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Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune–Tumor Interactions: Engage, Expand, Enable

Kellsye P. Fabian, Anthony S. Malamas, Michelle R. Padget, Kristen Solocinski, Benjamin Wolfson, Rika Fujii, Houssein Abdul Sater, Jeffrey Schlom and James W. Hodge
Kellsye P. Fabian
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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  • ORCID record for Kellsye P. Fabian
Anthony S. Malamas
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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Michelle R. Padget
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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Kristen Solocinski
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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Benjamin Wolfson
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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Rika Fujii
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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Houssein Abdul Sater
2Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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Jeffrey Schlom
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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James W. Hodge
1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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  • For correspondence: jh241d@nih.gov
DOI: 10.1158/2326-6066.CIR-20-0638 Published February 2021
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Abstract

Immunotherapy of immunologically cold solid tumors may require multiple agents to engage immune effector cells, expand effector populations and activities, and enable immune responses in the tumor microenvironment (TME). To target these distinct phenomena, we strategically chose five clinical-stage immuno-oncology agents, namely, (i) a tumor antigen–targeting adenovirus-based vaccine (Ad-CEA) and an IL15 superagonist (N-803) to activate tumor-specific T cells, (ii) OX40 and GITR agonists to expand and enhance the activated effector populations, and (iii) an IDO inhibitor (IDOi) to enable effector-cell activity in the TME. Flow cytometry, T-cell receptor (TCR) sequencing, and RNA-sequencing (RNA-seq) analyses showed that in the CEA-transgenic murine colon carcinoma (MC38-CEA) tumor model, Ad-CEA + N-803 combination therapy resulted in immune-mediated antitumor effects and promoted the expression of costimulatory molecules on immune subsets, OX40 and GITR, and the inhibitory molecule IDO. Treatment with Ad-CEA + N-803 + OX40 + GITR + IDOi, termed the pentatherapy regimen, resulted in the greatest inhibition of tumor growth and protection from tumor rechallenge without toxicity. Monotherapy with any of the agents had little to no antitumor activity, whereas combining two, three, or four agents had minimal antitumor effects. Immune analyses demonstrated that the pentatherapy combination induced CD4+ and CD8+ T-cell activity in the periphery and tumor, and antitumor activity associated with decreased regulatory T-cell (Treg) immunosuppression in the TME. The pentatherapy combination also inhibited tumor growth and metastatic formation in 4T1 and LL2-CEA murine tumor models. This study provides the rationale for the combination of multimodal immunotherapy agents to engage, enhance, and enable adaptive antitumor immunity.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2021;9:239–52

  • Received July 27, 2020.
  • Revision received October 23, 2020.
  • Accepted December 7, 2020.
  • Published first December 22, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 9 (2)
February 2021
Volume 9, Issue 2
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Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune–Tumor Interactions: Engage, Expand, Enable
Kellsye P. Fabian, Anthony S. Malamas, Michelle R. Padget, Kristen Solocinski, Benjamin Wolfson, Rika Fujii, Houssein Abdul Sater, Jeffrey Schlom and James W. Hodge
Cancer Immunol Res February 1 2021 (9) (2) 239-252; DOI: 10.1158/2326-6066.CIR-20-0638

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Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune–Tumor Interactions: Engage, Expand, Enable
Kellsye P. Fabian, Anthony S. Malamas, Michelle R. Padget, Kristen Solocinski, Benjamin Wolfson, Rika Fujii, Houssein Abdul Sater, Jeffrey Schlom and James W. Hodge
Cancer Immunol Res February 1 2021 (9) (2) 239-252; DOI: 10.1158/2326-6066.CIR-20-0638
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