Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers

Abstract

Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSC), early progenitor cells, immature thymocytes, and steady state dendritic cells (DC) and induces their proliferation, differentiation, development and mobilization in the bone marrow, peripheral blood, and lymphoid organs. CDX-301 has an identical amino acid sequence and comparable biologic activity as the previously-tested rhuFlt3L which had discontinued clinical development over a decade ago. This Phase 1 trial assessed the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301, explored alternate dosing regimens and examined the impact of rhuFlt3L on key immune cell subsets. Thirty healthy volunteers received CDX-301 (1–75 μg/kg/day) over 5–10 days. One event of Grade 3 community acquired pneumonia occurred. There were no other infections, DLTs, or SAEs. CDX-301 resulted in effective peripheral expansion of monocytes, hematopoietic stem and progenitor cells, and key subsets of myeloid DC and plasmacytoid DC, with no clear effect on regulatory T cells. These data from healthy volunteers support the potential for CDX-301, as monotherapy or in combination with other agents, in various indications including allogeneic HSC transplantation and immunotherapy, but the effects of CDX-301 will need to be investigated in each of these patient populations.

Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival

“…29 Of note, a recombinant human Flt3L has recently shown to be safe and effective for PBSC mobilization in healthy donors. 39 In conclusion, our study shows that the dose of iNKTs in a G-CSF-mobilized PBSC graft is associated with improved GPFS, highlighting the beneficial role of iNKTs on the usually antagonistic GVHD and GVT effects. However, confirmatory studies on larger numbers of patients are required to confirm this beneficial role and to decipher the respective GVT effect of iNKTs on both myeloid and lymphoid malignancies.…”

Thymic Mesenchymal Cells Have a Distinct Transcriptomic Profile

“…5A). Indeed, these three genes code for molecules implicated in the extravasation of thymus-seeding progenitors across corticomedullary junction venules and the expansion of early thymocyte progenitors (ETP) (43)(44)(45). From the analysis of cluster #1, we therefore conclude that thymic MCs show higher expression of genes instrumental in clearance of apoptotic thymocytes by macrophages, maintenance of a noninflammatory milieu, and attraction-expansion of ETPs.…”

Plasmacytoid dendritic cells in allogeneic hematopoietic cell transplantation: benefit or burden?

“…6,49 Experience using FL in the allogeneic HCT setting is largely limited to pre-clinical studies in which FL has been shown to modulate GvHD 50,51 and to augment thympoiesis and T-cell reconstitution 52 to confer protective antiviral immunity 53 in mice and to enhance donor HSC engraftment in dogs. 54 Of interest, comparing PB murine LSK (Lin − Sca-1 + c-kit + ) HSC mobilization following administration of G alone, FL alone, P alone, FL+P and G+P, He et al 55 recently showed that FL+P mobilized the most LSK cells, which produced more colony-forming units and expanded the greatest numbers of PB NK, Treg and conventional and plasmacytoid DCs.…”

“…Recombinant human FL alone 49 or in combination with perixafor 55 is emerging as an alternative HSC mobilization regimen to G following chemotherapy. Given its NK and DC induction, recombinant human FL may offer a novel means to enhance both HSC and pDC expansion and to augment innate immune recovery and associated antiviral and antitumor response.…”