Trials in Progress: Decoy-Resistant Interleukin-18 (DR-18) for Relapse or Pre-Emptive Treatment of Measurable Residual Disease after Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome (DR. DREAM), a Phase I Trial

Background:

Hematopoietic cell transplant (HCT), a potentially curative therapy for high risk and relapsed AML, combines chemotherapy with the immunologic graft-versus-leukemia (GVL) effect. The most common cause of AML patient death following HCT is disease recurrence, implying the loss of GVL. Therefore, methods to restore GVL, particularly through reversal of T cell exhaustion may rescue some patients. Interleukin-18 (IL-18) is an immune agonist capable of eliciting powerful antitumor responses by increasing interferon gamma (IFNg) production by T and NK cells. This activity is restrained by IL18 binding protein (IL-18 BP), a secreted immune checkpoint that blocks IL-18/IL-18 receptor interactions. Decoy-resistant IL-18 (DR-18) is a synthetic protein engineered for minimal affinity to IL-18BP but strong IL-18 receptor binding and activation properties (Zhou et al, Nature. 2020, PMID: 32581358). Using murine models, we found DR-18 overcomes IL18BP mediated immune suppression and reverses CD8+ T cell exhaustion by increasing NK cell activity. As a result, DR18 stimulates IFNγ-mediated GVL effects without exacerbating graft-vs-host disease (Minnie et al, Sci Immunol. 2022, PMID: 36240285). Therefore, we designed a clinical trial in patients with post-HCT AML relapse to (1) determine the maximum tolerated dose of DR-18 and (2) to explore whether T cell exhaustion is present in post-HCT AML relapse and is reversed following DR-18 treatment.

Study Design and Methods:

We initiated a single-center, investigator-initiated, phase I trial (NCT06492707) to evaluate the feasibility and safety of DR-18 immunotherapy in patients with relapsed AML or MDS after 10/10 HLA-matched HCT.

The primary end points are 1) feasibility of administering DR-18, defined as administration of 4 weekly doses of DR-18 and 2) incident dose-limiting toxicity.

Major eligibility criteria are: age ≥ 18, persistent or recurrent AML or MDS, including measurable residual disease or overt leukemia, no prior grade 3 or 4 acute GvHD or moderate/severe chronic GvHD, and peripheral T cell chimerism ≥ 40%. Patients treated with stable or decreasing doses of systemic immunosuppression in the 4 weeks prior to trial enrollment are eligible to participate and may continue immunosuppressive therapy. The 5 planned dose levels incorporate intra-patient dose escalation and dose modification for side effects. DR-18 is administered by once weekly subcutaneous (SC) injection. Four doses are planned during “induction”, followed by a 2-week pause to avoid tachyphylaxis and allow disease restaging, and “maintenance”, which is a second cycle of 4 doses, given once weekly. Dose levels will be evaluated according to a Bayesian Optimal Interval Design (BOIN) algorithm. Doses range from 15 to 120 mcg/kg SC.

The study open to recruitment date is August 2024. A total of 12 to 20 subjects are anticipated.

Outlook:

DR-18 immunotherapy may offer effective management of post-HCT relapse while avoiding significant GvHD. This study represents the first time DR-18 will be evaluated for treatment of hematologic malignancies. By targeting the post-HCT population we will evaluate whether DR-18 restores T cell function and reverses exhaustion. If safety is demonstrated herein, DR-18 may be further evaluated for its ability to (1) prevent post-transplant relapse among high-risk transplant patients, (2) supplant or potentiate the efficacy of donor lymphocyte infusion (DLI) and to (3) augment engineered adoptive T cell therapeutic strategies.