Top

Published in:

01-09-2019 | Solid Tumor | Original Article

Safety and efficacy of PD-1 blockade-activated multiple antigen-specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: a pooled analysis of two prospective trials

Authors: Lijun Liang, Yixuan Wen, Rong Hu, Lei Wang, Youyou Xia, Chenxi Hu, Yun Qiao, Xiaowei Geng, Ting Chen, Jiayan Fei, Kaiyuan Hui, Xiaodong Jiang

Published in: Cancer Immunology, Immunotherapy | Issue 9/2019

Abstract

Background

The lethal effects of multiple antigen-specific cellular therapy (MASCT) may be enhanced by blocking PD-1 in vitro and vascular endothelial growth factor receptor 2 inhibitor (apatinib). We analyzed the pooled data from our phase I/II trials to determine the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in advanced solid tumors.

Methods

Patients with advanced solid tumors received aMASCT alone (n = 32) or aMASCT plus apatinib (500 mg q.d., n = 38) after standard treatment. The safety profile was the primary end point. The secondary end points were antitumor response, progression-free survival (PFS), and overall survival (OS). The circulating T cells were quantified before and after aMASCT infusion.

Results

Treatment-related adverse events (AEs) occurred in 18/32 (56.3%) and 25/38 (65.8%) patients in the aMASCT and aMASCT plus apatinib groups, respectively. No serious AEs were reported, and apatinib did not increase immunotherapy-related toxicity. The objective response rate (34.2% and 18.8%) and PFS (median 6.0 and 4.5 months, P = 0.002) were improved in the aMASCT plus apatinib group compared with the aMASCT group; however, the OS was not improved (median 10.0 and 8.2 months, P = 0.098). Multivariate analyses indicated that two or more cycles of aMASCT treatment was an independent and favorable prognostic factor of PFS and OS. The circulating T cells increased and Tregs decreased in both groups after one cycle of aMASCT treatment.

Conclusions

Treatment with aMASCT plus apatinib was safe and effective for the management of advanced solid tumors.

Available only for authorised users

Liang L, Wen Y, Hui K, Jiang X (2019) Safety and efficacy of PD-1 blockade-activated multiple antigen specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: A pooled analysis of two prospective trials. ASCO Annual Meeting 2019. J Clin Oncol 37 (suppl; abstract e14014)

Khalil DN, Smith EL, Brentjens RJ, Wolchok JD (2016) The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol 13(5):273–290. https://doi.org/10.1038/nrclinonc.2016.25 CrossRefPubMedPubMedCentral

Kim JM, Chen DS (2016) Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol 27(8):1492–1504. https://doi.org/10.1093/annonc/mdw217 CrossRefPubMed

Teng MWL, Ngiow SF, Ribas A, Smyth MJ (2015) Classifying cancers based on T-cell infiltration and PD-L1. Can Res 75(11):2139–2145. https://doi.org/10.1158/0008-5472.can-15-0255 CrossRef

Yu H, Jove R (2004) The STATs of cancer–new molecular targets come of age. Nat Rev Cancer 4(2):97–105. https://doi.org/10.1038/nrc1275 CrossRefPubMed

Han Y, Wu Y, Yang C, Huang J, Guo Y, Liu L, Chen P, Wu D, Liu J, Li J, Zhou X, Hou J (2017) Dynamic and specific immune responses against multiple tumor antigens were elicited in patients with hepatocellular carcinoma after cell-based immunotherapy. J Transl Med 15(1):64. https://doi.org/10.1186/s12967-017-1165-0 CrossRefPubMedPubMedCentral

He Y, Guo Y, Chen J, Hu X, Li X, Kong Y, Zhang X, Zhou X, Liu L, Hou J (2018) Multiple antigen stimulating cellular therapy (MASCT) for hepatocellular carcinoma after curative treatment: a retrospective study. J Cancer 9(8):1385–1393. https://doi.org/10.7150/jca.23725 CrossRefPubMedPubMedCentral

Zhou Q, Munger ME, Highfill SL, Tolar J, Weigel BJ, Riddle M, Sharpe AH, Vallera DA, Azuma M, Levine BL, June CH, Murphy WJ, Munn DH, Blazar BR (2010) Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood 116(14):2484–2493. https://doi.org/10.1182/blood-2010-03-275446 CrossRefPubMedPubMedCentral

Poh SL, Linn YC (2016) Immune checkpoint inhibitors enhance cytotoxicity of cytokine-induced killer cells against human myeloid leukaemic blasts. Cancer Immunol Immunother 65(5):525–536. https://doi.org/10.1007/s00262-016-1815-8 CrossRefPubMed

10.

Chen CL, Pan QZ, Weng DS, Xie CM, Zhao JJ, Chen MS, Peng RQ, Li DD, Wang Y, Tang Y, Wang QJ, Zhang ZL, Zhang XF, Jiang LJ, Zhou ZQ, Zhu Q, He J, Liu Y, Zhou FJ, Xia JC (2018) Safety and activity of PD-1 blockade-activated DC-CIK cells in patients with advanced solid tumors. Oncoimmunology 7(4):e1417721. https://doi.org/10.1080/2162402X.2017.1417721 CrossRefPubMedPubMedCentral

11.

Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23(5):1011–1027. https://doi.org/10.1200/jco.2005.06.081 CrossRefPubMed

12.

Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, Liu W, Tong J, Liu Y, Xu R, Wang Z, Wang Q, Ouyang X, Yang Y, Ba Y, Liang J, Lin X, Luo D, Zheng R, Wang X, Sun G, Wang L, Zheng L, Guo H, Wu J, Xu N, Yang J, Zhang H, Cheng Y, Wang N, Chen L, Fan Z, Sun P, Yu H (2016) Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol 34(13):1448–1454. https://doi.org/10.1200/JCO.2015.63.5995 CrossRefPubMed

13.

