Preliminary Safety and Potential Effect of 6B11-OCIK Adoptive Cell Therapy Against Platinum-Resistant Recurrent or Refractory Ovarian Cancer
Hongyan Cheng, Ruiqiong Ma, Shang Wang, Yu Wang, Yingchun Li, Zhijian Tang, Sha Dou, Yuanfen Wang, Honglan Zhu, Xue Ye, Tianyu Zhang, Yonghua Zhang, Shufen Li, Yonghong Zhao, Yi Li, Heng Cui, Xiaohong Chang, Hongyan Cheng, Ruiqiong Ma, Shang Wang, Yu Wang, Yingchun Li, Zhijian Tang, Sha Dou, Yuanfen Wang, Honglan Zhu, Xue Ye, Tianyu Zhang, Yonghua Zhang, Shufen Li, Yonghong Zhao, Yi Li, Heng Cui, Xiaohong Chang
Abstract
Ovarian cancer is a leading cause of death among gynecological malignancies, and novel therapies are urgently needed. Here we report preliminary findings on the potential safety and efficacy of 6B11-OCIK, an adoptive cell therapy of autologous T cells induced by the humanized anti-idiotypic antibody 6B11 minibody plus dendritic cells and cytokines, against platinum-resistant recurrent or refractory ovarian cancer in three patients. We found that 6B11-OCIK treatment was safe and well tolerated after five cycles of intravenous infusion with an initial dose of 1-2×109 cells and a dose-climbing strategy. Hemoglobin, platelets, white cell count, creatinine or liver enzyme values, coagulation function, kidney and heart function were not significantly affected over the duration of therapy. Two of the three enrolled patients showed potentially drug-related grade 1 and 2 weakness, and no other adverse events were observed. Of the three enrolled patients, one had stable disease and two showed disease progression. The patient with favorable clinical efficacy had better immune response as measured by 6B11-OCIK proliferation capacity, activation ability of CD3+CD8+ tumor-specific cytotoxic T lymphocytes and CD3+CD56+ cytokine-induced killer cells, and tumor cell killing efficiency. Changes in circulating tumor cells after treatment were consistent with serum level CA125 in the patient with stable disease (both decreased), while differences were observed in the two patients with disease progression (increased CA125 in both and decreased CTC in the patient with better immune response), suggesting that variation of circulating tumor cells was more consistent with immune response and reflected efficacy directly. This preliminary study suggested that autologous 6B11-OCIK treatment was safe and had potential clinical efficacy against ovarian cancer. Patients with better immune response had more favorable efficacy. In addition to imaging, CA125 and immunophenotypes, CTC monitoring may represent a potential indicator of immunotherapy response.
Trial registration: ClinicalTrials.gov NCT03542669.
Keywords: adoptive cell therapy; circulating tumor cell; immunotherapy; ovarian cancer; safety and efficiency evaluation.
Conflict of interest statement
Authors YW, YCL, YZhan, SL, and YZhan were employed by Beijing Weixiao Biotechnology Development Limited, Beijing, China. The remaining 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 © 2021 Cheng, Ma, Wang, Wang, Li, Tang, Dou, Wang, Zhu, Ye, Zhang, Zhang, Li, Zhao, Li, Cui and Chang.
