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Orca-T, an engineered Treg donor product, as an aGvHD prophylaxis

Feb 10, 2021
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Impaired development of regulatory T cells (Tregs) following hematopoietic stem cell transplant (HSCT) has been associated with enhanced graft-versus-host disease (GvHD), causing significant rates of morbidity and mortality. At the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, Everett Meyer spoke about Orca-T, an engineered Treg donor product, as an agent for treating acute GvHD (aGvHD).1 Orca-T was awarded regenerative medicine advanced therapy and orphan drug designation by the U.S. Food and Drug Administration (FDA) in 2019. See our interview with Meyer here and another interview with Barbara Fazekas de St Groth on why Treg reconstitution is important to prevent GvHD.

Orca-T is a CD34-selected Treg-engineered graft that has shown promising initial results but requires further testing. Compared with traditional HSCT, the donor cells in Orca-T are processed and the Tregs, hematopoietic stem cells, and progenitor cells are separated out from the conventional T cells and infused back into the patient according to the schema in Figure 1.

Figure 1. Protocol schema2

HSPCs, hematopoietic stem and progenitor cells; MA, myeloablative; Tcon, conventional T cell; Treg, regulatory T cell.

Study design

This analysis includes data from phase Ib (n = 11; NCT04013685) and phase I/II (n = 40; NCT01660607) trials.

Purification of Tregs was performed by immunomagnetic selection of CD25+ cells of granulocyte colony-stimulating factor-mobilized peripheral blood cells followed by flow cytometric cell sorting of CD4+CD127lo cells. The infused target dose was 23 million Tregs/kg with a 1:1 ratio of conventional T cells and Tregs.

The primary objective of the studies was the rate of GvHD relapse-free survival (GRFS) at 1 year. Secondary objectives were dose limiting toxicity, overall survival, incidence and severity of chronic GvHD, and incidence of infections.

Results were compared with a historical standard of care (SoC) cohort treated at Stanford University Medical Center (N = 138) with both matched related (n = 79) and unrelated (n = 59) allo-HSCT consisting of unmanipulated peripheral blood stem cell products. Patients were treated with methotrexate plus tacrolimus for GvHD prophylaxis.

Eligibility criteria:

  • Patients with high-risk, measurable residual disease-positive active disease (leukemia, lymphoma, myelodysplastic syndromes, or myeloproliferative neoplasms) and candidates for allo-HSCT with a matched related or unrelated donor.
  • Patients aged < 65 years with a Karnofsky Performance Status score > 70 and adequate organ function.

Table 1. Baseline patient characteristics1

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BCL, B-cell lymphoma; CML, chronic myeloid leukemia; HLA, human leukocyte antigen; MDS, myelodysplastic syndromes; MF, myelofibrosis; SoC, standard of care; URD, unrelated donor.

*Subjects with ≥ 30 days follow-up; mixed phenotype acute leukemia.

 

Orca-T (N = 50)*

SoC control cohort (N = 144)

Median age, years (range)

47 (20–65)

48 (20–64)

Male, %

52

49

Ethnicity, %

 

 

  White

60

44

  African American

2

2

  Asian

14

19

  Unspecified

26

30

Primary disease, %

 

 

  AML

42

53

  ALL

28

26

  CML

4

7

  BCL

2

6

  MDS/MF

16

22

  Other

8

2

Graft source, %

 

 

  HLA-matched siblings

62

56

  URD

38

44

Active leukemia at time of transplant, %

23

21

Median follow-up, days (range)

223 (30−1,561)

886 (55−1,783)

Key points

  • The study was carried out in > 12 clinical sites across the US.
  • The products were sourced from matched related and matched unrelated donors and produced with a vein-to-vein time of < 72 hours without manufacturing nor logistic failures.
  • Orca-T was found to result in significantly quicker engraftment and reduced hospital stays for patients compared with the current SoC.
  • Furthermore, Orca-T significantly reduced the incidence of severe acute and chronic GvHD, and treatment-related mortality, while it improved relapse-free survival (Table 2).

Table 2. Engraftment length and hospital stay duration1

aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; GRFS, graft-versus-host disease relapse-free survival; SoC, standard of care.

 

Orca-T

SoC

p value

Median time to neutrophil engraftment, days

12

14

< 0.0001

Median time to platelet engraftment, days

11

17

< 0.0001

Median time from Day 0 hospital discharge, days

15

17

0.01

aGvHD Grade ≥ 2 at Day 100, %

10

30

0.005

cGvHD at 1 year, %

3

46

0.0002

GRFS at 1 year, %

75

31

0.001

Treatment-related mortality at 1 year, %

0

11

0.04

Table 3 shows a doubling of the number of patients achieving a complete response with measurable residual disease-negativity at 90 days after treatment with Orca-T and this was maintained for 180 days. The response lasted for a year in 11 patients. This included four patients with active/refractory disease/partial response before Orca-T administration.

Table 3. Duration of response and variation over time1

CR, complete response; MRD, measurable residual disease; PR, partial response.

 

CR, MRD‑negative

CR, MRD‑positive

Active/refractory disease/PR

Deaths

Pre-Orca-T, n

12

6

9

0

Day 90, n

24

1

2

0

Day 180, n

24

1

2

0

Day 356, n

11

1

1

2

Conclusion

Orca-T was able to effectively reduce the incidence of acute and chronic GvHD compared with the current SoC. No treatment-related mortality was recorded in patients treated with Orca-T, and relapse-free survival was more than doubled compared with the SoC cohort. While further testing in larger clinical trials is required, these initial results are promising. Orca-T is currently being assessed in an ongoing multicenter trial.

Expert Opinion

  1. Meyer EH, Hoeg R, Moroz A, et al. Orca-T, a precision Treg-engineered donor product, prevents acute Gvhd with less immunosuppression in an early multicenter experience with myeloablative HLA-matched transplant. Oral abstract #722. 62nd ASH Meeting and Exposition; Dec 6, 2020; Virtual.
  2. Meyer EH, Laport G, Xie BJ et al. Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients. JCI Insight. 2019;4(10):e127244. DOI: 1172/jci.insight.127244

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