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Combination Therapy with NHS-muIL12 and Avelumab (anti-PD-L1) Enhances Antitumor Efficacy in Preclinical Cancer Models.

Publication ,  Journal Article
Xu, C; Zhang, Y; Rolfe, PA; Hernández, VM; Guzman, W; Kradjian, G; Marelli, B; Qin, G; Qi, J; Wang, H; Yu, H; Tighe, R; Lo, K-M; English, JM ...
Published in: Clinical cancer research : an official journal of the American Association for Cancer Research
October 2017

Purpose: To determine whether combination therapy with NHS-muIL12 and the anti-programmed death ligand 1 (PD-L1) antibody avelumab can enhance antitumor efficacy in preclinical models relative to monotherapies.Experimental Design: BALB/c mice bearing orthotopic EMT-6 mammary tumors and μMt- mice bearing subcutaneous MC38 tumors were treated with NHS-muIL12, avelumab, or combination therapy; tumor growth and survival were assessed. Tumor recurrence following remission and rechallenge was evaluated in EMT-6 tumor-bearing mice. Immune cell populations within spleen and tumors were evaluated by FACS and IHC. Immune gene expression in tumor tissue was profiled by NanoString® assay and plasma cytokine levels were determined by multiplex cytokine assay. The frequency of tumor antigen-reactive IFNγ-producing CD8+ T cells was evaluated by ELISpot assay.Results: NHS-muIL12 and avelumab combination therapy enhanced antitumor efficacy relative to either monotherapy in both tumor models. Most EMT-6 tumor-bearing mice treated with combination therapy had complete tumor regression. Combination therapy also induced the generation of tumor-specific immune memory, as demonstrated by protection against tumor rechallenge and induction of effector and memory T cells. Combination therapy enhanced cytotoxic NK and CD8+ T-cell proliferation and T-bet expression, whereas NHS-muIL12 monotherapy induced CD8+ T-cell infiltration into the tumor. Combination therapy also enhanced plasma cytokine levels and stimulated expression of a greater number of innate and adaptive immune genes compared with either monotherapy.Conclusions: These data indicate that combination therapy with NHS-muIL12 and avelumab increased antitumor efficacy in preclinical models, and suggest that combining NHS-IL12 and avelumab may be a promising approach to treating patients with solid tumors. Clin Cancer Res; 23(19); 5869-80. ©2017 AACR.

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Published In

Clinical cancer research : an official journal of the American Association for Cancer Research

DOI

EISSN

1557-3265

ISSN

1078-0432

Publication Date

October 2017

Volume

23

Issue

19

Start / End Page

5869 / 5880

Related Subject Headings

  • Recombinant Fusion Proteins
  • Programmed Cell Death 1 Receptor
  • Oncology & Carcinogenesis
  • Neoplasm Recurrence, Local
  • Mice
  • Lymphocyte Activation
  • Interleukin-12
  • Immunotherapy
  • Immunoglobulin G
  • Humans
 

Citation

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Xu, C., Zhang, Y., Rolfe, P. A., Hernández, V. M., Guzman, W., Kradjian, G., … Lan, Y. (2017). Combination Therapy with NHS-muIL12 and Avelumab (anti-PD-L1) Enhances Antitumor Efficacy in Preclinical Cancer Models. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 23(19), 5869–5880. https://doi.org/10.1158/1078-0432.ccr-17-0483
Xu, Chunxiao, Yanping Zhang, P Alexander Rolfe, Vivian M. Hernández, Wilson Guzman, Giorgio Kradjian, Bo Marelli, et al. “Combination Therapy with NHS-muIL12 and Avelumab (anti-PD-L1) Enhances Antitumor Efficacy in Preclinical Cancer Models.Clinical Cancer Research : An Official Journal of the American Association for Cancer Research 23, no. 19 (October 2017): 5869–80. https://doi.org/10.1158/1078-0432.ccr-17-0483.
Xu C, Zhang Y, Rolfe PA, Hernández VM, Guzman W, Kradjian G, et al. Combination Therapy with NHS-muIL12 and Avelumab (anti-PD-L1) Enhances Antitumor Efficacy in Preclinical Cancer Models. Clinical cancer research : an official journal of the American Association for Cancer Research. 2017 Oct;23(19):5869–80.
Xu, Chunxiao, et al. “Combination Therapy with NHS-muIL12 and Avelumab (anti-PD-L1) Enhances Antitumor Efficacy in Preclinical Cancer Models.Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, vol. 23, no. 19, Oct. 2017, pp. 5869–80. Epmc, doi:10.1158/1078-0432.ccr-17-0483.
Xu C, Zhang Y, Rolfe PA, Hernández VM, Guzman W, Kradjian G, Marelli B, Qin G, Qi J, Wang H, Yu H, Tighe R, Lo K-M, English JM, Radvanyi L, Lan Y. Combination Therapy with NHS-muIL12 and Avelumab (anti-PD-L1) Enhances Antitumor Efficacy in Preclinical Cancer Models. Clinical cancer research : an official journal of the American Association for Cancer Research. 2017 Oct;23(19):5869–5880.

Published In

Clinical cancer research : an official journal of the American Association for Cancer Research

DOI

EISSN

1557-3265

ISSN

1078-0432

Publication Date

October 2017

Volume

23

Issue

19

Start / End Page

5869 / 5880

Related Subject Headings

  • Recombinant Fusion Proteins
  • Programmed Cell Death 1 Receptor
  • Oncology & Carcinogenesis
  • Neoplasm Recurrence, Local
  • Mice
  • Lymphocyte Activation
  • Interleukin-12
  • Immunotherapy
  • Immunoglobulin G
  • Humans