Evaluating Adoptive Immunotherapy to Prevent Acute GVHD

Adoptive immunotherapy with CD4+/CD25/+FOXP3+ regulatory T cells (Tregs) and conventional T cells (Tcons) has been used as prevention of graft-versus-host disease (GVHD) in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). In a poster presented at the 2021 ASH Annual Meeting by Samanta Bonato, MD, from the University of Perugia in Italy, researchers evaluated clinical and histological characteristics of acute GVHD and their impact on outcomes in patients who received Treg/Tcon haploidentical alloHCT.

The investigators retrieved data from patients who underwent Treg/Tcon haploidentical alloHCT at Perugia University Hospital and were evaluable for acute GVHD from January 2015 until June 2021. They also analyzed histological features and lymphoid infiltration by immunohistochemistry in gut samples of patients who received diagnostic colonscopy and biopsy for gastrointestinal symptoms.

The study included 105 patients who had engraftment after Treg/Tcon haploidentical alloHCT. Mean age at alloHCT was 48 years, and acute leukemia was the most frequent diagnosis (n = 78/105). Twenty-seven patients (26%) had active disease at the time of transplantation.

Thirty-one patients (29%) developed grade II-IV aGVHD: four with grade II, 23 with grade III, and four with grade IV. Nearly all patients (90%) presented gut involvement, while skin was involved in 64% of them and liver in 35%.

“To explain why gut symptoms such as diarrhea and abdominal pain were more frequently present than symptoms of skin or liver involvement, we evaluated 40 histological samples from 34 patients who received colonoscopy for suspected aGVHD,” the authors explained. Nearly two-thirds of these patients (n = 22) received a clinical diagnosis of aGVHD and pharmacologic immune suppression was promptly initiated. However, clinical diagnosis did not always match histological findings. Biopsies were suggestive of aGVHD in 20 of the 22 patients who required treatment, as well as in eight of the 12 patients who did not.

The investigators found no difference in median CD3+ cell infiltration among patients who did not need immune-suppressive treatments and patients with aGVHD. However, FOXP3+ Tregs preferentially infiltrated gut mucosa of patients who resolved clinical symptoms with no need of immune-suppressive treatments. “This observation suggested Treg defective homing to gut mucosa of aGVHD patients,” they reported. “Indeed, we found infused Tregs expressed lower levels of gut homing receptor α4β7 in comparison with Tcons.”

While most patients had severe aGVHD at diagnosis, disease resolved in most patients (71%), and immune-suppressive therapy could be completely withdrawn after a relatively short course (median of 98 days).

The researchers also reported that an aGVHD diagnosis did not lead to higher incidence of non-relapse mortality, relapse, or chronic GVHD compared with controls who never developed GVHD.

Overall, they concluded that Treg/Tcon haploidentical alloHCT is associated with good rates of chronic GVHD- and leukemia-free survival in patients with high-risk leukemia. “Strategies that enhance Treg homing in the gut (e.g., low-dose IL-2) may help reduce aGVHD after Treg/Tcon haploidentical alloHCT,” they wrote.