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

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Purpose: 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. Results: 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 CD45RA þ 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). Conclusions: 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
JournalClinical Cancer Research
Volume25
Issue number7
DOIs
Publication statusPublished - 2019

Cite this

de Goeje, Pauline L. ; Poncin, Myrthe ; Bezemer, Koen ; Kaijen-Lambers, Margaretha E. H. ; Groen, Harry J. M. ; Smit, Egbert F. ; Dingemans, Anne-Marie C. ; Kunert, Andre ; Hendriks, Rudi W. ; Aerts, Joachim G. J. V. / Induction of peripheral effector CD8 T-cell proliferation by combination of paclitaxel, carboplatin, and bevacizumab in non–small cell lung cancer patients. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 7. pp. 2219-2227.
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title = "Induction of peripheral effector CD8 T-cell proliferation by combination of paclitaxel, carboplatin, and bevacizumab in non–small cell lung cancer patients",
abstract = "Purpose: 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. Results: 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 CD45RA {\th} 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). Conclusions: 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.",
author = "{de Goeje}, {Pauline L.} and Myrthe Poncin and Koen Bezemer and Kaijen-Lambers, {Margaretha E. H.} and Groen, {Harry J. M.} and Smit, {Egbert F.} and Dingemans, {Anne-Marie C.} and Andre Kunert and Hendriks, {Rudi W.} and Aerts, {Joachim G. J. V.}",
year = "2019",
doi = "10.1158/1078-0432.CCR-18-2243",
language = "English",
volume = "25",
pages = "2219--2227",
journal = "Clinical Cancer Research",
issn = "1078-0432",
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Induction of peripheral effector CD8 T-cell proliferation by combination of paclitaxel, carboplatin, and bevacizumab in non–small cell lung cancer patients. / de Goeje, Pauline L.; Poncin, Myrthe; Bezemer, Koen; Kaijen-Lambers, Margaretha E. H.; Groen, Harry J. M.; Smit, Egbert F.; Dingemans, Anne-Marie C.; Kunert, Andre; Hendriks, Rudi W.; Aerts, Joachim G. J. V.

In: Clinical Cancer Research, Vol. 25, No. 7, 2019, p. 2219-2227.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Induction of peripheral effector CD8 T-cell proliferation by combination of paclitaxel, carboplatin, and bevacizumab in non–small cell lung cancer patients

AU - de Goeje, Pauline L.

AU - Poncin, Myrthe

AU - Bezemer, Koen

AU - Kaijen-Lambers, Margaretha E. H.

AU - Groen, Harry J. M.

AU - Smit, Egbert F.

AU - Dingemans, Anne-Marie C.

AU - Kunert, Andre

AU - Hendriks, Rudi W.

AU - Aerts, Joachim G. J. V.

PY - 2019

Y1 - 2019

N2 - Purpose: 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. Results: 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 CD45RA þ 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). Conclusions: 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.

AB - Purpose: 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. Results: 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 CD45RA þ 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). Conclusions: 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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30642911

U2 - 10.1158/1078-0432.CCR-18-2243

DO - 10.1158/1078-0432.CCR-18-2243

M3 - Article

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SP - 2219

EP - 2227

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

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