Abstract
Immune checkpoint inhibitor therapies and allogeneic hematopoietic cell transplant (alloHCT) represent two distinct modalities that offer a chance for long-term cure in a diverse array of malignancies and have experienced many breakthroughs in recent years. Herein, we review the CD27-CD70 co-stimulatory pathway and its therapeutic potential in 1) combination with checkpoint inhibitor and other immune therapies and 2) its potential ability to serve as a novel approach in graft-versus-host disease (GVHD) prevention. We further review recent advances in the understanding of GVHD as a complex immune phenomenon between donor and host immune systems, particularly in the early stages with mixed chimerism, and potential novel therapeutic approaches to prevent the development of GVHD.
Highlights
Allogeneic hematopoietic cell transplant provides the greatest probability for long-term cure in many hematologic malignancies where few other effective therapeutic options exist
The role of persistent host T-cells mediating acute graft-versus-host disease (GVHD) by interaction with donor Antigen Presenting Cells (APCs) has been noted in murine models and in Allogeneic hematopoietic cell transplant (alloHCT) transplant patients with increased IFNg–secreting CD4+ T-cells in skin GVHD biopsies compared to healthy controls, as well as an increased monocyte population with upregulation of chemoattractant receptors and IFN-response genes (IFITM1 and GBP1) compared with healthy controls [77]
To better elucidate the mechanism of the CD27-CD70 pathway and its impact on GVHD pathogenesis, cytokines associated with GVHD were measured in CD70 knockout host mice which showed significantly higher levels of pro-inflammatory IFNg, TNFa, IL-2, and IL-17 when compared to WT mice [35]
Summary
Allogeneic hematopoietic cell transplant (alloHCT) provides the greatest probability for long-term cure in many hematologic malignancies where few other effective therapeutic options exist. In the limited clinical trials to date, the CD27 agonizing monoclonal antibody, varlilumab, as monotherapy and with PD1/ PDL1 checkpoint inhibitor therapy (nivolumab, atezolizumab), has resulted in varying degrees of objective clinical responses in a subset of cancer patients enrolled This has included complete remission in Hodgkin’s lymphoma and partial responses in ovarian, colorectal, and squamous cell cancer of the head and neck (see Table 1). The role of persistent host T-cells mediating acute GVHD by interaction with donor APCs has been noted in murine models and in alloHCT transplant patients with increased IFNg–secreting CD4+ T-cells in skin GVHD biopsies compared to healthy controls, as well as an increased monocyte population with upregulation of chemoattractant receptors and IFN-response genes (IFITM1 and GBP1) compared with healthy controls [77]. Renal Cell, Urogenital/Urologic varlilumab and Neoplasms, Melanoma, Triple negative atezolizumab breast cancer, Head and neck cancer, Nonsmall cell lung cancer
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