Benedetta Rambaldi, MD, is a hematologist, a PhD student at the University of Milano-Bicocca, Milan, IT, and a research fellow in medicine at the laboratory of Jerome Ritz, Dana-Farber Cancer Institute, Boston, US. During the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), she presented the talk ‘Early reconstitution of CD6+ T cells after hematopoietic cell transplantation identifies a suitable target for acute graft-versus-host disease treatment using anti-CD6 monoclonal antibody itolizumab.’1
The GvHD Hub is delighted to interview Benedetta Rambaldi and understand her expert opinion on the promising results obtained when targeting CD6+ T cells in patients with acute graft-versus-host disease (aGvHD).
GH: GvHD Hub and BR: Benedetta Rambaldi
GH: Why is the targeting of CD6+ T cells a promising strategy for treating aGvHD?
BR: aGvHD continues to be a leading cause of morbidity and mortality after hematopoietic cell transplantation (HCT), and its treatment and prevention still represent an area of high unmet clinical need. Early studies by Soiffer and colleagues at the Dana-Farber Cancer Institute demonstrated that ex vivo depletion of CD6+ donor T cells prior to HCT decreased the incidence of aGvHD, highlighting the importance of CD6+ cells in GvHD pathogenesis.2
BR: CD6 is a co-stimulatory receptor expressed on almost all T cells, with higher expression on CD4+ conventional central memory and naïve T cells and lower expression on CD4+ regulatory T cells. The primary ligand for CD6 is CD166, activated leukocyte cell adhesion molecule (ALCAM), which is expressed on antigen-presenting cells (APCs) as well as some epithelial and endothelial cells. Upon ligation, the CD6–ALCAM complex contributes to stabilization of the immune-synapse between T cells and APC (co-stimulation) which promotes T-cell activation, proliferation, and development, and facilitates the trafficking of T cells into tissues. For these reasons, targeting CD6 represents a promising strategy for aGvHD treatment.
GH: What is the mechanism of action of itolizumab?
BR: Itolizumab, a humanized IgG1 anti-CD6 monoclonal antibody, has been shown to block CD6 signaling, leading to a reduction in T-cell activation, proliferation, and trafficking. As a validated therapeutic, itolizumab has shown promising results in the treatment of autoimmune disorders such as plaque psoriasis and COVID-19 cytokine release syndrome.3 Our data presented on-demand at the virtual 47th Annual Meeting of the EBMT,1 showed that itolizumab inhibits T-cell activation and proliferation in vitro, using cells from aGvHD patients. Itolizumab effects are dependent on the presence of ALCAM, highlighting that its effect is mediated specifically by blocking the CD6–ALCAM interaction.
GH: Itolizumab is under investigation in a phase Ib study, can you describe the study design and the patient population? What are the preliminary results showing?
BR: The EQUATE study is a phase Ib/II trial designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of itolizumab for first-line treatment of aGvHD in combination with steroids (NCT03763318). The phase Ib part of the trial is an open-label, dose escalation study in adult patients who present with high-risk aGvHD that typically respond poorly to steroids.
BR: Results of the phase Ib study were presented by John Koreth, Harvard Medical School, Boston, US, on-demand at the virtual 47th Annual Meeting of the EBMT.4 They showed that a majority of patients in the EQUATE study achieved a complete response within 15 days, which was maintained through Day 85. Importantly, there was a clinically meaningful reduction in corticosteroid use in these patients. Safety profile is consistent with that observed in the aGvHD population. The favorable benefit–risk profile observed supports continued clinical development.
GH: Where would you see itolizumab being used in acute GvHD treatment?
BR: Our in vitro studies and initial clinical trial results suggest that itolizumab may be an effective first line treatment option in combination with steroids for patients with high-grade (3–4) aGvHD, and the phase Ib clinical trial is ongoing. Another potential use for itolizumab may be for GvHD prophylaxis, to avoid the use of pan-T cell depletion, as with anti-thymocyte globulin (ATG). Indeed, itolizumab treatment may spare regulatory T cells and may have limited effects on T-cell reconstitution after allo-HCT.