Dilanubicel, a Non-HLA-Matched Pooled Universal Product, Transforming Single Cord Blood Transplantation Success Rates

Background: Recent clinical data has demonstrated that the use of 3^rd party donor granulocyte transfusions was associated with donor CD8⁺ T cell expansion and remission induction in patients with relapsed acute myeloid leukemia (AML) undergoing cord blood transplant (CBT) (Hiwarker P, 2020; Borrill R, 2023). Further, accessibility to CBT will be improved by strategies that eliminate the need for a second CB unit without increasing risk to patients. Dilanubicel, a cryopreserved non-HLA-matched expanded progenitor cell product has been shown to be safe, to contribute to early myelomonocytic recovery, and is also known to contain antigen presenting cells. Thus, the addition of dilanubicel, as an adjuvant, 3^rd party donor transient graft, was explored to obviate the need for a second CB unit and to enhance graft-vs-leukemia.

Methods: From March ‘22 to June ‘24, 15 patients with hematologic malignancies were enrolled in a single center Phase II trial to assess safety of dilanubicel to augment conventional single CBT. Patients received conditioning with either FLU 75mg/m2, TBI 13.2 Gy, CY120 mg/kg (n=8) or with FLU 150mg/m2, TBI 4Gy, CY 50 mg/kg and Thiotepa 10 mg/kg (n=7). Per accepted criteria, CB units had to be at least 4/6 HLA-matched to the patient while dilanubicel was used off-the-shelf with no HLA matching required. The CB unit selected for transplant had to have a minimum of 2.5 x 10⁷ TNC/kg and 1.7 x 10⁵ CD34/kg. The single unmanipulated CB unit was infused first followed 4 hours later by infusion of dilanubicel which contained a total of 800x10⁶ CD34+ cells derived from the expansion of CD34+ cells pooled from 6-8 CB units. Donor/host chimerism studies were performed weekly from day 7 to 28, then at days 80, 180 and 1-year post-HCT on peripheral blood flow sorted into myeloid and lymphoid fractions. Graft versus host disease (GVHD) prophylaxis consisted of Cyclosporine and Mycophenolate Mofetil.

Results: With a median follow-up of 12 months (range, 6-26), all patients but one received dilanubicel. Eight patients (53%) were male and 6 were (40%) ethnic minorities. The median age was 33 years (range, 10-63) and weight 73 kg (range, 46-115). All patients had acute leukemias (AML=8, ALL=6, MPAL=1) and 4 (26%) had minimal residual disease pre-HCT. Most (n=11) received a 4/6 HLA-matched CB unit. The median infused TNCx10⁷ and CD34x10⁵ per Kg was 3.38 (range, 2.5-5.8) and 2.43 (range, 1.7-4.3), respectively. All patients engrafted neutrophils (ANC) at a median of 18 days (range, 14-27) and platelets (>20 x 10^9/L) at 31 days (range, 26–42). Early (day 7) myelomonocytic (CD33 and CD14) recovery was entirely derived from dilanubicel and no longer present by day 14. Of note, early lymphocyte cell expansion was observed in all patients starting on day +8 or +9 (median 880 with a range of 100 to 1316 per microliter), which was both transient and preceding ANC recovery. Concurrent chimerism analysis showed that the lymphocyte burst derived exclusively from the unmanipulated CB unit. To date, all patients are alive and in remission. No cases of relapse or transplant-related mortality were observed. Infusion of a non-HLA matched pooled donor derived product was not associated with increased GVHD with no cases of grade III-IV GVHD and chronic GVHD observed.

Conclusion: The addition of dilanubicel in the setting of single CBT was safe and resulted in excellent clinical outcomes. As an allogeneic and off-the-shelf cell therapy that does not require donor-recipient matching, dilanubicel is readily accessible on demand and easily adopted into standard CBT. With a significant follow-up, the observation of no relapses may be related to the infusion of 3^rd party donor APCs for presentation of MHC and activation of donor T cell responses. These promising results warrant further biological investigations and evaluation in a larger study.