Results of a Phase 1 Open Label Dose Escalation Trial of AB-205 (Allogeneic Engineered Endothelial Cell Therapy) in Adults with Lymphoma Undergoing High-Dose Therapy and Autologous Hematopoietic Cell Transplantation (HDT-AHCT)

Introduction: HDT-AHCT is a standard and potentially curative therapy for patients with high risk, chemosensitive lymphomas. Improvements in supportive care and HCT practices have led to increasing use of HDT-AHCT worldwide particularly in elderly and more comorbid patients at higher risk of complications. However, HDT is associated with severe regimen-related toxicities (SRRT) which lead to considerable symptom burden and in some cases, life-threatening organ toxicities. Moreover, the risk of SRRT is a significant concern and may lead to patients being denied a potentially curative therapy. Although SRRT can affect many organs, the most commonly affected are those with high cell turnover, including the hematopoietic system and oral-gastrointestinal tract (oral/GI tract). While the hematopoietic system is rescued by AHCT, there are no effective therapies to substantially reduce SRRT.

AB-205 is a novel experimental engineered-cell therapy intended to reduce SRRT associated with HDT-AHCT. AB-205 contains clinical-grade, allogeneic E4ORF1⁺ CD31⁺ umbilical vein endothelial cells, or 'universal' E-CEL® cells, and has been shown to accelerate the recovery of the vascular niches in various organs through autocrine and juxtacrine mechanisms of action on resident tissue capillary endothelial cells and resident progenitors in preclinical studies. It also has a beneficial effect in chaperoning exogenously administered stem cells.

Here we report results of a Phase I study of AB-205 in adults with lymphoma undergoing HDT-AHCT.

Methods: The primary objective is to assess the safety of AB-205. Secondary objectives include assessment of grade (G) ≥ 3 AEs (NCI-CTCAE v5.0), G ≥ 3 oral/GI SSRT (defined as oral mucositis (OM), nausea, vomiting and diarrhea) and time to neutrophil and platelet engraftment. Subjects with chemosensitive lymphomas who are eligible for HDT-AHCT using myeloablative conditioning regimens were enrolled.

Three dose-levels have been tested: 5, 10 and 20 x 10⁶ cells/kg. AB-205 is administered intravenously after and on the same day (D) as AHCT. The highest level (20x10⁶ cells/kg) was given either as single dose on D0 or split into equal doses on D0 and D2.

Results: As of 9^th July, 2020, 31 subjects had been treated with AB-205. Median follow-up was 132 D (range, 3-352). 24 subjects had systemic lymphoma (6 HL, 18 NHL) and were treated with BEAM, BeEAM or CBV. 7 subjects had lymphoma with CNS involvement (5 primary CNS lymphoma) and were treated with TBC. Median (range) lines of prior therapy was 2 (1-4) and 1 (1-4) for the groups respectively. Median infused CD34⁺ dose was 4.74 x 10⁶ cells/kg (range: 2.00, 8.38).

No maximum tolerated dose has been established through dosing up to 20 x 10⁶ cells/kg. One DLT, prolonged thrombocytopenia (D32), occurred with 10 x 10⁶ cells/kg. Treatment emergent AEs were consistent with those expected in subjects undergoing HDT-AHCT. At the time of last follow-up, one subject with primary CNS lymphoma died after cognitive decline (D166) and one subject had disease relapse (D101).

AB-205 therapy was associated with low rates of G ≥3 oral/GI SRRT (Table 1). Effects were most pronounced among subjects with systemic lymphoma who had no (0%) G ≥3 nausea, vomiting, or diarrhea at any dose level, and only one subject (4%) with G3 OM (at the 10 x 10⁶ cells/kg dose level). No G ≥3 oral/GI SRRTs have been reported in systemic lymphoma in 13 subjects who received 20 x 10⁶ cells/kg (single or split dose). No other G ≥3 SRRT such as nephritis, pneumonitis or carditis was observed.

In addition to dose dependent reduction of oral/GI SRRT, a trend for a dose dependent decrease in the incidence of febrile neutropenia (FN) was observed (Table 1).

Median (IQR) time to neutrophil and platelet engraftment was 10 D (9-11) and 11 D (9-13) respectively. In 21 (68%) subjects, platelet engraftment occurred prior to or within 1 day of neurophil engraftment.

Conclusion: AB-205 appears to be safe and potentially effective in subjects undergoing HDT-AHCT for lymphoma. Compared to published rates of 24-41% for G ≥3 OM (Singer 2019; Colita 2109) and 86% for FN (Caimi 2105) in subjects with systemic lymphoma, we observed 0% SRRT and 31% FN with the highest dose of AB-205 tested. AB-205 has significant potential to address a serious unmet medical need in patients undergoing HDT-AHCT and will be assessed in a forthcoming pivotal, double-blinded, placebo-controlled, randomized clinical trial for potential registration.

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