Sintilimab maintenance therapy post first-line cytokine-induced killer cells plus chemotherapy for extensive-stage small cell lung cancer

Baozhen Ma, Yu Zhou, Yiman Shang, Yong Zhang, Benling Xu, Xiaomin Fu, Jindong Guo, Yonghao Yang, Fang Zhang, Mengyuan Zhou, Hao Huang, Fanghui Li, Hongwei Lin, Lingdi Zhao, Zibing Wang, Quanli Gao, Baozhen Ma, Yu Zhou, Yiman Shang, Yong Zhang, Benling Xu, Xiaomin Fu, Jindong Guo, Yonghao Yang, Fang Zhang, Mengyuan Zhou, Hao Huang, Fanghui Li, Hongwei Lin, Lingdi Zhao, Zibing Wang, Quanli Gao

Abstract

Despite recent progress in treating advanced non-small cell lung cancer, clinical intervention in extensive-stage small-cell lung cancer (ES-SCLC) remains stagnant. The purpose of this study was to evaluate the clinical efficacy of cytokine-induced killer (CIK) cells combined with cytotoxic chemotherapy, followed by anti-programmed death 1 antibody (sintilimab) maintenance, in ES-SCLC patients. To explore a new method for safe treatment of ES-SCLC patients, thirteen ES-SCLC patients were enrolled between June 2019 and December 2021. All patients received first-line chemotherapy (etoposide plus platinum) combined with CIK cell therapy. Patients who reached a stable disease state or responded well to treatment received sintilimab maintenance treatment. The primary objective of this study was to determine the median overall survival (OS); the secondary objective was to assess the objective response rate (ORR), progression-free survival 1 and 2 (PFS1 was defined as the duration from the signing of informed consent to the date of tumor progression, or death, or the last follow-up. PFS2 was defined as the duration from the first day of sintilimab treatment to the date of tumor progression, death, or the last follow-up.), and adverse reactions. At a 24.1-month follow-up, the median OS was 11.8 (95% confidence interval [CI]: 10.6-13.0) months, median PFS1 was 5.5 (95% CI: 5.0-6.0) months, and the median PFS2 was 2.3 (95% CI: 0.5-4.1) months. The ORR was 76.9% (10/13), the disease control rate was 100% (13/13), and the 20-month survival rate was 41.7%. Eight participants exhibited grade 3 or 4 adverse events after combination therapy. During maintenance treatment with sintilimab, level 3 adverse events occurred in 1 patient (1/9). In conclusion, adding CIK cells to standard chemotherapy regimens, followed by maintenance therapy with sintilimab, may represent a new safe and effective treatment strategy.

Clinical trial registration: ClinicalTrials.gov (NCT03983759).

Keywords: chemotherapy; cytokine-induced killer cells; extensive-stage small-cell lung cancer; maintenance; sintilimab.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Ma, Zhou, Shang, Zhang, Xu, Fu, Guo, Yang, Zhang, Zhou, Huang, Li, Lin, Zhao, Wang and Gao.

Figures

Figure 1
Figure 1
Flow chart of ES-SCLC patient treatment.
Figure 2
Figure 2
Treatment and survival of ES-SCLC patients.
Figure 3
Figure 3
The efficacy of chemotherapy plus CIK cells followed by sintilimab (percentage changes of tumor burden by best response).
Figure 4
Figure 4
(A) PFS1 curve, the median PFS1 was 5.5 months; (B) PFS2 curve, the median PFS2 was 2.3 months; (C) OS curve, the median OS was 11.8 months.

