Top

Published in:

Open Access 01-08-2018 | Original Article

Randomized controlled phase III trial of adjuvant chemoimmunotherapy with activated cytotoxic T cells and dendritic cells from regional lymph nodes of patients with lung cancer

Authors: Hideki Kimura, Yukiko Matsui, Aki Ishikawa, Takahiro Nakajima, Toshihiko Iizasa

Published in: Cancer Immunology, Immunotherapy | Issue 8/2018

Abstract

Randomized controlled trial of adjuvant chemoimmunotherapy for lung cancer indicated a significant advantage in patients receiving immunotherapy. Herein we report the final results and immunological analysis with a median follow-up of 59.6 months. Patients with post-surgical lung cancer were randomly designated to receive either chemoimmunotherapy (group A, immunotherapy arm) or chemotherapy (group B, control arm). The immunotherapy comprised the adoptive transfer of autologous activated killer T cells and dendritic cells (AKT–DC). The 2- and 5-year overall survival (OS) rates were 96.0 and 69.4% in group A and 64.7 and 45.1% in group B, respectively. Multivariate analysis results revealed that the hazard ratio was 0.439. The 2- and 5-year recurrence-free survival rates were 70.0 and 57.9% in group A and 43.1 and 31.4% in group B, respectively. Subgroup analysis for the OS between treatment groups indicated that younger patients (≤ 55 years: HR 0.098), males (HR 0.474), patients with adenocarcinoma (HR 0.479), patients with stage III cancer (HR 0.399), and those who did not receive preoperative chemotherapy (HR 0.483) had lower HRs than those in the other groups. Immunological analysis of cell surface markers in regional lymph nodes of subjects receiving immunotherapy indicated that the CD8⁺/CD4⁺ T-cell ratio was elevated in survivors. Patients with non-small-cell lung cancer benefited from adoptive cellular immunotherapy as an adjuvant to surgery. Patients with stage III cancer, those with adenocarcinoma, and those not receiving preoperative chemotherapy were good candidates. Lastly, cytotoxic T cells were important for a favorable chemoimmunotherapy outcome.

Puri V, Crabtree TD, Bell JM, Broderick SR, Morgensztern D, Colditz GA, Kreisel D, Krupnick AS, Patterson GA, Meyers BF, Patel A, Robinson CG (2015) Treatment outcomes in stage I lung cancer: a comparison of surgery and stereotactic body radiation therapy. J Thorac Oncol 10:1776–1784. https://doi.org/10.1097/JTO.0000000000000680 CrossRefPubMedPubMedCentral

Khullar OV, Liu Y, Gillespie T, Higgins KA, Ramalingam S, Lipscomb J, Fernandez FG (2015) Survival after sublobar resection versus lobectomy for clinical stage ia lung cancer: an analysis from the national cancer data base. J Thorac Oncol 10:1625–1633. https://doi.org/10.1097/JTO.0000000000000664 CrossRefPubMedPubMedCentral

Pless M, Stupp R, Ris HB, Stahel RA, Weder W, Thierstein S, Gerard MA, Xyrafas A, Früh M, Cathomas R, Zippelius A, Roth A, Bijelovic M, Ochsenbein A, Meier UR, Mamot C, Rauch D, Gautschi O, Betticher DC, Mirimanoff RO, Peters S, SAKK Lung Cancer Project Group (2015) Induction chemoradiation in stage IIIA/N2 non-small cell lung cancer: a phase 3 randomised trial. Lancet 386:1049–1056. https://doi.org/10.1016/S0140-6736(15)60294-X CrossRefPubMed

Arriagada R, Bergman B, Dunant A (2004) International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin based adjuvant chemotherapy in patients with completely resected NSCLC. N Engl J Med 350:351–360CrossRefPubMed

Morgensztern D, Campo MJ, Dahlberg SE, Doebele RC, Garon E, Gerber DE, Goldberg SB, Hammerman PS, Heist RS, Hensing T, Horn L, Ramalingam SS, Rudin CM, Salgia R, Sequist LV, Shaw AT, Simon GR, Somaiah N, Spigel DR, Wrangle J, Johnson D, Herbst RS, Bunn P, Govindan R (2015) Molecularly targeted therapies in non-small cell lung cancer annual update 2014. J Thorac Oncol 10:S1–S63. https://doi.org/10.1097/JTO.0000000000000405 CrossRefPubMedPubMedCentral

Kimura H, Matsui Y, Ishikawa A, Nakajima T, Yoshino M, Sakairi Y (2015) Randomized controlled phase III trial of adjuvant chemoimmunotherapy with activated killer T cells and dendritic cells in patients with resected primary lung cancer. Cancer Immunol Immunother 64:51–59. https://doi.org/10.1007/s00262-014-1613-0 CrossRefPubMed

Kimura H, Yamaguchi Y (1997) A phase III randomized study of interleukin-2 lymphokine-activated killer cell immunotherapy combined with chemotherapy or radiotherapy after curative or noncurative resection of primary lung carcinoma. Cancer 80:42–49CrossRefPubMed

Kimura H, Dobrenkov K, Iida T, Suzuki M, Ando S, Yamamoto N (2005) Tumor-draining lymph nodes of primary lung cancer patients: a potent source of tumor-specific killer cells and dendritic cells. Anticancer Res 25:85–94PubMed

Kimura H, Iizasa T, Ishikawa A, Shingyouji M, Yoshino M, Kimura M, Inada Y, Matsubayashi K (2008) Prospective phase II study of post-surgical adjuvant chemo-immunotherapy using autologous dendritic cells and activated killer cells from tissue culture of tumor-draining lymph nodes in primary lung cancer patients. Anticancer Res 28:1229–1238PubMed

10.

Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immune-surveillance to tumor escape. Nat Immunol 3:991–998. https://doi.org/10.1038/ni1102-991 CrossRefPubMed

11.

Whiteside TL (2008) The tumor microenvironment and its role in promoting tumor growth. Oncogene 27:5904–5912. https://doi.org/10.1038/onc.2008.271 CrossRefPubMedPubMedCentral

12.

Becker JC, Andersen MH, Schrama D, Thor Straten P (2013) Immune-suppressive properties of the tumor microenvironment. Cancer Immunol Immunother 62:1137–1148. https://doi.org/10.1007/s00262-013-1434-6 CrossRefPubMed

13.

Kerkar SP, Restifo NP (2012) Cellular constituents of immune escape within the tumor microenvironment. Cancer Res 72:3125–3130. https://doi.org/10.1158/0008-5472.CAN-11-4094 CrossRefPubMedPubMedCentral

14.

O’Flaherty JD, Gray S, Richard D, Fennell D, O’Leary JJ, Blackhall FH, O’Byrne KJ (2012) Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer. Lung Cancer 76:19–25. https://doi.org/10.1016/j.lungcan.2011.10.018 CrossRefPubMed

15.

Gorges TM, Pantel K (2013) Circulating tumor cells as therapy related biomarkers in cancer patients. Cancer Immunol Immunother 62:931–939. https://doi.org/10.1007/s00262-012-1387-1 CrossRefPubMed

16.

Kim R, Emi M, Tanabe K (2007) Cancer immunoediting from immune surveillance to immune escape. Immunology 121:1–14. https://doi.org/10.1111/j.1365-2567.2007.02587.x CrossRefPubMedPubMedCentral

17.

Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570. https://doi.org/10.1126/science.1203486 CrossRefPubMed

18.

Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883–892. https://doi.org/10.1056/NEJMoa1113205 CrossRefPubMedPubMedCentral

19.

Marusyk A, Almendro V, Polyak K (2012) Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 12:323–334. https://doi.org/10.1038/nrc3261 CrossRefPubMed

20.

Kuwai T, Nakamura T, Kim SJ, Sasaki T, Kitadai Y, Langley RR, Fan D, Hamilton SR, Fidler IJ (2008) Intratumoral heterogeneity for expression of tyrosine kinase growth factor receptors in human colon cancer surgical specimens and orthotopic tumors. Am J Pathol 172:358–366. https://doi.org/10.2353/ajpath.2008.070625 CrossRefPubMedPubMedCentral

21.

Furnari FB, Cloughesy TF, Cavenee WK, Mischel PS (2015) Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma. Nat Rev Cancer 15 1:302–310. https://doi.org/10.1038/nrc3918 CrossRef

22.

Maass G, Schmidt W, Berger M, chilcher F, Koszik F, Schneeberger A, Stingl G, Birnstiel ML, Schweighoffer T (1995) Priming of tumor-specific T cells in the draining lymph nodes after immunization with interleukin 2-secreting tumor cells: three consecutive stages may be required for successful tumor vaccination. Proc Natl Acad Sci USA 92:5540–5544CrossRefPubMedPubMedCentral

23.

Schweighoffer T, Schmidt W, Buschle M, Birnstiel ML (1996) Depletion of naive T cells of the peripheral lymph nodes abrogates systemic antitumor protection conferred by IL-2 secreting cancer vaccines. Gene Ther 3:819–824PubMed

24.

Adema GJ, Hartgers F, Verstraten R, de Vries E, Marland G, Menon S, Foster J, Xu Y, Nooyen P, McClanahan T, Bacon KB, Figdor CG (1997) A dendritic-cell derived C–C chemokine that preferentially attracts naive T cells. Nature 387:713–717. https://doi.org/10.1038/42716 CrossRefPubMed

Title: Randomized controlled phase III trial of adjuvant chemoimmunotherapy with activated cytotoxic T cells and dendritic cells from regional lymph nodes of patients with lung cancer
Authors: Hideki Kimura
Yukiko Matsui
Aki Ishikawa
Takahiro Nakajima
Toshihiko Iizasa
Publication date: 01-08-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 8/2018
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-018-2180-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 8/2018

Targeting myeloid-derived suppressor cells for cancer immunotherapy

Response to “Immune-mediated cholangitis: is it always nivolumab’s fault?”

Expression of CD3, PD-L1 and CTLA-4 in mammary and extra-mammary Paget disease

Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients

Immune-mediated cholangitis: is it always nivolumab’s fault?

Antibody-dependent cell-mediated cytotoxicity induced by active immunotherapy based on racotumomab in non-small cell lung cancer patients

Keynote webinar | Spotlight on antibody–drug conjugates in cancer