Can IL-15 superagonist ALTer GVL?

In this issue of Blood, Romee et al report results of the first-in-human clinical trial of interleukin-15 (IL-15) superagonist ALT-803 in patients with hematologic malignancies relapsed after allogeneic hematopoietic cell transplantation (allo-HCT).¹ 

Relapse continues to be the most common cause of treatment failure after allo-HCT in patients with hematologic malignancies. Outcomes for patients who relapse after allo-HCT are dismal with long-term survival <20%. T-cell adoptive immunotherapy with donor lymphocyte infusions (DLIs) can induce remissions in some patients. Unfortunately, in patients with acute myeloid leukemia (AML), responses to DLI are infrequent and typically short lived. In addition, graft-versus-host disease (GVHD) can be a common complication. Although posttransplant cellular therapy strategies have focused on infusions of unmodified or manipulated T lymphocytes, harnessing the innate immune system with natural killer (NK) cells has been explored in only a limited fashion.

The current study demonstrates that it is potentially feasible to promote graft-versus-leukemia (GVL) effects without increasing risk of severe GVHD by primarily activating the donor derived NK cells in the post–allo-HCT setting. NK cells are innate lymphocytes whose function is regulated by several key receptors including inhibitory killer immunoglobulin-like receptors (KIRs), some of which recognize major histocompatibility complex (MHC) class I molecules.²  In the haploidentical T-cell-depleted allogeneic stem cell transplantation setting, Ruggeri et al demonstrated that the lack of KIR-mediated inhibition on donor-derived NK cells by the absence of cognate MHC class I molecules on the mismatched patient AML blasts leads to enhanced antileukemia activity translating into clinically impactful protection from relapse.³  Several subsequent studies demonstrated the impact of different donor KIR genotypes on relapse-free survival after allo-HCT providing further evidence that NK cells can contribute significantly to GVL effects.^4-6  These studies make a strong case for developing innovative strategies to enhance donor-derived NK cell function in the allo-HCT setting to potentially target disease relapse.

IL-15 is a γ-chain cytokine, critical for NK cell development and maintaining normal NK cell and T-cell homeostasis. Under physiologic conditions, accessory immune cells including dendritic cells express IL-15 bound to its IL-15 receptor α chain (IL-15Rα) and trans-present it to the IL-2/IL-15βγc receptor on the neighboring effector immune cells, thereby ensuring context dependent activation.⁷  Potent NK and CD8 T-cell activation without inducing activation-induced cell death and minimal effects on regulatory T cells make IL-15 an attractive molecule for immunotherapy approaches. However, in the past, use of IL-15 in clinical trials has been hampered by the limited availability of recombinant human IL-15 (rhIL-15). Additionally, although IV rh1L-15 increased NK and CD8 T-cell numbers, its use was associated with a short half-life and was poorly tolerated by patients with advanced solid tumors in an early phase clinical trial.⁸  ALT-803 is a high-molecular-weight IL-15 superagonist molecule consisting of an IL-15 mutein (N72D) bound to IL-15Rα fused to IgG1Fc (see figure).⁹  This unique molecule aims to mimic the physiologic trans-presentation of IL-15 and significantly increase its half-life. In the current study, the drug was well tolerated, and none of the patients had any flare-up of GVHD needing systemic treatment. The subcutaneous (SC) form of the drug was associated with more favorable pharmacokinetic profile with lower peak but more sustained serum concentrations. Patients who received ALT-803 via the SC route also had a lower elevation in the inflammatory cytokines like IL-6 and interferon γ, which is probably the reason why it was better tolerated in these patients. Interestingly, most of the SC cohort patients developed self-limited injection site rash with predominantly γδ T-cell infiltration. ALT-803 use was associated with activation, proliferation, and expansion of the NK cell numbers in the peripheral blood; however, more modest effects were seen in the CD8 T cells. Encouragingly, clinical responses were observed with 1 prolonged complete remission lasting several months in a myelodysplastic syndrome patient.

This study demonstrates the feasibility of safely using ALT-803 in a patient population with otherwise extremely poor prognosis. Even though as a single agent it is unlikely to be effective in controlling disease in patients with advanced malignancies, its potent NK and CD8 T-cell stimulant properties with a prolonged half-life make it an attractive molecule for combinatorial approaches. It is currently being evaluated in several ongoing clinical studies in conjunction with NK cell infusions (#NCT01898793, #NCT02782546), immune checkpoint blockade (#NCT02523469), and bispecific monoclonal antibodies (#NCT02384954).

Furthermore, ALT-803 is one of the several agents currently at various stages of clinical development incorporating novel modifications in the key cytokine molecules aimed at enhancing their ability to stimulate cytotoxic T and NK cells. Immunoengineering of molecules like rhIL-2 is leading to a whole new class of agents that can target specific T-cell subsets differentially, leading to selective activation of cytotoxic T cells or regulatory cells in order to promote antitumor or anti-inflammatory activity, respectively. Most recently, Sockolosky and colleagues have reported on the construction of IL-2 cytokine-receptor orthogonal pairs that interact with each other to deliver native signals but do not interact with their natural counterparts, limiting off-target effects and providing an avenue to stimulate natural or engineered immune effectors in vivo.¹⁰  The current study by Romee and colleagues is another promising step in the development of approaches that safely leverage the potential of cytokine-mediated immune stimulation in the clinical setting.