References

    1. Mankor JM, Zwierenga F, Dumoulin DW, Neefjes JJC, Aerts JGJV. A brief report on combination chemotherapy and anti-programmed death (ligand) 1 treatment in small-cell lung cancer: Did we choose the optimal chemotherapy backbone? Eur J Cancer (2020) 137:40–4. doi: 10.1016/j.ejca.2020.06.029
    1. Sundstrøm S, Bremnes RM, Kaasa S, Aasebø U, Hatlevoll R, Dahle R, et al. . Norwegian Lung cancer study group. cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: Results from a randomized phase III trial with 5 years’ follow-up. J Clin Oncol (2002) 20:4665–72. doi: 10.1200/JCO.2002.12.111
    1. Rossi A, Di Maio M, Chiodini P, Rudd RM, Okamoto H, Skarlos DV, et al. . Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: The COCIS meta-analysis of individual patient data. J Clin Oncol (2012) 30:1692–8. doi: 10.1200/JCO.2011.40.4905
    1. Semenova EA, Nagel R, Berns A. Origins, genetic landscape, and emerging therapies of small cell lung cancer. Genes Dev (2015) 29:1447–62. doi: 10.1101/gad.263145.115
    1. Früh M, De Ruysscher D, Popat S, Crinò L, Peters S, Felip E, et al. . Small-cell lung cancer (SCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol (2013) 24 Suppl 6:vi99–105. doi: 10.1093/annonc/mdt178
    1. Wang S, Zimmermann S, Parikh K, Mansfield AS, Adjei AA. Current diagnosis and management of small-cell lung cancer. Mayo Clin Proc (2019) 94:1599–622. doi: 10.1016/j.mayocp.2019.01.034
    1. Yang S, Zhang Z, Wang Q. Emerging therapies for small cell lung cancer. J Hematol Oncol (2019) 12:47. doi: 10.1186/s13045-019-0736-3
    1. Frampton JE. Atezolizumab: A review in extensive-stage SCLC. Drugs (2020) 80:1587–94. doi: 10.1007/s40265-020-01398-6
    1. Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, et al. . CASPIAN investigators. Caspian investigators. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): A randomised, controlled, open-label, phase 3 trial. Lancet (2019) 394:1929–39. doi: 10.1016/S0140-6736(19)32222-6
    1. Iams WT, Porter J, Horn L. Immunotherapeutic approaches for small-cell lung cancer. Nat Rev Clin Oncol (2020) 17:300–12. doi: 10.1038/s41571-019-0316-z
    1. Zhang Y, Schmidt-Wolf IGH. Ten-year update of the international registry on cytokine-induced killer cells in cancer immunotherapy. J Cell Physiol (2020) 235:9291–303. doi: 10.1002/jcp.29827
    1. Introna M. CIK as therapeutic agents against tumors. J Autoimmun (2017) 85:32–44. doi: 10.1016/j.jaut.2017.06.008
    1. Yu SJ, Ma C, Heinrich B, Brown ZJ, Sandhu M, Zhang Q, et al. . Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma. J Hepatol (2019) 70:449–57. doi: 10.1016/j.jhep.2018.10.040
    1. Wang Z, Liu Y, Li R, Shang Y, Zhang Y, Zhao L, et al. . Autologous cytokine-induced killer cell transfusion increases overall survival in advanced pancreatic cancer. J Hematol Oncol (2016) 9:6. doi: 10.1186/s13045-016-0237-6
    1. Zhang Y, Ellinger J, Ritter M, Schmidt-Wolf IGH. Clinical studies applying cytokine-induced killer cells for the treatment of renal cell carcinoma. Cancers (Basel) (2020) 12:2471. doi: 10.3390/cancers12092471
    1. Liu L, Gao Q, Jiang J, Zhang J, Song X, Cui J, et al. . Randomized, multi-center, open-label trial of autologous cytokine-induced killer cell immunotherapy plus chemotherapy for squamous non-small-cell lung cancer: NCT01631357. Signal Transduct Target Ther (2020) 5:244. doi: 10.1038/s41392-020-00337-x
    1. Wang Z, Liu X, Till B, Sun M, Li X, Gao Q. Combination of cytokine-induced killer cells and programmed cell death-1 blockade works synergistically to enhance therapeutic efficacy in metastatic renal cell carcinoma and non-small cell lung cancer. Front Immunol (2018) 9:1513. doi: 10.3389/fimmu.2018.01513
    1. Han L, Shang YM, Song YP, Gao QL. Biological character of RetroNectin activated cytokine-induced killer cells. J Immunol Res (2016) 2016:5706814. doi: 10.1155/2016/5706814
    1. Zhao L, Han L, Zhang Y, Li T, Yang Y, Li W, et al. . Combination of PD-1 blockade and RetroNectin®-activated cytokine-induced killer in preheavily treated non-small-cell lung cancer: A retrospective study. Immunotherapy (2018) 10:1315–23. doi: 10.2217/imt-2018-0125
    1. Ding X, Cao H, Chen X, Jin H, Liu Z, Wang G, et al. . Cellular immunotherapy as maintenance therapy prolongs the survival of the patients with small cell lung cancer. J Transl Med (2015) 13:158. doi: 10.1186/s12967-015-0514-0
    1. Huang J, Kan Q, Zhao X, Zhang Z, Yang S, Li H, et al. . Chemotherapy in combination with cytokine-induced killer cell transfusion: An effective therapeutic option for patients with extensive stage small cell lung cancer. Int Immunopharmacol (2017) 46:170–7. doi: 10.1016/j.intimp.2016.12.005
    1. Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, et al. . Wherry EJ. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature (2017) 545:60–5. doi: 10.1038/nature22079
