SMART101 Donor T-Lymphoid Progenitors to Accelerate Immune Reconstitution Post HLA Mismatched Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide: Reset-02 First-in-Human Phase I/II

Background and Significance

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for many patients with hematological malignancies. In absence of an HLA-matched donor, the use of post-transplant cyclophosphamide in unmanipulated HLA mismatched HSCT (PTCy HSCT) is the favored strategy. However, in vivo T-cell depletion with PTCy significantly impairs immune reconstitution, resulting in higher infection-related mortality and relapse rate.

SMART101 is a cell therapy using allogeneic CD7+ T-lymphoid progenitors (TLP) produced in culture from mobilized peripheral blood CD34+ cells via Smart Immune’s GMP manufacturing process. This ex vivo lymphoid niche culture system uses Notch ligand Delta-like 4 coupled to IgG2 Fc fragment (DLL4-Fc), RetroNectin® and a specific combination of cytokines, mimicking the initial steps of bone marrow T-cell differentiation.

Aims

The ReSET-02 clinical study (NCT05768035) seeks to provide proof of concept that SMART101 cells can rapidly complete their differentiation within patient’s thymus into T cells, improving the immune recovery by accelerating the production of polyclonal donor T-cells, and thus reduce the non-relapse and disease relapse mortality post HLA mismatched (haploidentical or MUD 9/10) PTCy HSCT.

Study Design and Methods

This first-in-human, open-label, randomized, multicenter phase I/II study will evaluate the safety and activity of a single infusion of SMART101 post-HSCT in adult patients with AML, ALL or high-risk MDS eligible for an HLA mismatched PTCy HSCT as standard of care.

The study will comprise two segments: (i) a phase I dose-escalation segment evaluating three prespecified dose-levels of SMART101 to define the SMART101 RecD, and (ii) a randomized phase II segment including 2 arms of patients. Patients will be randomized to receive SMART101 after HSCT (SMART101 arm) or as per standard of care with HSCT (SoC; control arm). The randomization will be in a 2:1 ratio and will be stratified by type of standard of care conditioning regimen (myeloablative or of reduced intensity). The primary endpoint in segment 1 is the occurrence of unexpected unacceptable toxicity within 28 days after the infusion of SMART101. In segment 2 randomized setting, the key endpoints are immune reconstitution (IR) (CD4+ T cells and naïve CD4+ T cells ≥ 50/μL by D100); overall safety profile, especially the occurrence of severe GvHD, the incidence of non-relapse/relapse mortality, and overall survival.

Preliminary data

11 patients (8 females, 3 males) were included and treated in 4 sites in EU. The median age was 67 years old [range: 54-70]. Diagnoses were acute myeloid leukemia (10) and myelodysplastic syndrome (1). All patients received a haploidentical HSCT with reduced intensity conditioning and GvHD prophylaxis post-HSCT with cyclophosphamide at D3, 4 and sirolimus ±MMF. Median transplanted CD34+ cells dose was 6.4x10⁶ cells/kg. All patients received SMART101 post HSCT between D6 and D10. SMART101 was produced from CD34+ from the same donor as the HSCT. 4 patients were treated at the dose level 1 (1.5 x 10⁶ CD7+ cells/kg of body weight); 5 patients were treated at the dose level 2 (4.5 x 10⁶ CD7+ cells/kg of body weight) and 2 patients at the dose level 3 (9 x 10⁶ CD7+ cells/kg of body weight).

Median follow-up was 4 months [range: 0.5-11]. The median time to neutrophil engraftment was 21 days [range: 16-36]. No primary graft failure occurred. No unexpected unacceptable toxicity (UUT), no severe acute GvHD, no AE related to SMART101 were reported showing an excellent tolerability and safety profile of SMART101 in patients enrolled so far.

The preliminary data of IR is very promising in patients treated with the intermediate dose and high doses of SMART101. A peak of CD4+ cells above 200 CD4+/µl [range: 215-408] at D60 was observed suggesting a dose-effect of the product. In addition, the preliminary analysis of the TCR repertoire early post-HSCT showed a polyclonality of the T cells compartment indicating a good immune recovery.

Conclusion

SMART101 is the first-generation of allogeneic TLP cell therapy obtained from Smart Immune’s proprietary GMP manufacturing platform. The preliminary data showed excellent safety and tolerability of the product without any dose limiting toxicity in 11 patients treated with SMART101 and very promising data regarding the early immune recovery of the patients post-HSCT.