Induction of peripheral effector CD8 T-cell proliferation by combination of paclitaxel, carboplatin, and bevacizumab in non–small cell lung cancer patients

Pauline L. de Goeje, Myrthe Poncin, Koen Bezemer, Margaretha E.H. Kaijen-Lambers, Harry J.M. Groen, Egbert F. Smit, Anne Marie C. Dingemans, Andre Kunert, Rudi W. Hendriks, Joachim G.J.V. Aerts*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

28 Citations (Scopus)



Chemotherapy has long been the standard treatment for advanced stage non–small cell lung cancer (NSCLC), but checkpoint inhibitors are now approved for use in several patient groups and combinations. To design optimal combination strategies, a better understanding of the immune-modulatory capacities of conventional treatments is needed. Therefore, we investigated the immune-modulatory effects of paclitaxel/carboplatin/bevacizumab (PCB), focusing on the immune populations associated with the response to checkpoint inhibitors in peripheral blood. 

Experimental Design

A total of 223 patients with stage IV NSCLC, enrolled in the NVALT12 study, received PCB, with or without nitroglycerin patch. Peripheral blood was collected at baseline and after the first and second treatment cycle, proportions of T cells, B cells, and monocytes were determined by flow cytometry. Furthermore, several subsets of T cells and the expression of Ki67 and coinhibitory receptors on these subsets were determined. 


Although proliferation of CD4 T cells remained stable following treatment, proliferation of peripheral blood CD8 T cells was significantly increased, particularly in the effector memory and CD45RAþ effector subsets. The proliferating CD8 T cells more highly expressed programmed death receptor (PD)-1 and cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) compared with nonproliferating CD8 T cells. Immunologic responders (iR; >2 fold increased proliferation after treatment) did not show an improved progression-free (PFS) or overall survival (OS). 


Paclitaxel/carboplatin/bevacizumab induces proliferation of CD8 T cells, consisting of effector cells expressing coinhibitory checkpoint molecules. Induction of proliferation was not correlated to clinical outcome in the current clinical setting. Our findings provide a rationale for combining PCB with checkpoint inhibition in lung cancer.

Original languageEnglish
Pages (from-to)2219-2227
Number of pages9
JournalClinical Cancer Research
Issue number7
Publication statusPublished - 1 Apr 2019

Bibliographical note

Funding Information:
The authors would like to thank Vincent van der Noort for study data management and Eric Boersma for statistical assistance. Financial support for this study was provided by the Stichting NVALT studies (via an unrestricted grant by Roche).

Publisher Copyright:
© 2019 American Association for Cancer Research.

Research programs

  • EMC MM-03-86-08
  • EMC MM-04-42-02


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