Strategies to improve hematopoietic stem cell engraftment and reduce GvHD

Engraftment of transplanted hematopoietic stem cells (HSCs) is essential for effective long-term hematopoiesis and an important factor influencing the survival of patients undergoing stem cell transplantation.¹

During the Transplantation and Cellular Therapy (TCT) 2021 Meetings of ASTCT and CIBMTR, Heather Stefanski and Kevin Goncalves presented results for two products—MGTA-456² and MGTA-145³—being investigated for rapid and reliable engraftment of transplanted HSCs and improved transplant outcomes. Here, we summarize their findings.

MGTA-456

MGTA-456 is a CD34⁺ cell-expanded umbilical cord blood product designed to provide a high dose of HSCs with improved HLA match. MGTA-456 is being evaluated in a single-arm, open-label, phase II study of patients with high-risk malignancies (NCT03674411).

Expansion characteristics

• Median expansion of CD34⁺ cells was 34-fold (range, 1–79) at Day 7 and 392-fold (range, 14–672) at Day 15. MGTA-456 comprised the following median cell doses:
  • 17 × 10⁶ CD34⁺ cells/kg (range, 2.7–130 × 10⁶)
  • 1.1 × 10⁶ CD34⁺CD90⁺ cells/kg (range, 0.2–7.0 × 10⁶)
  • 5.7 × 10⁶ CD3⁺ cells/kg (range, 2.2–38 × 10⁶)

Efficacy

• Results for key study outcomes are shown in Table 1.

Table 1. MGTA-456 efficacy*

*Data from Stefanski, et al.2
Outcome	MGTA-456 cohort (N = 18)	Historic control cohort (N = 167)	p value
Neutrophil recovery               Cumulative incidence, %               Median time, days	100 17	90 23	<0.01
Platelet recovery               Cumulative incidence, %               Median time, days	94 36	74 59	<0.01
Incidence of GvHD, %               Acute GvHD, Grade 2–4               Chronic GvHD, any grade	24 6	46 16	0.04 0.19
Overall survival, %	72	63	0.24
Non-relapse mortality, %	12	31	0.13
Median time to first hospital discharge, days	24	33	0.01

• Neutrophil and platelet recovery times were significantly reduced in the MGTA-456 cohort compared with the historical control cohort, and the dose of CD34⁺CD90⁺ cells correlated with a more rapid time to neutrophil and platelet recovery (R² = 0.4997 and 0.498, respectively).
• For most adult patients (10/14), MGTA-456 provided better HLA-matched cord blood units, and it is noteworthy that single umbilical cord blood transplantation could be provided for five patients who would otherwise have undergone a double transplant.
• The incidence of Grade 2−4 acute GvHD was significantly lower in the MGTA-456 cohort compared with the historic control cohort. In the MGTA-456 cohort, only one patient had Grade 3 acute GvHD and no patients had Grade 4 acute GvHD; one patient had chronic GvHD.
• With a median follow-up of 325 days, the overall survival probability was higher, and the incidence of non-relapse mortality was lower, for patients in the MGTA-456 cohort, although neither outcome was significantly different to the control cohort.
• There was no significant difference in the incidence of relapse between the MGTA-456 and control cohorts when accounting for disease risk index.
• Median time to first discharge from hospital was significantly shorter for patients in the MGTA-456 cohort.

MGTA-145

In most cases, HSCs used for transplantation are sourced from mobilized peripheral blood. One of the most used mobilization agents is granulocyte-colony stimulating factor (G-CSF); however, it is hampered by the requirement for daily injections over a ≥5-day duration, variable cell yields, and adverse events. MGTA-145 is a CXCR2 agonist that, when combined with the CXCR4 antagonist, plerixafor, has been shown to induce rapid and robust mobilization of HSCs in animal models.

MGTA-145-101 (NCT03932864) is a four-part, phase I study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of MGTA-145 in healthy volunteers, either as a single agent or in combination with plerixafor:

• Part A: single-dose MGTA-145, dose escalation
• Part B: single-dose MGTA-145 + plerixafor
• Part C: two daily doses of MGTA-145 + plerixafor
• Part D: apheresis with single-dose MGTA-145 + plerixafor

Safety

• MGTA-145 was well tolerated, both alone and in combination with plerixafor (Table 2).

