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Evaluation of therapeutic targeting of CCR7 in acute graft-versus-host disease

Bone Marrow Transplantation volume 55, pages 1935–1945 (2020)Cite this article

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Abstract

Graft-versus-host disease (GVHD) is the main complication after allogeneic hematopoietic stem cell transplantation. We previously unveiled a correlation between proportions of C-C motif chemokine receptor 7 (CCR7)+ T cells in the apheresis and the risk of developing GVHD. We wanted to evaluate in vivo whether apheresis with low proportion of CCR7+ cells or treatment with an anti-human CCR7 monoclonal antibody (mAb) were suitable strategies to prevent or treat acute GVHD in preclinical xenogeneic models. Therapeutic anti-CCR7 mAb was the most effective strategy in both prophylactic and therapeutic settings where antibody drastically reduced in vivo lymphoid organ infiltration of donor CCR7+ T cells, extended lifespan and solved clinical signs. The antibody neutralized in vitro migration of naïve and central memory T cells toward CCR7 ligands and depleted target CCR7+ subsets through complement activation. Both mechanisms of action spared CCR7− subsets, including effector memory and effector memory CD45RA+ T cells which may mediate graft versus leukemia effect and immunity against infections. Accordingly, the numbers of donor CCR7+ T cells in the apheresis were not associated to cytomegalovirus reactivation or the recurrence of the underlying disease. These findings provide a promising new strategy to prevent and treat acute GVHD, a condition where new specific, safety and effective treatment is needed.

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Fig. 1: Engraftment of low proportions of CD4+CCR7+ cells does not prevent aGVHD development.
Fig. 2: Mechanisms of action of a neutralizing anti-CCR7 antibody.
Fig. 3: Proportion of infused CCR7+ T-cells subpopulations in the apheresis does not correlate with CMV reactivation or relapse rates.
Fig. 4: In vivo proofs of concept.

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Acknowledgements

Funding for this work was by a grant PI018/01163 from the Fondo de Investigaciones Sanitarias, Instituto de Investigación Carlos III, Ministerio de Sanidad y Consumo, Spain, to CMC who also was cofinanced by FEDER funds. CCM was supported by RTC-2015-3318-1 (Ministerio de Economía y Competitividad, Spain). MLT was granted by SAF2016-75442-R (Agencia Estatal de Investigación/European Regional Development Fund, European Union, Spain). We thank Lawrence Baron for linguistic and grammatical editing of the manuscript.

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  1. These authors contributed equally: Carlos Cuesta-Mateos, Itxaso Portero-Sainz

Authors and Affiliations

  1. Department of Immunology, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de La Princesa, Madrid, Spain

    Carlos Cuesta-Mateos, Itxaso Portero-Sainz, Raquel Juárez-Sánchez, Yaiza Pérez-García, Tamara Mateu-Albero, Paula Díaz-Fernández, Blanca A. Sánchez-López, Ana Marcos-Jiménez & Cecilia Muñoz-Calleja

  2. Immunological and Medicinal Products S.L. (IMMED), Madrid, Spain

    Carlos Cuesta-Mateos & Raquel Juárez-Sánchez

  3. Centro de Biología Molecular Severo Ochoa (CBM-SO), Madrid, Spain

    Marina García-Peydró, Juan Alcain, Patricia Fuentes & María Luisa Toribio

  4. Methodology Unit, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de La Princesa, Madrid, Spain

    Lorena Vega-Piris

  5. Department of Microbiology, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de La Princesa, Madrid, Spain

    Laura Cardeñoso

  6. Department of Hematology, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de La Princesa, Madrid, Spain

    Valle Gómez-García de Soria

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Correspondence to Cecilia Muñoz-Calleja.

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CCM declares that he is an employee of Immunological and Medical Products (IMMED S.L.), Madrid, Spain. CMC is a consultant of IMMED S.L., has a granted patent for the use of therapeutic antibodies targeting CCR7 in cancer and has received research funds from IMMED.S.L. The other authors declare that they have no competing interests.

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Cuesta-Mateos, C., Portero-Sainz, I., García-Peydró, M. et al. Evaluation of therapeutic targeting of CCR7 in acute graft-versus-host disease. Bone Marrow Transplant 55, 1935–1945 (2020). https://doi.org/10.1038/s41409-020-0830-8

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