Tian S, Quan H, Xie C, Guo H, Lu F, Xu Y, Li J, Lou L (2011) YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci 102(7):1374–1380. https://doi.org/10.1111/j.1349-7006.2011.01939.x CrossRefPubMed

14.

Scott LJ (2018) Apatinib: a review in advanced gastric cancer and other advanced cancers. Drugs 78(7):747–758. https://doi.org/10.1007/s40265-018-0903-9 CrossRefPubMed

15.

Liang L, Wang L, Zhu P, Xia Y, Qiao Y, Wu J, Zhuang W, Fei J, Wen Y, Jiang X (2018) A pilot study of apatinib as third-line treatment in patients with heavily treated metastatic colorectal cancer. Clin Colorectal Cancer. https://doi.org/10.1016/j.clcc.2018.02.011 CrossRefPubMed

16.

Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA (2010) Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Can Res 70(15):6171–6180. https://doi.org/10.1158/0008-5472.can-10-0153 CrossRef

17.

Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, Carbone DP, Gabrilovich DI (1998) Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 160(3):1224–1232PubMed

18.

Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, Jain RK (2011) Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 91(3):1071–1121. https://doi.org/10.1152/physrev.00038.2010 CrossRefPubMed

19.

Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, Lal P, Feldman MD, Benencia F, Coukos G (2014) Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 20(6):607–615. https://doi.org/10.1038/nm.3541 CrossRefPubMedPubMedCentral

20.

Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174. https://doi.org/10.1038/nri2506 CrossRefPubMedPubMedCentral

21.

Hu C, Jiang X (2017) The effect of anti-angiogenic drugs on regulatory T cells in the tumor microenvironment. Biomed Pharmacother 88:134–137. https://doi.org/10.1016/j.biopha.2017.01.051 CrossRefPubMed

22.

Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378(24):2288–2301. https://doi.org/10.1056/NEJMoa1716948 CrossRefPubMed

23.

Mo H, Huang J, Xu J, Chen X, Wu D, Qu D, Wang X, Lan B, Wang X, Xu J, Zhang H, Chi Y, Yang Q, Xu B (2018) Safety, anti-tumour activity, and pharmacokinetics of fixed-dose SHR-1210, an anti-PD-1 antibody in advanced solid tumours: a dose-escalation, phase 1 study. Br J Cancer. https://doi.org/10.1038/s41416-018-0100-3 CrossRefPubMedPubMedCentral

24.

Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine BL, June CH, Schuster SJ (2017) PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood 129(8):1039–1041. https://doi.org/10.1182/blood-2016-09-738245 CrossRefPubMedPubMedCentral

25.

Zhou Y, Tang F, Min L, Zhang W, Shi R, Luo Y, Duan H, Tu C (2017) A preliminary study of apatinib in Chinese patients with osteosarcoma. J Clin Oncol 35(15_suppl):e22500–e22500. https://doi.org/10.1200/jco.2017.35.15_suppl.e22500 CrossRef

26.

(2019) Institute NC surveillance, epidemiology, and end results program (SEER) cancer stat facts. https://seer.cancer.gov/statfacts/. Accessed 30 Mar 2019

27.

Jiang N, Qiao G, Wang X, Morse MA, Gwin WR, Zhou L, Song Y, Zhao Y, Chen F, Zhou X, Huang L, Hobeika A, Yi X, Xia X, Guan Y, Song J, Ren J, Lyerly HK (2017) Dendritic cell/cytokine-induced killer cell immunotherapy combined with S-1 in patients with advanced pancreatic cancer: a prospective study. Clin Cancer Res 23(17):5066–5073. https://doi.org/10.1158/1078-0432.CCR-17-0492 CrossRefPubMed

28.

Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, Korenstein D (2018) Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ 360:k793. https://doi.org/10.1136/bmj.k793 CrossRefPubMedPubMedCentral

29.

Deng W, Qin S, Li J, Wen L, Wang J, Zhang G, Zhong H, Yang J, Ba Y, Bai Y, Lin X, Wang M, Wang L, Liu L, He Y, Tao M, Xie C, Ye F, Wu X-y, Jia T (2018) Initial dose of apatinib in Chinese patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction in third- or later-line setting: 500 mg or 850 mg? J Clin Oncol 36(4_suppl):35. https://doi.org/10.1200/jco.2018.36.4_suppl.35 CrossRef

Title: Safety and efficacy of PD-1 blockade-activated multiple antigen-specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: a pooled analysis of two prospective trials
Authors: Lijun Liang
Yixuan Wen
Rong Hu
Lei Wang
Youyou Xia
Chenxi Hu
Yun Qiao
Xiaowei Geng
Ting Chen
Jiayan Fei
Kaiyuan Hui
Xiaodong Jiang
Publication date: 01-09-2019
Publisher: Springer Berlin Heidelberg
Keyword: Solid Tumor
Published in: Cancer Immunology, Immunotherapy / Issue 9/2019
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-019-02375-z

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 STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 9/2019

Melanoma-conditioned medium promotes cytotoxic immune responses by murine bone marrow-derived monocytes despite their expression of ‘M2’ markers

Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone

Morphomolecular analysis of the immune tumor microenvironment in human head and neck cancer

Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells

Independent expression of circulating and tissue levels of PD-L1: correlation of clusters with tumor metabolism and outcome in patients with non-small cell lung cancer

TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma

Keynote webinar | Spotlight on antibody–drug conjugates in cancer