Figures
References
- Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2019. CA Cancer J Clin (2019) 69(1):7–34. 10.3322/caac.21551
- Armbruster S, Coleman RL, Rauh-Hain JA. Management and Treatment of Recurrent Epithelial Ovarian Cancer. Hematol Oncol Clin North Am (2018) 32(6):965–82. 10.1016/j.hoc.2018.07.005
- Marth C, Reimer D, Zeimet AG. Front-Line Therapy of Advanced Epithelial Ovarian Cancer: Standard Treatment. Ann Oncol (2017) 28(suppl_8):viii36– 9. 10.1093/annonc/mdx450
- Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. . Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer. N Eng J Med (2010) 363(10):943–953. 10.1056/NEJMoa0908806
- Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. . Cancer Treatment and Survivorship Statistics,2016. CA Cancer J Clin (2016) 66:271–89. 10.3322/caac.21349
- Odunsi K. Immunotherapy in Ovarian Cancer. Ann Oncol (2017) 28 suppl_8):viii1–7. 10.1093/annonc/mdx444
- Ghisoni E, Imbimbo M, Zimmermann S, Valabrega G. Ovarian Cancer Immunotherapy: Turning Up the Heat. Int J Mol Sci (2019) 20(12):pii: E2927. 10.3390/ijms20122927
- Fan CA, Reader J, Roque DM. Review of Immune Therapies Targeting Ovarian Cancer. Curr Treat Options Oncol (2018) 19(12):74. 10.1007/s11864-018-0584-3
- Mittica G, Capellero S, Genta S, Cagnazzo C, Aglietta M, Sangiolo D, et al. . Adoptive Immunotherapy Against Ovarian Cancer. J Ovarian Res (2016) 9:30. 10.1186/s13048-016-0236-9
- Yang S, Yin X, Yue Y, Wang S. Application of Adoptive Immunotherapy in Ovarian Cancer. Onco Targets Ther (2019) 12:7975–91. 10.2147/OTT.S221773.eCollection2019
- Jiang N, Qiao G, Wang X, Morse MA, Gwin WR, Zhou L, et al. . Dendritic Cell/Cytokine-Induced Killer Cell Immunotherapy Combined With S-1 in Patientswith Advanced Pancreatic Cancer: A Prospective Study. Clin Cancer Res (2017) 23(17):5066–73. 10.1158/1078-0432.CCR-17-0492
- Li C, Zhu D, Zhao Y, Guo Q, Sun W, Li L, et al. . Dendritic Cells Therapy With Cytokine-Induced Killer Cells and Activated Cytotoxic T Cells Attenuated Th2 Bias Immune Response. Immunol Invest (2019) 3:1–13. 10.1080/08820139.2019.1696360
- Cao J, Kong FH, Liu X, Wang XB. Immunotherapy With Dendritic Cells and Cytokine-Induced Killer Cells for Hepatocellular Carcinoma: A Meta-Analysis. World J Gastroenterol (2019) 25(27):3649–63. 10.3748/wig.v25.i27.3649
- Liu C, Cui X, Zhou D, Li C, Zhao M, Jin Y, et al. . Cytokine-Induced Killer Cells Co-Cultured With Non-Cell Derived Targeting Peptide-Loaded Dendritic Cells Induce a Specific Antitumor Response. Cancer Biol Ther (2019) 20(5):720–8. 10.1080/15384047.2018.1564561
- Qian HN, Lu WY. Anti-Idiotypic Monoclonal Antibodies Against Anti-Ovarian Carcinoma Monoclonal Antibody COC166-9. Generation and Application. Chin Med J (Engl) (1994) 107(2):99–103.
- Chang X, Cui H, Feng J, Li Y, Liu B, Cao S, et al. . Preparation of Humanized Ovarian Carcinoma Anti-Idiotypic Minibody. Hybrid Hybridomics (2003) 22(2):109–15. 10.1089/153685903321948030
- Yang W, Feng J, Chang X, Fu T, Ye X, Zhang H, et al. . Cytotoxic Effects of T Cells Induced by Fusion Protein 6B11-Pulsed Dendritic Cells on Ovarian Carcinoma Cells. Gynecol Oncol (2007) 105(1):238–43. 10.1016/j.ygyno.2006.04.028
- Tazdait M, Mezquita L, Lahmar J, Ferrara R, Bidault F, Ammari S, et al. . Patterns of Responses in Metastatic NSCLC During PD-1 or PD L-1 Inhibitor Therapy: Comparison of RECIST1.1, irRECIST and iRECIST Criteria. Eur J Cancer (2018) 88:38–47. 10.1016/j.ejca.2017.10.017
- Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. . iRECIST: Guidelines for Response Criteria for Use in Trials Testing Immunotherapeutics. Lancet Oncol (2017) 18(3):e143–52. 10.1016/S1470-2045(17)30074-8
- Rossi E, Fabbri F. CTCs 2020: Great Expectations or Unreasonable Dreams. Cells (2019) 8(9):E989. 10.3390/cells8090989
- Heller G, McCormack R, Kheoh T, Molina A, Smith MR, Dreicer R, et al. . Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: A Comparison With Prostate-Specific Antigen Across Five Randomized Phase III Clinical Trials. J Clin Oncol (2018) 36(6):572–80. 10.1200/JCO.2017.75.2998
- Cheng H, Wang S, Luan W, Ye X, Dou S, Tang Z, et al. . Combined Detection and Subclass Characteristics Analysis of CTCs and CTECs by SE-iFISH in Ovarian Cancer. Chin J Cancer Res (2021) 33(2):256–70. 10.21147/j.issn.1000-9604
- Moon DH, Lindsay DP, Hong S, Wang AZ. Clinical Indications for, and the Future of, Circulating Tumor Cells. Adv Drug Delivery Rev (2018) 125:143–50. 10.1016/j.addr.2018.04.002
- Van Berckelaer C, Brouwers AJ, Peeters DJ, Tjalma W, Trinh XB, van Dam PA. Current and Future Role of Circulating Tumor Cells in Patients With Epithelial Ovarian Cancer. Eur J Surg Oncol (2016) 42(12):1772–9. 10.1016/j.ejso.2016.05.010
- Pradeep S, Kim SW, Wu SY, Nishimura M, Chaluvally-Raghavan P, Miyake T, et al. . Hematogenous Metastasis of Ovarian Cancer: Rethinking Mode of Spread. Cancer Cell (2014) 26(1):77–91. 10.1016/j.ccr.2014.05.002
- Romero-Laorden N, Olmos D, Fehm T, Garcia-Donas J, Diaz-Padilla I. Circulating and Disseminated Tumor Cells in Ovarian Cancer: A Systematic Review. Gynecol Oncol (2014) 133(3):632–9. 10.1016/j.ygyno.2014.03.016
- Giannopoulou L, Kasimir-Bauer S, Lianidou ES. Liquid Biopsy in Ovarian Cancer: Recent Advances on Circulating Tumor Cells and Circulating Tumor DNA. Clin Chem Lab Med (2018) 56(2):186–97. 10.1515/cclm-2017-0019
- Yan-xiu G, Kuang Hong N, Xiao-hong C, Sun Y, Cheng HY, Ye X, et al. . Diagnostic Value of Circulating Tumor Cells (CTCs) With HE4+ in Patients With Suspicious Ovarian Cancer. Oncotarget (2018) 9(7):7522–33. 10.18632/oncotarget.23943
- Chebouti I, Kuhlmann JD, Buderath P, Weber S, Wimberger P, Bokeloh Y, et al. . ERCC1-Expressing Circulating Tumor Cells as a Potential Diagnostic Tool for Monitoring Response to Platinum-Based Chemotherapy and for Predicting Post-Therapeutic Outcome of Ovarian Cancer. Oncotarget (2017) 8(15):24303–13. 10.18632/oncotarget.13286
- Lee M, Kim EJ, Cho Y, Kim S, Chung HH, Park NH, et al. . Predictive Value of Circulating Tumor Cells (CTCs) Captured by Microfluidic Device in Patients With Epithelial Ovarian Cancer. Gynecol Oncol (2017) 145(2):361–5. 10.1016/j.ygyno.2017.02.042
- Ge F, Zhang H, Wang DD, Li L, Lin PP. Enhanced Detection and Comprehensive in Situ Phenotypic Characterization of Circulating and Disseminated Heteroploid Epithelial and Glioma Tumor Cells. Oncotarget (2015) 6(29):27049–64. 10.18632/oncotarget.4819
- Lin PP. Integrated EpCAM-Independent Subtraction Enrichment and iFISH Strategies to Detect and Classify Disseminated and Circulating Tumors Cells. Clin Transl Med (2015) 4(1):38–44. 10.1186/s40169-015-0081-2
