Blocking T Cell Co-Stimulation Via CD70 As a Target for Gvhd in Allogeneic Stem Cell Transplantation (SCT)

Background: CD27 is expressed on naïve and early memory T cells and engages with CD70 on antigen presenting cells (APC). CD70 is also expressed on recently activated T cells where expression is mutually exclusive of CD27. The functional significance of the CD27-CD70 checkpoint on T cells and its potential manipulation in hemopoietic transplantation or CAR-T therapy is unclear. We studied the expression of CD27 and CD70 on T cells following allogeneic SCT where graft vs host disease (GvHD) remains a major clinical complication. Co-stimulatory molecule blockade is being investigated as a mechanism to prevent or treat patients with GvHD and the CD27-CD70 axis may represent one such unexplored opportunity.

Method: Blood samples were collected from patients who had undergone SCT at Queen Elizabeth Hospital, Birmingham. CD70 and CD27 expression was determined on CD4+ and CD8+ T cells isolated from peripheral blood at several time points post-allogeneic or autologous SCT. Expression of CD70 and chemokine receptors on T cells was also studied in skin biopsies of three patients with acute or chronic GvHD. The level of soluble CD27 was measured in the serum of patients collected two weeks post allogeneic or autologous transplant. In vitro CD70 blocking assays were carried out on PBMCs isolated from healthy volunteers.

Result: CD70 was expressed transiently on activated T cells very early after allogeneic SCT. Interestingly, only 5% of all T cells were CD70+ following autologous SCT compared to 36% post allogeneic SCT suggesting that CD70 expression is not driven primarily by homeostatic expansion. Of note, a significant increase in CD70+CD4+ T cells was seen in the peripheral blood of patients with GvHD whilst CCR4+CD70+CD8+ T cells were increased within GvHD skin. No correlation was seen between the number of CD27+ T cells and GvHD. Importantly, increased serum levels of soluble CD27 and enhanced CD70+ T cell reconstitution within blood at two weeks post-transplant were predictive of the subsequent development of GvHD. Blockade of CD27-CD70 co-stimulation with anti-CD70 antibody decreased T cell proliferation and IFN-ƴ production in-vitro.

Conclusion: These findings indicate that CD70 is upregulated on antigen-stimulated T cells and that its sustained expression may indicate antigen-specific alloreactive T cell activation post-allogeneic SCT. Blockade of the CD70-CD27 pathway therefore represents a potential strategy for prophylactic prevention or treatment of GvHD. Furthermore, based on these findings CD70 may be explored as a promising co-stimulatory molecule to enhance CAR-T cell expansion and cytotoxic activity.

Kinsella:TC biopharm: Other: Data Safety and Monitoring Board ; Therakos: Honoraria; Gilead: Research Funding. Moss:astrazeneca: Research Funding.