Itolizumab Leads to Sustained Clinical Responses in Newly Diagnosed Acute GVHD

Itolizumab, a humanized IgG1 monoclonal antibody that modulates the activated leukocyte cell adhesion molecule (ALCAM) pathway, represents a promising approach for the treatment of patients with newly diagnosed acute graft-versus-host disease (GVHD), according to part A results of the multicenter dose-ascending phase 1b/2 EQUATE study that were presented during the virtual 2021 Transplantation & Cellular Therapy Meetings.

Data showed that administration of itolizumab resulted in a dose-dependent reduction of CD6 expression on T-effector cells and a 100% overall response rate (ORR) at the 2 highest dose levels at day 29, with almost all responses being complete responses, said lead study author John Koreth, MBBS, PhD.

“The dose-dependent reduction of CD6 expression on CD4+ and CD8+ T cells is consistent with the expected mechanism of action [of itolizumab],” said Koreth, director of translational research, stem cell transplantation, Dana-Farber Cancer Institute, Boston.

The CD6 ALCAM pathway is central to immune infiltration, he explained. “CD6 is a costimulatory receptor that is upregulated and expressed on CD4+ and CD8+ effector T cells. There are multiple CD6 ligands, most prominently ALCAM that is expressed on both antigen-presenting cells and tissues, including the skin and the GI [gastrointestinal] tract,” Koreth said. “ALCAM overexpression leads to the increased infiltration of CD6^high cells. The CD6 ALCAM pathway, therefore, potentially can modulate both the activity of T cells and the trafficking of T cells to sites of inflammation.”

CD6^high cells adopt a pathogenic phenotype to secrete high amounts of gamma interferon and high amounts of interleukin-17. Itolizumab acts by causing antigenic modulation of cell surface CD6, a pathogenic CD6^high cell, resulting in a switch to a CD6 low phenotype in a dose-dependent manner.

Part A of EQUATE is an open-label 3+3 dose escalation design evaluating 4 itolizumab doses ranging from 0.4 mg/kg to 2.4 mg/kg. Patients received intravenous itolizumab administered every 2 weeks for 5 doses, with corticosteroids tapered over the treatment period. At the time of data cutoff, 4 patients were enrolled in cohort 1 (0.4 mg/kg), 3 in cohort 2 (0.8 mg/kg), and 3 in cohort 3 (1.6 mg/kg).

All patients are adult recipients of first allogeneic hematopoietic stem cell transplant with grade III/IV acute GVHD at screening or baseline. Primary disease was acute myeloid leukemia in 4 patients, acute lymphoblastic leukemia in 2, myelofibrosis in 2, and other in 2. The graft source was peripheral blood in 8 of the 10 patients.

Nine patients had lower gastrointestinal (GI) involvement and 2 had upper GI involvement. Eight of the 10 were high risk based on the MacMillan risk score and all patients had Ann Arbor scores of 2 (30%) or 3 (70%). All patients received either methotrexate (70%), tacrolimus (70%), or sirolimus (60%) prophylaxis.

As early as day 15, an ORR of 100% was observed for the 0.8 and 1.6-mg/kg dose level cohorts, all but 1 being a complete response. These responses were sustained through day 57 in the 2 highest dose cohorts. One patient in cohort 1 experienced acute GVHD progression and required rescue therapy at day 7.

The overall CR rate was 100% in cohort 2. In cohort 3, 1 patient who had a partial response at day 15 improved to a CR by day 85 but then experienced grade 2 acute GVHD on steroid taper and drug discontinuation beyond day 57, indicating durability on treatment and the need for potentially longer-term treatment in some patients, said Koreth.

Itolizumab was associated with a reduction in the dose of systemic steroids by 93%, 87%, and 91% at day 85 for cohorts 1, 2, and 3, respectively. A dose-dependent reduction in cell surface CD6 levels, on both CD4 and CD8 T cells, as early as 24 hours after the initiation of therapy was also observed. At the 0.8- and 1.6-mg/kg dose levels, the suppression of CD6 levels was sustained though day 15.

The adverse event (AE) rate was 100%, which was “consistent with this high-risk acutely sick patient population,” he said. Five patients experienced serious AEs; only 2 were considered treatment related. Four patients had serious infections, 1 was grade 4 sepsis deemed to be a dose-limiting toxicity. Three patients, 2 in cohort 2 and 1 in cohort 3, had AEs that led to discontinuation of itolizumab. One patient in cohort 3 had an AE leading to death, unrelated to the study intervention.

Patients experienced a transient decline in absolute lymphocyte count, most commonly with the first dose of itolizumab. “Importantly, there were no infectious or clinical sequelae during this period of transient lymphopenia,” he said.

Reference

1. Koreth J, Loren AW, Nakamura R, et al. Preliminary safety and efficacy of itolizumab, a novel targeted anti-CD6 therapy, in newly diagnosed severe acute graft-versus-host disease: interim results from Equate study. Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; Virtual. Abstract LBA4.