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2527 Background: Allogeneic chimeric antigen receptor (CAR) T cell therapy holds promise in addressing logistical/manufacturing challenges of autologous CAR T cell therapy. ALLO-501 (anti-CD19; uses Cellectis technologies) and ALLO-715 (anti-BCMA) are allogeneic CAR T cell products whose a) disrupted TCRα constant gene may reduce GvHD risk, and b) edited CD52 gene may permit use of ALLO-647 (a humanized anti-CD52 mAb) to selectively deplete host T cells. Methods: The ongoing ALPHA (ALLO-501) and UNIVERSAL (ALLO-715) trials include patients (pts) with relapsed/refractory large B-cell or follicular lymphoma and multiple myeloma, respectively. The lymphodepletion regimen included ALLO-647 (39 mg [low dose, LD; n = 33], 60 mg [n = 12], or 90 mg [high dose, HD; n = 27]) with Flu 30 mg/m2/d x 3d +/- Cy 300 mg/m2/d x 3d (Flu+Cy, n = 66; Cy, n = 6) (ALLO-647/Flu +/- Cy) before CAR T infusion. A mixed-effects population pharmacokinetic (PK) model was fit to ALLO-647 concentration vs. time data. Pharmacodynamic (PD) effects on host T cells, IL15, and CAR T cell expansion were also studied. Results: As of the data cut, 72 pts were treated. Common Grade ≥3 AEs were neutropenia (71%), thrombocytopenia (42%), anemia (39%), and lymphopenia (28%). Neutrophil, hemoglobin, and platelet counts did not differ by ALLO-647 dose, suggesting these dim-CD52+ cells were unaffected. Gr ≥3 infections were seen in 21% pts; 33 had infusion-related reactions (IRR; Gr 1: 13%; Gr 2: 32%; Gr 3: 1.4%). IRR incidence and severity were higher with HD ALLO-647. The optimal PK model included a saturable (concentration-dependent) elimination pathway; clearance varied as a function of baseline lymphocyte count (LC). Serum ALLO-647 levels increased with dose; median modelled Cmax was 4,224 and 14,139 ng/mL for LD and HD, respectively. With ALLO-647/Flu +/- Cy, all but 2 pts reached a LC nadir < 0.05x109 cells/L, typically by D-3. Duration of lymphodepletion was typically longer with HD ALLO-647. Median duration of T-cell suppression ( < 10 cells/µl) was ̃ 8.5 and 13.6 days from CAR T infusion, respectively, for LD and HD ALLO-647. With HD, T cell counts were < 10 through D+28 in 17 pts and > 10 in 2. In 68 evaluable pts, compared to LD, HD ALLO-647 was associated with higher D0 serum IL15 levels, which have been linked to improved clinical response (eg, Kochenderfer JCO 2017). Higher CAR T expansion was also observed post D+14 with HD ALLO-647 compared to LD, creating an opportunity for clinical response. Conclusions: ALLO-647/Flu +/- Cy had a tolerable safety profile and produced a deep and durable window of lymphocyte depletion. ALLO-647 exhibited target-mediated drug disposition; clearance increased with higher baseline LC. HD was associated with higher IL15 levels and better CAR T expansion, suggesting dose responses. Enrollment in both studies is ongoing; updated safety and PK/PD data will be presented. Clinical trial information: NCT04093596.

Summary Advances in pluripotent stem cell and reprogramming technologies have given us the hope of generating hematopoietic stem cells (HSCs) in culture. To succeed, greater understanding of the self-renewing HSC during human development is required. We discovered that the glycophosphatidylinositol-anchored surface protein GPI-80 defines a subpopulation of human fetal liver hematopoietic stem/progenitor cells (HSPCs) with self-renewal ability. CD34 + CD38 lo/− CD90 + GPI-80 + HSPCs were the sole population that maintained proliferative potential and an undifferentiated state in stroma coculture and engrafted in immunodeficient mice. GPI-80 expression also enabled tracking of HSPCs once they emerged from endothelium and migrated between human fetal hematopoietic niches. GPI-80 colocalized on the surface of HSPCs with Integrin alpha-M (ITGAM), which in leukocytes cooperates with GPI-80 to support migration. Knockdown of GPI-80 or ITGAM was sufficient to compromise HSPC expansion in culture and engraftment in vivo. These findings indicate that human fetal HSCs employ mechanisms used in leukocyte adhesion and migration to mediate HSC self-renewal.