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Strategies to improve hematopoietic stem cell engraftment and reduce GvHD

Apr 13, 2021
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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*

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

*Data from Stefanski, et al.2

  • 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, %

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

TEAE, treatment-emergent adverse event.
*Adapted from Gonclaves, et al.3
Back pain was transient (<20 minutes in most cases).

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*

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)

*Adapted from Goncalves, et al.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.

  1. Cluzeau T, Lambert J, Raus N, et al. Risk factors and outcome of graft failure after HLA matched and mismatched unrelated donor hematopoietic stem cell transplantation: a study on behalf of SFGM-TC and SFHI. Bone Marrow Transplant. 2016;51(5):687-91. DOI: 1038/bmt.2015.351
  2. Stefanski HE, Brunstein CG, McKenna DH, et al. MGTA-456, a CD34 expanded cord blood product, permits selection of better HLA matched units and results in rapid hematopoietic recovery, uniform engraftment and reduced graft-versus-host disease in adults with high-risk hematologic malignancies. Transplant Cell Ther. 2021;27(3, Supplement):S30. DOI: 1016/S2666-6367(21)00057-9
  3. Goncalves KA, Hyzy SL, Hammond KJ, et al. Mgta-145, in combination with plerixafor in a phase 1 clinical study, mobilizes large numbers of hematopoietic stem cells and a graft with potent immunosuppressive properties for autologous and allogeneic transplant. Transplant Cell Ther. 2021;27(3, Supplement):S34. DOI: 1016/S2666-6367(21)00061-0

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