Table 2. Treatment-emergent adverse events for study parts A and B*

TEAE, treatment-emergent adverse event. *Adapted from Gonclaves, et al.3 †Back pain was transient (<20 minutes in most cases).
TEAE, %	Part A	Part B
	MGTA-145, 0.0075–0.3 mg/kg (n = 24)	Plerixafor + MGTA-145, 0.015–0.15 mg/kg (n = 38)	Plerixafor (n = 14)
Any drug-related TEAE	79.2	81.6	57.1
Diarrhea	—	15.8	35.7
Nausea	—	18.4	14.3
Abdominal discomfort/pain	—	13.2	28.6
Vomiting	—	7.9	7.1
Back/musculoskeletal pain†	79.2	63.2	14.3
Dizziness/lightheadedness	—	15.6	7.1
Headache	—	10.5	7.1
Dysgeusia	—	—	14.3
Paresthesia	—	5.3	—

On-target activity

• On-target activity of MGTA-145 was demonstrated by dose-dependent neutrophil mobilization, downregulation of the target receptor CXCR2, a transient increase in MMP9 levels, and minimal neutrophil activation.

Mobilization of CD34⁺ cells

• MGTA-145 plus plerixafor effectively mobilizes CD34⁺ cells and exceeds the target dose of 2 × 10⁶ CD34⁺ cells/kg collected from healthy volunteers (Table 3).
• In a single day, MGTA-145 plus plerixafor enabled a CD34⁺ cell yield equivalent to that collected after 5 days using G-CSF, and a 2-fold higher yield than plerixafor alone (p < 0.05).
• The number of CD34⁺CD90⁺CD45RA⁻ cells (known to be enriched for functional HSCs) collected after mobilization with MGTA-145 plus plerixafor was 3-fold higher than with G-CSF (p < 0.05) and 4-fold higher than with plerixafor alone (p < 0.01).

Table 3. Single-day mobilization of CD34⁺ cells*

*Adapted from Goncalves, et al.3
Part B: dose escalation	MGTA-145 (0.015 mg/kg) + plerixafor (n = 6)	MGTA-145 (0.03 mg/kg) + plerixafor (n = 6)	Plerixafor (n = 14)
Median peak CD34+ cells/µL (range)	35 (17–78)	40 (18–63)	26 (13–78)
>20 CD34+ cells/µL, %	83	83	64
>40 CD34+ cells/µL, %	33	50	21
Part D: apheresis	MGTA-145 (0.015 mg/kg) + plerixafor (n = 4)	MGTA-145 (0.03 mg/kg) + plerixafor (n = 4)	—
Median CD34+ cell yield, ×106 (range)	35 (17–78)	40 (18–63)	—
Median CD34+ cell dose, ×106/kg (range)	3.7 (1.5–7.0)	4.3 (2.7–5.3)	—

Engraftment in NSG mice

• Week 16 engraftment of CD34⁺ cells mobilized with MGTA-145 plus plerixafor in primary transplanted NSG mice was 23-fold higher than for cells mobilized with G-CSF (p < 0.001) and 11-fold higher than for cells mobilized with plerixafor alone (p < 0.001).
• Similar engraftment results were observed in secondary NSG mouse transplants; these engrafted cells were multilineage, including myeloid and lymphoid, with no skewed lineage compared with other graft sources.
• The authors also demonstrate successful engraftment of CRISPR/Cas9 gene-edited CD34⁺ cells from the MGTA-145/plerixafor apheresis product.

Functional characterization

• In a xenotransplant mouse model, the MGTA-145/plerixafor grafts resulted in lower incidences of GvHD and longer median survival (>60 days) compared with G-CSF-mobilized (25 days; p < 0.01) and plerixafor-mobilized (15 days; p < 0.001) grafts.

Conclusion

These results highlight the advances being made to increase the success of HSC engraftment and improve clinical outcomes for patients undergoing HSC transplants.

Enriched for CD34⁺CD90⁺ cells, MGTA-456 promotes rapid and sustained hematopoietic recovery, complete engraftment, and improved HLA match in adult patients.

MGTA-145 is a well-tolerated and effective CD34⁺ cell mobilization agent in combination with plerixafor. The MGTA-145/plerixafor mobilized peripheral blood graft, enriched for HSCs, results in reduced GvHD in a xenotransplant mouse model compared with other graft sources.