    1. Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: Implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ (2014) 21:15–25. doi: 10.1038/cdd.2013.67
    1. Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature (2005) 436:1186–90. doi: 10.1038/nature03884
    1. Huang W, Chen JJ, Xing R, Zeng YC. Combination therapy: Future directions of immunotherapy in small cell lung cancer. Transl Oncol (2021) 14:100889. doi: 10.1016/j.tranon.2020.100889
    1. Demedts IK, Vermaelen KY, van Meerbeeck JP. Treatment of extensive-stage small cell lung carcinoma: Current status and future prospects. Eur Respir J (2010) 35:202–15. doi: 10.1183/09031936.00105009
    1. Rudin CM, Awad MM, Navarro A, Gottfried M, Peters S, Csőszi T, et al. . KEYNOTE-604 investigators. Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: Randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol (2020) 38:2369–79. doi: 10.1200/JCO.20.00793
    1. Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, et al. . IMpower133 study group. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med (2018) 379:2220–9. doi: 10.1056/NEJMoa1809064
    1. Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: Reinstating immunosurveillance. Immunity (2013) 39:74–88. doi: 10.1016/j.immuni.2013.06.014
    1. Qiao G, Wang X, Zhou L, Zhou X, Song Y, Wang S, et al. . Autologous dendritic cell-cytokine induced killer cell immunotherapy combined with s-1 plus cisplatin in patients with advanced gastric cancer: A prospective study. Clin Cancer Res (2019) 25:1494–504. doi: 10.1158/1078-0432.CCR-18-2360
    1. Herber DL, Nagaraj S, Djeu JY, Gabrilovich DI. Mechanism and therapeutic reversal of immune suppression in cancer. Cancer Res (2007) 67:5067–9. doi: 10.1158/0008-5472.CAN-07-0897
    1. Hong M, Puaux AL, Huang C, Loumagne L, Tow C, Mackay C, et al. . Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Res (2011) 71:6997–7009. doi: 10.1158/0008-5472.CAN-11-1466
    1. Gammaitoni L, Giraudo L, Macagno M, Leuci V, Mesiano G, Rotolo R, et al. . Cytokine-induced killer cells kill chemo-surviving melanoma cancer stem cells. Clin Cancer Res (2017) 23:2277–88. doi: 10.1158/1078-0432.CCR-16-1524
    1. Templeton AJ, McNamara MG, Šeruga B, Vera-Badillo FE, Aneja P, Ocaña A, et al. . Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: A systematic review and meta-analysis. J Natl Cancer Inst (2014) 106:dju124. doi: 10.1093/jnci/dju124
    1. Gammaitoni L, Giraudo L, Leuci V, Todorovic M, Mesiano G, Picciotto F, et al. . Effective activity of cytokine-induced killer cells against autologous metastatic melanoma including cells with stemness features. Clin Cancer Res (2013) 19:4347–58. doi: 10.1158/1078-0432.CCR-13-0061
    1. Yang L, Du C, Wu L, Yu J, An X, Yu W, et al. . Cytokine-induced killer cells modulates resistance to cisplatin in the A549/DDP cell line. J Cancer (2017) 8:3287–95. doi: 10.7150/jca.19426
    1. Ready NE, Pang HH, Gu L, Otterson GA, Thomas SP, Miller AA, et al. . Chemotherapy with or without maintenance sunitinib for untreated extensive-stage small-cell lung cancer: A randomized, double-blind, placebo-controlled phase II study-CALGB 30504 (alliance). J Clin Oncol (2015) 33:1660–5. doi: 10.1200/JCO.2014.57.3105
    1. Gadgeel SM, Pennell NA, Fidler MJ, Halmos B, Bonomi P, Stevenson J, et al. . Phase II study of maintenance pembrolizumab in patients with extensive-stage small cell lung cancer (SCLC). J Thorac Oncol (2018) 13:1393–9. doi: 10.1016/j.jtho.2018.05.002
    1. Poh SL, Linn YC. Immune checkpoint inhibitors enhance cytotoxicity of cytokine-induced killer cells against human myeloid leukaemic blasts. Cancer Immunol Immunother (2016) 65:525–36. doi: 10.1007/s00262-016-1815-8
    1. Dehno MN, Li Y, Weiher H, Schmidt-Wolf IGH. Increase in efficacy of checkpoint inhibition by cytokine-induced-killer cells as a combination immunotherapy for renal cancer. Int J Mol Sci (2020) 21:3078. doi: 10.3390/ijms21093078
    1. Pan QZ, Gu JM, Zhao JJ, Tang Y, Wang QJ, Zhu Q, et al. . Retrospective analysis of the efficacy of cytokine-induced killer cell immunotherapy combined with first-line chemotherapy in patients with metastatic colorectal cancer. Clin Transl Immunol (2020) 9:e1113. doi: 10.1002/cti2.1113
    1. Han Y, Mu D, Liu T, Zhang H, Zhang J, Li S, et al. . Autologous cytokine-induced killer (CIK) cells enhance the clinical response to PD-1 blocking antibodies in patients with advanced non-small cell lung cancer: A preliminary study. Thorac Cancer (2021) 12:145–52. doi: 10.1111/1759-7714.13731
    1. Ribas A, Shin DS, Zaretsky J, Frederiksen J, Cornish A, Avramis E, et al. . PD-1 blockade expands intratumoral memory T cells. Cancer Immunol Res (2016) 4:194–203. doi: 10.1158/2326-6066.CIR-15-0210
    1. Lu Y, Jiang J, Ren C. The clinicopathological and prognostic value of the pre-treatment neutrophil-to-lymphocyte ratio in small cell lung cancer: A meta-analysis. PLoS One (2020) 15:e0230979. doi: 10.1371/journal.pone.0230979

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit