Serial immunomonitoring of cancer patients receiving combined antagonistic anti-CD40 and chemotherapy reveals consistent and cyclical modulation of T cell and dendritic cell parameters

Our plain-English summary of Serial immunomonitoring of cancer patients receiving combined antagonistic anti-CD40 and chemotherapy reveals consistent and cyclical modulation of T cell and dendritic cell parameters, by A.M. McDonnell, A. Cook, B.W.S. Robinson, et al (BMC Cancer, 2017).

The study

• Authors: A.M. McDonnell, A. Cook, B.W.S. Robinson, R.A. Lake, A.K. Nowak
• Journal: BMC Cancer
• Published: 2017;17(1):417
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: CD40 signalling can synergise with chemotherapy in preclinical cancer models, and early clinical studies are promising. We set out to define the immunological changes associated with this therapeutic combination to identify biomarkers for a response to the therapy. Here, we present serial immunomonitoring examining dendritic cell and T cell subpopulations over sequential courses of chemoimmunotherapy.

Methods: Fifteen patients with mesothelioma received up to six 21-day cycles of pemetrexed plus cisplatin chemotherapy and anti-CD40 (CP-870,893). Peripheral blood was collected weekly, and analysed by flow cytometry. Longitudinal immunophenotyping data was analysed by linear mixed modelling, allowing for variation between patients. Exploratory analyses testing for any correlation between overall survival and immunophenotyping data were undertaken up to the third cycle of treatment.

Results: Large statistically significant cyclical variations in the proportions of BDCA-1+, BDCA-2+ and BDCA-3+ dendritic cells were observed, although all subsets returned to baseline levels after each cycle and no significant changes were observed between start and end of treatment. Expression levels of CD40 and HLA-DR on dendritic cells were also cyclically modulated, again without significant change between start and end of treatment. CD8 and CD4 T cell populations, along with regulatory T cells, effector T cells, and markers of proliferation and activation, showed similar patterns of statistically significant cyclical modulation in response to therapy without changes between start and end of treatment. Exploratory analysis of endpoints revealed that patients with a higher than average proportion of BDCA-2+ dendritic cells (p = 0.010) or a higher than average proportion of activated (ICOS+) CD8 T cells (0.022) in pretreatment blood samples had better overall survival. A higher than average proportion of BDCA-3+ dendritic cells was associated with poorer overall survival at both the second (p = 0.008) and third (p = 0.014) dose of anti-CD40.

Conclusions: Substantial cyclical variations in DC and T cell populations during sequential cycles of chemoimmunotherapy highlight the critical importance of timing of immunological biomarker assessments in interpretation of results and the value of linear mixed modelling in interpretation of longitudinal change over a full treatment course.

Trial Registration: Australia New Zealand Clinical Trials Registry number ACTRN12609000294257 (18th May 2009).

In plain English

This study analysed blood from patients with malignant pleural mesothelioma in a single-centre phase Ib trial in Western Australia. The trial combined pemetrexed and cisplatin chemotherapy with CP-870,893, an antibody that targets the immune molecule CD40. Patients had up to six 21-day cycles. Blood was taken weekly and two kinds of immune cells, dendritic cells and T cells, were measured. Many of these cells rose and fell in a repeating pattern within each cycle. For example, T cell numbers halved at Day 1, after steroid (dexamethasone) premedication, then recovered. Across the whole course the authors found no lasting change, except a small drop in one marker (HLA-DR) on one dendritic cell type, which they judged not biologically relevant. In exploratory analyses, patients above the median for some cell types before treatment lived longer. An above-median proportion of BDCA-3+ dendritic cells at the second and third antibody doses was linked to poorer survival. The authors said these results came from few patients and only generate hypotheses. They concluded that blood-sampling timing and control groups matter when interpreting such tests.

