Conditioning treatment with CD27 Ab enhances expansion and antitumor activity of adoptively transferred T cells in mice

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2022-01, Vol.71 (1), p.97-109
• Main Authors: Wasiuk, Anna, Weidlick, Jeff, Sisson, Crystal, Widger, Jenifer, Crocker, Andrea, Vitale, Laura, Marsh, Henry C., Keler, Tibor, He, Li-Zhen
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal, Humanized - pharmacology; Antitumor activity; Blocking antibodies; Cancer Research; CD27 antigen; CD27 Ligand - immunology; CD4-Positive T-Lymphocytes - cytology; CD70 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; Cell Line, Tumor; Cell Proliferation; Cell therapy; Chemotherapy; Cyclophosphamide; Fludarabine; Immune System; Immunology; Immunotherapy; Leukopenia; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neoplasms - metabolism; Neoplasms - therapy; Oncology; Original; Original Article; Signal Transduction; T-Lymphocytes - cytology; Transgenic mice; Transplantation Conditioning; Treatment Outcome; Tumor Necrosis Factor Receptor Superfamily, Member 7 - chemistry; Tumors
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-021-02958-9

Cyclophosphamide plus fludarabine (C/F) are currently used to improve the expansion and effectiveness of adoptive cell therapy (ACT). However, these chemotherapeutics cause pan-leukopenia and adverse events, suggesting that safer and more effective conditioning treatments are needed to improve ACT outcomes. Previously, we reported that varlilumab, a CD27-targeting antibody, mediates T reg -preferential T cell depletion, CD8-T cell dominant costimulation, and systemic immune activation in hCD27 transgenic mice and cancer patients. We reasoned that the activities induced by varlilumab may provide an effective conditioning regimen for ACT. Varlilumab pretreatment of h CD27 + / + m CD27 − /− mice resulted in prominent proliferation of transferred T cells isolated from wild-type mice. These studies uncovered a critical role for CD27 signaling for the expansion of transferred T cells, as transfer of T cells from CD27 deficient mice or treatment with a CD70 blocking antibody greatly reduced their proliferation. In this model, varlilumab depletes endogenous h CD27 + / + T cells and blocks their subsequent access to CD70, allowing for more CD70 costimulation available to the m CD27 + / + transferred T cells. CD27-targeted depletion led to a greater expansion of transferred T cells compared to C/F conditioning and resulted in longer median survival and more cures than C/F conditioning in the E.G7 tumor model receiving OT-I cell therapy. We propose that translation of this work could be achieved through engineering of T cells for ACT to abrogate varlilumab binding but preserve CD70 ligation. Thus, varlilumab could be an option to chemotherapy as a conditioning regimen for ACT.