IL-7 earns her ticket in allo-HSCT

In this issue of Blood, Perales and colleagues report the first trial of recombinant in recipients of T cell–depleted allogeneic hematopoietic stem cell transplantation (allo-HSCT) showing the safety of the drug and improvement in T-cell recovery.¹ 

The study by Perales et al is the first study tackling the critical issue of T-cell reconstitution in human allo-HSCT by administration of IL-7. Accelerated T-cell recovery is a desirable goal, especially in cord blood HSCT, transplants from haplo-identical family donors, or stem cell grafts that are T cell–depleted (TCD). In these settings, the profound and long-lasting immunodeficiency is a significant concern, contributing to life-threatening infections and disease relapse. T-cell physiology makes this a difficult task. Reconstitution of T-cell adaptive immunity in allo-HSCT is a long process dependent on the thymus for T-cell development. Sequential steps within the thymus lead to egress of recent thymic emigrants in the periphery where they undergo final maturation into naive T cells, are exposed to homeostatic cytokines, mainly IL-2, -7 and -15, and differentiate into effector and memory cells after antigen stimulation.²  Tools have recently improved to assess precisely the quality of the T-cell reconstitution: multiparametric flow cytometry to define the various T-cell subsets, molecular analysis of the T-cell repertoire diversity, and thymic function analysis by direct measurements of T-cell receptor excision circles generated during T-cell differentiation (see figure).

Among the options to improve T-cell reconstitution, IL-7 is certainly on the top of the list.³  IL-7 is a nonredundant cytokine mandatory for T-cell development and may also play a role in B-cell development, although not absolutely required in humans. It mediates homeostatic proliferation of peripheral T cells in response to low-affinity interactions with self-antigens in a context of lymphopenia. IL-7 is signaling through a heterodimeric receptor comprising the IL-7Rα chain (CD127) and the common cytokine receptor γ-chain (CD132). IL-7 therapy may have broad application in immunodeficient patients, from HIV-infected to heavily treated cancer chemotherapy patients. Indeed, phase 1 or 1/2a trials have been conducted in these indications, showing a lack of toxicity and some evidence for a quantitative and qualitative improvement of T-cell subsets, especially naive and central memory T cells.^4,5 

Why did we have to wait until now in allo-HSCT, even though it is one of the most obvious clinical indications? The answer comes from the duality of T-cell reconstitution in allo-HSCT and the risk of boosting alloreactive T-cell population and GVHD by IL-7, as indicated by murine experimental models.⁶  This risk is dependent on the dose of T cells present in the graft, the reason why indications are limited now to TCD allo-HSCT as in Perales et al.¹  Hopefully, this is also where the drug is perhaps most needed. The trial tells us more than feasibility and low toxicity of the drug. Although limited by small patient numbers, as usual in a phase 1 trial, there is some evidence for improvement of T-cell recovery and T-cell repertoire diversity. This is most apparent in the effector memory CD4⁺ and CD8⁺ subsets, in contrast with the other trials in HIV and cancer patients showing a more clear effect on naive T cells.^4,5  An explanation could be differences in the ages of the patients, those included in this trial being slightly older and more heterogeneous (median age older than 60 years and no patient younger than 25 years). Age is a critical determinant of thymic function, and impacts the risk of acute GVHD, which also has a profound impact on thymic recovery.²  Age would be expected to impact IL-7 therapy as well. Interestingly, the 2 patients showing a concomitant increase in naive T cells, thymic function, and T-cell repertoire diversity were the youngest ones (27 and 43 years old, respectively). This may suggest that IL-7 effect could depend on the prior patient immune status as suggested in the trial in HIV-infected patients.⁵  The more we know of the patient's immune status at the onset of treatment, including the pretreatment levels of homeostatic cytokines, the better we should be able to predict the effects of treatment. It would also be valuable to obtain longer follow-up of T-cell recovery in future prospective trials. In allo-HSCT, younger patients may be best served using IL-7 to boost naive T-cell reconstitution, and older patients may be best helped by boosting antigen-specific memory populations. A boost of T-cell immunity by IL-7 during vaccination could be of special interest in the latter group.

Another mechanistic issue to consider is the lymphocyte population targeted by IL-7. IL-7 acts on CD127-expressing lineages and, in that view, the lack of impact on B and natural killer cells in the periphery is not surprising. More interestingly, among the growing family of so-called innate lymphoid cells,⁷  some express CD127, namely IL-22–producing innate cells. Given the protective role of IL-22 in intestinal GVHD⁸  and in thymic regeneration recently shown by the same group of investigators,⁹  it is extremely tempting to speculate that IL-7 may also act indirectly via IL-22 production by IL-22 innate lymphoid cells.

In all, these data should be considered very promising and IL-7 deserves further evaluation in allo-HSCT. However, there is no magic bullet. IL-7–treated patients remain lymphopenic, meaning that other attempts to target thymic epithelial cells and/or thymocyte differentiation and maturation in combination with IL-7 still have a place.