Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy

Our plain-English summary of Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy, by L. Noordam, M.E.H. Kaijen, K. Bezemer, et al (Oncoimmunology, 2018).

The study

• Authors: L. Noordam, M.E.H. Kaijen, K. Bezemer, R. Cornelissen, L.A.P.W.M. Maat, H.C. Hoogsteden, J.G.J.V. Aerts, R.W. Hendriks, J.P.J.J. Hegmans, H. Vroman
• Journal: Oncoimmunology
• Published: 2018;7(12):e1474318
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Rationale: Regulatory T cells (Treg) play a pivotal role in the immunosuppressive tumor micro-environment in cancer, including mesothelioma. Recently, the combination of autologous tumor lysate-pulsed dendritic cells (DC) and metronomic cyclophosphamide (mCTX) was reported as a feasible and well-tolerated treatment in malignant pleural mesothelioma patients and further as a method to reduce circulating Tregs. Objectives: The aim of this study was to establish the immunological effects of mCTX alone and in combination with DC-based immunotherapy on circulating Treg and other T cell subsets in mesothelioma patients. Methods: Ten patients received mCTX and DC-based immunotherapy after chemotherapy (n = 5) or chemotherapy and debulking surgery (n = 5). Peripheral blood mononuclear cells before, during and after treatment were analyzed for various Treg and other lymphocyte subsets by flow cytometry. Results: After one week treatment with mCTX, both activated FoxP3hi and naïve CD45RA+ Tregs were effectively decreased in all patients. In addition, a shift from naïve and central memory towards effector memory and effector T cells was observed. Survival analysis showed that overall Treg levels before treatment were not correlated with survival, however, nTreg levels before treatment were positively correlated with survival. After completion of mCTX and DC-based immunotherapy treatment, all cell subsets returned to baseline levels, except for the proportions of proliferating EM CD8 T cells, which increased. Conclusions: mCTX treatment effectively reduced the proportions of circulating Tregs, both aTregs and nTregs, thereby favoring EM T cell subsets in mesothelioma patients. Interestingly, baseline levels of nTregs were positively correlated to overall survival upon complete treatment.

In plain English

This study analysed blood samples from ten patients with malignant pleural mesothelioma in a phase I/II clinical trial at Erasmus MC in Rotterdam, the Netherlands, with patients enrolled between August 2009 and October 2011. All patients had a response or stable disease after chemotherapy, and five had also had debulking surgery. Patients received low-dose (metronomic) cyclophosphamide tablets, 50 mg twice daily in alternating weeks, along with at least three vaccinations of dendritic cells loaded with material from their own tumor. The study did not examine asbestos exposure. After one week of cyclophosphamide, the average share of naïve regulatory T cells fell from 1.97% to 0.86% of CD4 T cells, and of activated regulatory T cells from 3.23% to 1.52%. Regulatory T cells are immune cells that can dampen anti-tumor responses. Other T cells shifted toward effector types. After the full treatment, nearly all measures returned to baseline. The exception was a rise in proliferating central memory CD8 T cells. Higher pre-treatment naïve regulatory T cell levels were correlated with longer overall survival, while total regulatory T cells were not. The authors noted possible selection bias and the small number of patients. They said this survival link should be validated in a larger group.

