Itolizumab Induces Durable Clinical Responses in Newly Diagnosed aGVHD

For the treatment of patients with newly diagnosed acute graft-versus-host disease (GVHD, itolizumab, a humanized IgG1 monoclonal antibody that modulates the activated leukocyte cell adhesion molecule (ALCAM) pathway, has demonstrated promise in part A of the multicenter dose-ascending phase 1b/2 EQUATE study, according to results 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 CD6high 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.”

CD6high 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 CD6high 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:

_{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.}