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: Laboratory immune-monitoring analysis of blood samples taken during a prospective, single-centre, phase Ib clinical trial (dose-escalation design), with exploratory survival analyses
• Who was studied: Patients with confirmed malignant pleural mesothelioma receiving first-line chemotherapy at a single centre (Sir Charles Gairdner Hospital / University of Western Australia). The abstract says 15 patients, but the results section says 16 were enrolled. Enrolment dates are not given; the trial was registered on 18 May 2009.
• Exposure: This is not an asbestos exposure study. Treatment was cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 on day 1 of each 21-day cycle (maximum 6 cycles). The anti-CD40 antibody CP-870,893 was given on day 8 at 0.1, 0.15 or 0.2 mg/kg, and dexamethasone premedication was given before chemotherapy.
• Main results:
  • BDCA-1+ and BDCA-2+ dendritic cells, as a share of blood cells, fell by around 50% before Day 1 of each cycle, at the time of steroid premedication, and then recovered.
  • CD40 levels on dendritic cells varied with each cycle. No dendritic cell subset showed a significant overall change in CD40 across 6 cycles.
  • HLA-DR on BDCA-1+ dendritic cells showed a statistically significant but minor decrease from start to end of treatment (p = 0.022). The authors did not consider this decrease biologically relevant.
  • T cell numbers in the blood halved at Day 1 of each cycle and returned to baseline at Days 8 and 15.
  • Regulatory T cells fell by about 20% between Day 1 and Day 8 of each cycle, then returned to around baseline.
  • None of the CD8+ T cell measures changed significantly over the 6 cycles. The authors also reported no change over the six cycles in any CD4+ T cell population.
  • In exploratory survival analyses, two pretreatment measures were linked to better overall survival: the proportion of BDCA-2+ dendritic cells (p = 0.010) and the proportion of activated ICOS+ CD8 T cells (p = 0.022). The methods describe grouping patients by the median, while the abstract says 'higher than average'.
  • Patients with a higher than median proportion of BDCA-3+ dendritic cells (as a share of total blood mononuclear cells) on Day 8 of cycles 2 and 3, when the antibody was given, had poorer overall survival (p = 0.008 and p = 0.014).
  • The two baseline measures linked to better survival were correlated with each other (r = 0.563, p = 0.029).
• The authors' conclusion: The authors concluded that they found no longitudinal changes in dendritic cells or T cells associated with this treatment, and that B cells remain the best indicator of CP-870,893 activity. They also concluded that sampling timing, premedications and a control group need careful consideration when interpreting immune biomarkers in chemoimmunotherapy trials.
• Limitations the authors state:
  • The data came from a small number of patients and serve only to generate hypotheses.
  • The survival analyses were not corrected for multiple comparisons.
  • Blood was taken one week after each antibody dose, so short-term effects of the antibody may have been missed.
  • There was no control group, so changes cannot be attributed to the antibody rather than to the chemotherapy or the steroid premedication.

Topics

Medical terms in this study, explained in our Lexicon: Chemotherapy, Biomarker, Mesothelioma, Pemetrexed (Alimta), Cisplatin, Overall Survival, Clinical Trial.

Related studies

• Tumor-infiltrating dendritic cells exhibit defective cross-presentation of tumor antigens, but is reversed by chemotherapy — A.M. McDonnell, W.J. Lesterhuis, et al. (2015)
• 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)
• Anti-cancer therapy using dendritic cells and apoptotic tumour cells: pre-clinical data in human mesothelioma and acute myeloid leukaemia — M. Grégoire, C. Ligeza-Poisson, et al. (2003)
• A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma — A.K. Nowak, A.M. Cook, et al. (2015)
• Immunomodulatory activity of SGI-110, a 5-aza-2'-deoxycytidine-containing demethylating dinucleotide — S. Coral, G. Parisi, et al. (2013)
• Dendritic Cells in Human Lung Disease: Recent Advances — J.W. Upham, Y. Xi (2017)

Browse more research in BMC Cancer, or return to medical research.