Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study

Jeong Hoon Lee; Won Young Tak; Yoon Lee; Min Kyu Heo; Jae Sung Song; Hak Yeop Kim; Soo Young Park; Si Hyun Bae; Joon Hyeok Lee; Jeong Heo; Ki Hwan Kim; Yong Soo Bae; Yoon Jun Kim

doi:10.1080/2162402X.2017.1328335

Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study

Jeong Hoon Lee, Won Young Tak, Yoon Lee, Min Kyu Heo, Jae Sung Song, Hak Yeop Kim, Soo Young Park, Si Hyun Bae, Joon Hyeok Lee, Jeong Heo, Ki Hwan Kim, Yong Soo Bae, Yoon Jun Kim

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

Abstract

Our previous phase I/IIA study showed that autologous dendritic cells (DCs) pulsed with tumor-associated antigens are well tolerated in patients with hepatocellular carcinoma (HCC). In this randomized, multicenter, open-label, phase II trial, we investigated the efficacy and safety of this DC-based adjuvant immunotherapy with 156 patients, who treated for HCC with no evidence of residual tumor after standard treatment modalities. Patients were randomly assigned to immunotherapy (n = 77; injection of 3 × 10⁷ DC cells, six times over 14 weeks) or control (n = 79; no treatment). The primary end point was recurrence-free survival (RFS), and the secondary endpoints were immune response and safety. The RFS between the immunotherapy and control groups was not significantly different (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.60–1.56; p = 0.90). However, post-hoc subgroup analyses revealed that DC immunotherapy significantly reduced the risk of tumor recurrence of non-radiofrequency ablation (non-RFA) group patients (n = 83, HR, 0.49; 95% CI, 0.26–0.94; p = 0.03), whereas unexpectedly increased the risk of recurrence in RFA group (n = 61, p = 0.01). Tumor-specific immune responses were significantly enhanced (both p < 0.01) in the immunotherapy group. Baseline serum interleukin (IL)-15 was statistically correlated with RFS prolongation (HR, 0.16; 95% CI, 0.03–1.58; p = 0.001) within the immunotherapy groups. Overall adverse events were more frequent in the immunotherapy group (p < 0.001) but were mainly mild to moderate in severity. In conclusion, adjuvant immunotherapy with DC vaccine reduces the risk of tumor recurrence in HCC patients who underwent standard treatment modalities other than RFA. Baseline IL-15 might be a candidate biomarker for DC-based HCC immunotherapy.

Original language	English
Article number	e1328335
Journal	OncoImmunology
Volume	6
Issue number	7
DOIs	https://doi.org/10.1080/2162402X.2017.1328335
State	Published - 3 Jul 2017

Bibliographical note

Funding Information:
We thank the patients, physicians, nurses, trial coordinators, and pathologists who participated in this Phase II study of CreaVax-HCC at five academic hospitals. We acknowledge the members of the Data and Safety Monitoring Board (DSMB) for data monitoring, evaluation of interim analysis, and valuable criticism. We are grateful to personnel in the Medical Research Cooperating Center at Seoul National University Hospital (MRCC, http://mrcc.snuh.org) for their web-based randomization of enrolled patients according to the study design. We acknowledge Young-Jak Lee and his colleagues at LSK Global Pharma Services Co. Ltd for their study consulting, data monitoring and management, CRF development, statistical analysis, and CSR. We acknowledge Seung-Ho Hong, Jun-Eui Park, Jinah Jang, and research fellows at JW CreaGene Res. Institute for providing clinical grade CTP-attached HCC antigens, as well as Woo-Jeong Son and his colleagues who were involved in the production of DC vaccines and QC/QA at JW CreaGene Inc. This trial was funded by a Bio New Drug grant (HI11C0049, A110054) from the Ministry of Health & Welfare, Republic of Korea, and supported by JW CreaGene Inc. (Seongnam-si, Gyeonggi-do, Korea).

Publisher Copyright:
© 2017 Taylor & Francis Group, LLC.

