Safety and PK/PD of ALLO-647, an anti-CD52 antibody, with fludarabine (Flu)/cyclophosphamide (Cy) for lymphodepletion in the setting of allogeneic CAR-T cell therapy.
Authors: Michael Timothy Tees, Sattva Swarup Neelapu, Parameswaran Hari, Sham Mailankody, David Bernard Miklos, Frederick Lundry Locke, Rajneesh Nath, Sacha Leandra Prashad, Xiangdong Zhou, Eren Demirhan, Srinand Ponnathapura Nandakumar, Dennis Fisher, Gregory Opiteck, Ena Wang
Journal: Journal of Clinical Oncology (2021)

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/m 2 /d x 3d +/- Cy 300 mg/m 2 /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 &lt; 0.05x10 9 cells/L, typically by D-3. Duration of lymphodepletion was typically longer with HD ALLO-647. Median duration of T-cell suppression ( &lt; 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 &lt; 10 through D+28 in 17 pts and &gt; 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.