- Li Y, Zhang X, Gong J, Zhang Q, Gao J, Cao Y, et al. . Aneuploidy of Chromosome 8 in Circulating Tumor Cells Correlates With Prognosis in Patients With Advanced Gastric Cancer. Chin (2016) 28(6):579–88. 10.21147/j.issn.1000-9604.2016.06.04
- Wu W, Zhang Z, Gao XH, Shen Z, Jing Y, Lu H, et al. . Clinical Significance of Detecting Circulating Tumor Cells in Colorectal Cancer Using Subtractionenrichment and Immunostaining-Fluorescence In Situ Hybridization (SE-iFISH). Oncotarget (2017) 8(13):21639–49. 10.18632/oncotarget.15452
- Wang L, Li Y, Xu J, Zhang A, Wang X, Tang R, et al. . Quantified Postsurgical Small Cell Size CTCs and EpCAM+ Circulating Tumor Stem Cells With Cytogenetic Abnormalities in Hepatocellular Carcinoma Patients Determine Cancer Relapse. Cancer Lett (2018) 412:99–107. 10.1016/j.canlet.2017.10.004
- Wang Y, Xu Z, Zhou F, Sun Y, Chen J, Li L, et al. . The Combination of Dendritic Cells-Cytotoxic T Lymphocytes/Cytokine Induced Killer (DC-CTL/CIK) Therapy Exerts Immune and Clinical Responses in Patients With Malignant Tumors. Exp Hematol Oncol (2015) 4:32. 10.1186/s40164-015-0027-9
- Schmeel LC, Schmeel FC, Coch C, Schmidt-Wolf IG. Cytokine-Induced Killer (CIK) Cells in Cancer Immunotherapy: Report of the International Registry on CIK Cells (IRCC). J Cancer Res Clin Oncol (2015) 141(5):839–49. 10.1007/s00432-014-1864-3
- Zhou Y, Chen CL, Jiang SW, Feng Y, Yuan L, Chen P, et al. . Retrospective Analysis of the Efficacy of Adjuvant CIK Cell Therapy in Epithelial Ovarian Cancer Patients Who Received Postoperative Chemotherapy. Oncoimmunology (2018) 8(2):e1528411. 10.1080/2162402X.2018.1528411
- Huang RY, Eppolito C, Lele S, Shrikant P, Matsuzaki J, Odunsi K. LAG3 and PD1 Co-Inhibitory Molecules Collaborate to Limit CD8+ T Cell Signaling and Dampen Antitumor Immunity in a Murine Ovarian Cancer Model. Oncotarget (2015) 6(29):27359–77. 10.18632/oncotarget.4751
- Hanlon DJ, Aldo PB, Devine L, Alvero AB, Engberg AK, Edelson R, et al. . Enhanced Stimulation of Anti-Ovarian Cancer CD8 (+) T Cells by Dendritic Cells Loaded With Nanoparticle Encapsulated Tumor Antigen. Am J Reprod Immunol (2011) 65(6):597–609. 10.1111/j.1600-0897.2010.00968.x
- Liu YL, Zamarin D. Combination Immune Checkpoint Blockade Strategies to Maximize Immune Response in Gynecological Cancers. Curr Oncol Rep (2018) 20(12):94. 10.1007/s11912-018-0740-8
- Oza AM, Cibula D, Benzaquen AO, Poole C, Mathijssen RH, Sonke GS, et al. . Olaparib Combined With Chemotherapy for Recurrent Platinum-Sensitive Ovarian Cancer: A Randomised Phase 2 Trial. Lancet Oncol (2015) 16(1):87–97. 10.1016/S1470-2045(14)71135-0
- Liu JF, Barry WT, Birrer M, Lee JM, Buckanovich RJ, Fleming GF, et al. . Combination Cediranib and Olaparib Versus Olaparib Alone for Women With Recurrent Platinum-Sensitive Ovarian Cancer: A Randomised Phase 2 Study. Lancet Oncol (2014) 15(11):1207–14. 10.1016/S1470-2045(14)70391-2
- Ivy SP, Liu JF, Lee JM, Matulonis UA, Kohn EC. Cediranib, a Pan-VEGFR Inhibitor, and Olaparib, a PARP Inhibitor, in Combination Therapy for High Grade Serous Ovarian Cancer. Expert Opin Invest Drugs (2016) 25(5):597–611. 10.1517/13543784.2016.1156857
- Drew Y, de Jonge M, Hong SH, Park YH, Wolfer A, Brown MJ, et al. . An Open-Label, Phase II Basket Study of Olaparib and Durvalumab (MEDIOLA): Results in Germline BRCA-Mutated (gBRCAm) Platinum-Sensitive Relapsed (PSR) Ovarian Cancer (OC). Gynecol Oncol (2018) 149(S1):246–7. 10.1016/j.ygyno.2018.04.555
Source: PubMed