD69, BTLA, CD137, CD154 or CD134 on CD4 or CD8 T cells.
• The authors' conclusion: The authors concluded that vaccination with the allogeneic lysate increased T cell and B cell numbers in blood, with no sign of narrow (mono- or oligo-clonal) T cell expansion. They proposed the changes in CD4 T cell activation markers as parameters for monitoring dendritic cell vaccination. They said larger studies should test these markers against treatment efficacy.
• Limitations the authors state:
  • Patient numbers were too low to correlate immune monitoring data with clinical outcome.
  • The study did not examine T cell reactivity at the tumor site; no tumor material was collected.
  • It remains unknown whether the vaccine-specific response also reacted against the patients' own tumors.
  • Changes in blood occurring before week 6 may have been missed.
  • The flow cytometry panels could not assess whether ICOS and HLA-DR were expressed on the same cells.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Prognosis, Immunotherapy, Mesothelin.

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