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: Exploratory immunological analysis of blood samples from patients in a phase I/II clinical trial (no control group); blood cells were analysed by flow cytometry before, during and after treatment
• Who was studied: Ten patients with malignant pleural mesothelioma (MPM) at Erasmus MC, Rotterdam, the Netherlands, enrolled August 2009 to October 2011. All were suitable for pleurectomy/decortication and had stable disease or a response after antifolate-based chemotherapy. Five also had debulking surgery (P/D) before the trial treatment.
• Exposure: Treatment, not asbestos exposure. Patients received metronomic (low-dose) cyclophosphamide, 50 mg tablets twice daily for a week, alternating with weeks in which a vaccination was given. There were at least three vaccinations of 50 million mature dendritic cells pulsed with autologous tumor lysate, given at 2-week intervals. Asbestos is mentioned only in the introduction as the usual cause of MPM.
• Main results:
  • Baseline blood immune cell subsets, including regulatory T cells, were comparable between the five patients who had debulking surgery and the five who did not, so their data were pooled.
  • After one week of cyclophosphamide (t = 2), the mean percentage of naïve regulatory T cells fell significantly from 1.97% (SEM 0.40) to 0.86% (SEM 0.17) of CD4 T cells. Activated regulatory T cells fell from 3.23% (SEM 0.87) to 1.52% (SEM 0.36).
  • After cyclophosphamide, CD4 T cells decreased and CD8 T cells increased as a share of T cells. There was a shift from naïve and central memory subsets toward effector memory and effector (TEMRA) subsets.
  • After the complete dendritic cell plus cyclophosphamide treatment (t = 8), all immune cell subsets, including regulatory T cells, returned to baseline. The one exception was the share of proliferating central memory CD8 T cells, which rose from 4.23% (SEM 0.88) to 7.19% (SEM 1.50).
  • Pre-treatment percentage of total regulatory T cells was not correlated with survival.
  • Pre-treatment percentage of naïve regulatory T cells correlated positively with survival, while activated regulatory T cells showed no correlation.
  • Patients with pre-treatment naïve regulatory T cells above 2% of CD4 T cells (n = 5; range 2.46%-4.43%) were associated with higher overall survival than those below 2% (n = 5; range 0.46%-1.19%).
• The authors' conclusion: The authors concluded that low-dose cyclophosphamide reduced the proportions of both naïve and activated regulatory T cells among CD4 T cells. They also concluded that, in patients treated with dendritic cell plus cyclophosphamide immunotherapy, the pre-treatment percentage of circulating naïve regulatory T cells correlated positively with overall survival.
• Limitations the authors state:
  • Inclusion required enough tumor cells in pleural fluid (no-surgery group) or fitness for surgery (surgery group), which might have caused selection bias.
  • The study was exploratory with only ten patients, which might not be enough to detect smaller differences or establish significant results.
  • The positive correlation between pre-treatment naïve regulatory T cells and survival needs validation in a larger cohort.
  • The study cannot show whether the better survival with higher naïve regulatory T cells is due to cyclophosphamide, the dendritic cell therapy, the combination, or an initially better prognosis.
  • For the surgery comparison, preoperative data were not available and effects inside the tumor could not be studied.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Immunotherapy, Mesothelioma, Chemotherapy, Cytoreductive Surgery, Overall Survival.

Related studies

• The Regulatory Status Adopted by Lymph Node Dendritic Cells and T Cells During Healthy Aging Is Maintained During Cancer and May Contribute to Reduced Responses to Immunotherapy — J.K. Gardner, C. Jackaman, et al. (2018)
• Dendritic cell-based immunotherapy in mesothelioma — R. Cornelissen, L.A. Lievense, et al. (2012)
• Long-Term Follow-Up of Mesothelioma Patients Treated with Dendritic Cell Therapy in Three Phase I/II Trials — D.W. Dumoulin, R. Cornelissen, et al. (2021)
• Dendritic Cell-Based Immunotherapy in Patients With Resected Pancreatic Cancer — F.R. van 't Land, M. Willemsen, et al. (2024)
• Adjuvant dendritic cell-based immunotherapy after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with malignant peritoneal mesothelioma: a phase II clinical trial — M.V. Dietz, K.L.A. Quintelier, et al. (2023)
• Adjuvant dendritic cell based immunotherapy (DCBI) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal mesothelioma, a phase II single centre open-label clinical trial: rationale and design of the MESOPEC trial — N.L. de Boer, J.P. van Kooten, et al. (2019)

Browse more research in Oncoimmunology, or return to medical research.