Keywords

Adjuvant immunotherapy
biomarker
dendritic cell vaccine
hepatocellular carcinoma
recurrence-free survival

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1080/2162402X.2017.1328335

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title = "Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study",

abstract = "Our previous phase I/IIA study showed that autologous dendritic cells (DCs) pulsed with tumor-associated antigens are well tolerated in patients with hepatocellular carcinoma (HCC). In this randomized, multicenter, open-label, phase II trial, we investigated the efficacy and safety of this DC-based adjuvant immunotherapy with 156 patients, who treated for HCC with no evidence of residual tumor after standard treatment modalities. Patients were randomly assigned to immunotherapy (n = 77; injection of 3 × 107 DC cells, six times over 14 weeks) or control (n = 79; no treatment). The primary end point was recurrence-free survival (RFS), and the secondary endpoints were immune response and safety. The RFS between the immunotherapy and control groups was not significantly different (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.60–1.56; p = 0.90). However, post-hoc subgroup analyses revealed that DC immunotherapy significantly reduced the risk of tumor recurrence of non-radiofrequency ablation (non-RFA) group patients (n = 83, HR, 0.49; 95% CI, 0.26–0.94; p = 0.03), whereas unexpectedly increased the risk of recurrence in RFA group (n = 61, p = 0.01). Tumor-specific immune responses were significantly enhanced (both p < 0.01) in the immunotherapy group. Baseline serum interleukin (IL)-15 was statistically correlated with RFS prolongation (HR, 0.16; 95% CI, 0.03–1.58; p = 0.001) within the immunotherapy groups. Overall adverse events were more frequent in the immunotherapy group (p < 0.001) but were mainly mild to moderate in severity. In conclusion, adjuvant immunotherapy with DC vaccine reduces the risk of tumor recurrence in HCC patients who underwent standard treatment modalities other than RFA. Baseline IL-15 might be a candidate biomarker for DC-based HCC immunotherapy.",

keywords = "Adjuvant immunotherapy, biomarker, dendritic cell vaccine, hepatocellular carcinoma, recurrence-free survival",

author = "Lee, {Jeong Hoon} and Tak, {Won Young} and Yoon Lee and Heo, {Min Kyu} and Song, {Jae Sung} and Kim, {Hak Yeop} and Park, {Soo Young} and Bae, {Si Hyun} and Lee, {Joon Hyeok} and Jeong Heo and Kim, {Ki Hwan} and Bae, {Yong Soo} and Kim, {Yoon Jun}",

note = "Funding Information: We thank the patients, physicians, nurses, trial coordinators, and pathologists who participated in this Phase II study of CreaVax-HCC at five academic hospitals. We acknowledge the members of the Data and Safety Monitoring Board (DSMB) for data monitoring, evaluation of interim analysis, and valuable criticism. We are grateful to personnel in the Medical Research Cooperating Center at Seoul National University Hospital (MRCC, http://mrcc.snuh.org) for their web-based randomization of enrolled patients according to the study design. We acknowledge Young-Jak Lee and his colleagues at LSK Global Pharma Services Co. Ltd for their study consulting, data monitoring and management, CRF development, statistical analysis, and CSR. We acknowledge Seung-Ho Hong, Jun-Eui Park, Jinah Jang, and research fellows at JW CreaGene Res. Institute for providing clinical grade CTP-attached HCC antigens, as well as Woo-Jeong Son and his colleagues who were involved in the production of DC vaccines and QC/QA at JW CreaGene Inc. This trial was funded by a Bio New Drug grant (HI11C0049, A110054) from the Ministry of Health & Welfare, Republic of Korea, and supported by JW CreaGene Inc. (Seongnam-si, Gyeonggi-do, Korea). Publisher Copyright: {\textcopyright} 2017 Taylor & Francis Group, LLC.",

year = "2017",

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doi = "10.1080/2162402X.2017.1328335",

language = "English",

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T1 - Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study

AU - Lee, Jeong Hoon

AU - Tak, Won Young

AU - Lee, Yoon

AU - Heo, Min Kyu

AU - Song, Jae Sung

AU - Kim, Hak Yeop

AU - Park, Soo Young

AU - Bae, Si Hyun

AU - Lee, Joon Hyeok

AU - Heo, Jeong

AU - Kim, Ki Hwan

AU - Bae, Yong Soo

AU - Kim, Yoon Jun

N1 - Funding Information: We thank the patients, physicians, nurses, trial coordinators, and pathologists who participated in this Phase II study of CreaVax-HCC at five academic hospitals. We acknowledge the members of the Data and Safety Monitoring Board (DSMB) for data monitoring, evaluation of interim analysis, and valuable criticism. We are grateful to personnel in the Medical Research Cooperating Center at Seoul National University Hospital (MRCC, http://mrcc.snuh.org) for their web-based randomization of enrolled patients according to the study design. We acknowledge Young-Jak Lee and his colleagues at LSK Global Pharma Services Co. Ltd for their study consulting, data monitoring and management, CRF development, statistical analysis, and CSR. We acknowledge Seung-Ho Hong, Jun-Eui Park, Jinah Jang, and research fellows at JW CreaGene Res. Institute for providing clinical grade CTP-attached HCC antigens, as well as Woo-Jeong Son and his colleagues who were involved in the production of DC vaccines and QC/QA at JW CreaGene Inc. This trial was funded by a Bio New Drug grant (HI11C0049, A110054) from the Ministry of Health & Welfare, Republic of Korea, and supported by JW CreaGene Inc. (Seongnam-si, Gyeonggi-do, Korea). Publisher Copyright: © 2017 Taylor & Francis Group, LLC.

