P1257: smart101 donor t-lymphoid progenitors to accelerate immune reconstitution post-haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide: si101-02 phase i/ii

Topic: 21. Stem cell transplantation - Experimental Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for some patients with hematological malignancies, but an HLA-matched donor may not be available, eg for ethnic populations under-represented in donor registries. With no HLA-matched donor, the use of post-transplant cyclophosphamide in unmanipulated haploidentical HSCT (haplo PTCy HSCT) is a favorable strategy, but in-vivo T-cell depletion by PTCy may significantly impair immune reconstitution and a functional T-cell compartment can take up to 2 years, resulting in higher infection-related mortality and relapse rate. SMART101 is a cellular therapy using allogeneic CD34-CD7+ T-lymphoid progenitors produced in culture from mobilized peripheral blood CD34+ cells of the transplant donor via Smart Immune’s ProTcell platform. This GMP ex-vivo lymphoid niche culture system, using Notch ligand Delta-like 4 coupled to IgG2 Fc fragment (DLL4-Fc) and RetroNectin® in the presence of a specific combination of cytokines, mimics the initial steps of bone marrow lymphoid and T-cell differentiation. According to preclinical data, SMART101 cells infused into a patient should complete their differentiation directly in the thymus with positive and negative TCR selection, leading to the generation of a polyclonal repertoire of educated naïve T-cells faster than an allograft with hematopoietic stem cell alone. Aims: The SI101-02 clinical study seeks to provide proof of principle that SMART101 cells can rapidly complete their differentiation in the thymus into naïve T-cells, accelerating production of a polyclonal donor T-cell engraftment without GvHD-inducing potential, to reduce the non-relapse and disease relapse mortality. Methods: This phase I/II study (EudraCT#2022-002530-14) evaluates the safety and activity of SMART101 infusion on D6 at the dose of 1.5 x 106 CD7+ cells/kg following haplo PTCy HSCT (D0) in adults with AML, ALL or high-risk MDS. Patients will be enrolled in parallel into 2 cohorts (myeloablative conditioning and reduced intensity conditioning cohorts) in 2 consecutive stages according to a Simon’s 2 stage design, with a total of 17 patients (pts) in each cohort, including 9 pts in stage 1 and 8 new pts in stage 2, provided that the study is not terminated earlier due to toxicity or to CD4+ T-cell immune reconstitution futility endpoint. Each cohort will be analyzed separately. The co-primary endpoints of the trial are (i) occurrence of unexpected unacceptable toxicity within D14 after the infusion of SMART101 and acute GVHD; (ii) immune reconstitution defined by CD4+ T cells count ≥ 50/μL by D100. Secondary endpoints evaluate the overall safety profile and the incidence of non-relapse/relapse mortality. Results: Fig 1 shows SMART101 cell characterization by mass cytometry. Most of the cells express the lymphoid marker CD7 and about half of them are positive for CD161. A large portion of cells are positive for chemokine receptor CXCR4 and a fraction for the chemokine receptor CCR9, known to be important for thymus colonization. The expression of adhesion molecules involved in thymus entry such as P-selectin glycoprotein ligand-1 (PSGL-1, also called CD62) and L-selectin (CD62L) are also detectable within the cell product. The SI101-02 study will be initiated in H1-2023 at sites in France and Italy. The study design, preliminary safety and clinical data, and details of the ProTcell platform will be presented. Summary/Conclusion: SMART101 is the first-generation of allogeneic T lymphoid progenitor cell therapy obtained from Smart Immune’s proprietary ProTcell platform, the first scalable progenitor T-cell manufacturing system in clinics.Keywords: Notch, Thymus, Post-transplant, Allogeneic hematopoietic stem cell transplant