Donor regulatory/conventional T-cell grafts for the GVHD win?

In this issue of Blood, Meyer et al¹ report the promising outcomes of a phase 2 trial of 7 to 8 of 8 HLA-matched peripheral blood grafts that were manufactured to contain purified CD34⁺ cells plus T regulatory (Treg) and conventional (Tcon) cells in a ∼1:1 ratio. In the 44-patient (33 matched, 11 mismatched) single-center myeloablative transplant study, infusion of >2 × 10⁶ CD34⁺ cells per kilogram plus 2 to 3 × 10⁶ Treg cells per kilogram on day 0, with a target of 3 × 10⁶ Tcon cells per kilogram on day +2 to 3, followed by limited pharmacologic immune suppression with tacrolimus (Tac) ± short-course mycophenolate mofetil (MMF), resulted in low rates of acute and chronic graft-versus-host disease (GVHD) and low nonrelapse mortality (NRM), with promising GVHD and relapse-free survival (GRFS) compared with a contemporaneous cohort receiving calcineurin inhibitor (CNI) and methotrexate (MTX) prophylaxis.

Treg cells are CD4⁺CD25^hiFoxp3⁺ lymphocytes that comprise ∼5% to 10% of the circulating CD4⁺ T-cell population. Treg cells act to dominantly suppress autoreactive lymphocytes and control innate and adaptive immune responses.² In the allotransplant context, the Stanford group was among the first to demonstrate in mismatched mouse models that donor Treg-cell infusion prevented GVHD while preserving the graft-vs-tumor effect.³ In the clinical context, the Dana-Farber Group documented deficient Treg-cell reconstitution in patients with chronic GVHD⁴ and showed that in vivo Treg-cell augmentation via low-dose interleukin-2 treatment induced durable clinical benefit for patients with steroid-refractory disease.⁵ The clinical use of adoptive donor Treg cells was pioneered by the Perugia group, who infused Treg cell– and Tcon cell–modulated grafts in HLA-haploidentical transplants without use of posttransplant immune suppression.⁶ In the group’s most recent experience, the combination of an irradiation-based myeloablative regimen with Treg cell– and Tcon cell–modulated haploidentical graft resulted in low incidence of leukemia relapse and chronic GVHD. The main limitation was significant acute GVHD that occurred in about one-third of the patients.⁷ 

At Stanford, Meyer and colleagues have focused on addressing GVHD with a similar graft manipulation approach in the 7 to 8 of 8 HLA-matched donor setting, combining Treg cell– and Tcon cell–adoptive immunotherapy with limited pharmacologic immune suppression. Their outcomes are noteworthy, with grade 3 to 4 severe acute GVHD occurring in a single-digit minority of patients and a low incidence of chronic GVHD. Moreover, breakthrough grade 2 to 4 acute GVHD was highly responsive to first-line steroid therapy. Although a larger sample size will be needed to assess relapse risk, these outcomes suggest that Treg cell– and Tcon cell–adoptive immunotherapy with limited posttransplant immune suppression can protect against acute and chronic GVHD, with promising GRFS and quality of life as compared with CNI and MTX transplantation. To definitively assess these benefits vs CNI and MTX, a phase 3 randomized controlled trial (RCT) is ongoing (NCT05316701).

In the broader context, other novel approaches to GVHD prevention are also encouraging: the infusion of donor grafts depleted of naive T cells⁸; the Food and Drug Administration–approved addition of abatacept to CNI and MTX⁹; the addition of vedolizumab to CNI and MTX¹⁰; and most widespread, the use of posttransplant cyclophosphamide (PTCy) plus Tac and MMF, which has gained traction across all donor-recipient HLA-match combinations because of its easy applicability, efficacy, and low cost.^11,12 PTCy-based prophylaxis is associated with improved rates of acute and chronic GVHD compared with CNI and MTX and is now considered a standard-of-care regimen.

How might an adoptive Treg-cell and Tcon-cell strategy be deployed to centers lacking expertise in cellular manipulations? The involvement of a commercial central manufacturing partner (Orca Bio) in this report offers benefits and costs. Benefit-wise, it offers assurance regarding scale-up feasibility: timeliness of infusing the noncryopreserved product (72-hour vein-to-vein infusion); ability to use related or unrelated donors across the continental United States and Hawaii; and a standardized quality criteria for the product. The cost is unknown but will likely be significant, especially compared with PTCy. If so, does this graft manipulation approach offer advantages? It offers an anticipated low GVHD incidence, and due to reduced exposure to pharmacologic immune suppression, an opportunity for enhanced posttransplant immune reconstitution, with implications for NRM and GRFS benefit. Treg cell– and Tcon cell–adoptive immunotherapy with minimal posttransplant immune suppression may also offer an improved platform for cellular or biologic therapies, to better unleash donor immunity against leukemia and reduce relapse. However, confirming these benefits vs PTCy would likely require an appropriately sized head-to-head prospective RCT, which may be worth considering in the future.

For now, this report by Meyer et al highlights the potential of Treg cell– and Tcon cell–adoptive immunotherapy with limited pharmacologic immune suppression, to better prevent GVHD and improve NRM and GRFS, as a feasible and scalable option for HLA-matched and -mismatched donor transplantation.

Conflict-of-interest disclosure: A.P. reports no competing financial interests. J.K. serves on boards and/or consults for Mallinckrodt/Therakos, Cugene, Cue Biotherapeutics, Biolojic Design, Gentibio, Equillium, and Biopharm Communications LLC; and receives grant or research support from Bristol Myers Squibb, Miltenyi, Regeneron, Equillium, and Iovance.