PY - 2017/7/3

Y1 - 2017/7/3

N2 - Our previous phase I/IIA study showed that autologous dendritic cells (DCs) pulsed with tumor-associated antigens are well tolerated in patients with hepatocellular carcinoma (HCC). In this randomized, multicenter, open-label, phase II trial, we investigated the efficacy and safety of this DC-based adjuvant immunotherapy with 156 patients, who treated for HCC with no evidence of residual tumor after standard treatment modalities. Patients were randomly assigned to immunotherapy (n = 77; injection of 3 × 107 DC cells, six times over 14 weeks) or control (n = 79; no treatment). The primary end point was recurrence-free survival (RFS), and the secondary endpoints were immune response and safety. The RFS between the immunotherapy and control groups was not significantly different (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.60–1.56; p = 0.90). However, post-hoc subgroup analyses revealed that DC immunotherapy significantly reduced the risk of tumor recurrence of non-radiofrequency ablation (non-RFA) group patients (n = 83, HR, 0.49; 95% CI, 0.26–0.94; p = 0.03), whereas unexpectedly increased the risk of recurrence in RFA group (n = 61, p = 0.01). Tumor-specific immune responses were significantly enhanced (both p < 0.01) in the immunotherapy group. Baseline serum interleukin (IL)-15 was statistically correlated with RFS prolongation (HR, 0.16; 95% CI, 0.03–1.58; p = 0.001) within the immunotherapy groups. Overall adverse events were more frequent in the immunotherapy group (p < 0.001) but were mainly mild to moderate in severity. In conclusion, adjuvant immunotherapy with DC vaccine reduces the risk of tumor recurrence in HCC patients who underwent standard treatment modalities other than RFA. Baseline IL-15 might be a candidate biomarker for DC-based HCC immunotherapy.

AB - Our previous phase I/IIA study showed that autologous dendritic cells (DCs) pulsed with tumor-associated antigens are well tolerated in patients with hepatocellular carcinoma (HCC). In this randomized, multicenter, open-label, phase II trial, we investigated the efficacy and safety of this DC-based adjuvant immunotherapy with 156 patients, who treated for HCC with no evidence of residual tumor after standard treatment modalities. Patients were randomly assigned to immunotherapy (n = 77; injection of 3 × 107 DC cells, six times over 14 weeks) or control (n = 79; no treatment). The primary end point was recurrence-free survival (RFS), and the secondary endpoints were immune response and safety. The RFS between the immunotherapy and control groups was not significantly different (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.60–1.56; p = 0.90). However, post-hoc subgroup analyses revealed that DC immunotherapy significantly reduced the risk of tumor recurrence of non-radiofrequency ablation (non-RFA) group patients (n = 83, HR, 0.49; 95% CI, 0.26–0.94; p = 0.03), whereas unexpectedly increased the risk of recurrence in RFA group (n = 61, p = 0.01). Tumor-specific immune responses were significantly enhanced (both p < 0.01) in the immunotherapy group. Baseline serum interleukin (IL)-15 was statistically correlated with RFS prolongation (HR, 0.16; 95% CI, 0.03–1.58; p = 0.001) within the immunotherapy groups. Overall adverse events were more frequent in the immunotherapy group (p < 0.001) but were mainly mild to moderate in severity. In conclusion, adjuvant immunotherapy with DC vaccine reduces the risk of tumor recurrence in HCC patients who underwent standard treatment modalities other than RFA. Baseline IL-15 might be a candidate biomarker for DC-based HCC immunotherapy.

KW - Adjuvant immunotherapy

KW - biomarker

KW - dendritic cell vaccine

KW - hepatocellular carcinoma

KW - recurrence-free survival

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DO - 10.1080/2162402X.2017.1328335

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AN - SCOPUS:85021416127

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VL - 6

JO - OncoImmunology

JF - OncoImmunology

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ER -

Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

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