Human Effectors of Acute and Chronic GVHD Overexpress CD83 and Predict Mortality

Abstract

Purpose: Acute and chronic graft versus host disease (GVHD) remain major causes of transplant-related morbidity and mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). We have shown CD83 chimeric antigen receptor (CAR) T cells prevent GVHD and kill myeloid leukemia cells lines. In this pilot study we investigate CD83 expression on GVHD effector cells, correlate these discoveries with clinical outcomes, and evaluate critical therapeutic implications for transplant recipients. Experimental Design: CD83 expression was evaluated among circulating CD4+ T cells, B cell subsets, T follicular helper (Tfh) cells, and monocytes from patients with/without acute or chronic GVHD (n=48 for each group), respectively. CD83 expression was correlated with survival, TRM, and relapse after alloHCT. Differential effects of GVHD therapies on CD83 expression was determined. Results: CD83 overexpression on CD4+ T cells correlates with reduced survival and increased TRM. Increased CD83+ B cells and Tfh, but not monocytes, are associated with poor post transplant survival. CD83 CAR T eliminate autoreactive CD83+ B cells isolated from patients with chronic GVHD, without B cell aplasia as observed with CD19 CAR T. We demonstrate robust CD83 antigen density on human acute myeloid leukemia (AML), and confirm potent antileukemic activity of CD83 CAR T in vivo, without observed myeloablation. Conclusions: CD83 is a promising diagnostic marker of GVHD and warrants further investigation as a therapeutic target of both GVHD and AML relapse after alloHCT.

Phase II Study of Myeloablative 8/8- or 7/8-Matched Allotransplantation with Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil: Marked Reduction in GVHD Risk Without Increased Relapse Risk Compared to Historical Cyclosporine/Methotrexate

“…Shared targets of GVHD and malignancy exist, such as CD83, which could be exploited to control both alloreactivity and enhance GVL in future studies. 20 In summary, a GVHD prophylaxis regimen of PTCy/Tac/MMF shows significantly better acute and chronic GVHD control, without an increase in relapse risk, compared to historical CSA/MTX in well-matched MAC transplantation. The benefit of GVHD control is highest in adults.…”

“…Shared targets of GVHD and malignancy exist, such as CD83, which could be exploited to control both alloreactivity and enhance GVL in future studies. 20…”

Are we ready for personalized CAR‐T therapy?

“…Importantly, testing of such a modified product before releasing it for clinical use must include detection of the remaining CAR4 NK‐92, as they can cause T‐cell depletion after infusion. Interestingly, Holtan et al 61 in a myeloid leukemia cell line model demonstrated that anti‐CD83 CAR‐T prevented GvHD by eliminating autoreactive CD83+ B cells, whose overexpression is an adverse prognostic factor.…”

“…Strategies to overcome GvHD and alloimmunity [51][52][53][54][55][56][57][58][59][60][61][62]. CAR, chimeric antigen receptor; HLA, human leukocyte antigens; TCR, T-cell receptor.…”

Broadening the horizon: potential applications of CAR-T cells beyond current indications

“…Using CAR-T cells to “bridge” the time towards allo-HSCT or in patients ineligible for allo-HSCT could help enhancing their usability in AML patients ( 188 , 189 ). Anti-CD83 CAR-T cells even have the potential to be used in GvHD or AML relapse after allo-HSCT ( 190 ). Similarly, the combination with other pharmaceuticals might prove to be another therapeutic pathway ( 191 , 192 ).…”