Novel natural killer cell-based therapies for hematologic and solid malignancies: latest updates from ASCO 2024

Abstract

Natural killer (NK) cell-based therapies have made great progress in treating both hematological and solid tumors. Their unique mechanism of action does not rely on antigen presentation to recognize and eliminate tumor cells, making them a promising approach for cancer immunotherapy. In this review, we present a comprehensive summary of the latest clinical data of the novel NK cell-based therapies from the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, highlighting the potential of these advancements to revolutionize the treatment of hematologic malignancies and solid tumors.

To the editor

Unlike T cells, Natural killer (NK) cells could recognize and eliminate malignant cells independent of antigen presentation, making them particularly effective against various types of tumors [1]. This review summarizes the latest clinical findings of novel NK cell-based therapies as presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

Adoptive transfer of modified NK cell

One Phase I/II study [2] evaluated the efficacy of modified NK cells, resistant to TGFβ-induced suppression and expanded from a universal donor pool, in combination with irinotecan, temozolomide, and dinutuximab in children with relapsed or refractory (R/R) neuroblastoma. After administration of up to six cycles of treatment, 75% of patients achieved a partial response (PR). It manifests that the treatment strategy is safe and feasible, with early objective responses noted in the preliminary patient cohort.

NK cell engager

AFM24 is a bispecific, tetravalent innate cell engager binding CD16a on NK cells and epidermal growth factor receptor (EGFR) on solid tumors. AFM24 combined with atezolizumab was assessed in patients with EGFR-WT non-small cell lung cancer [3]. After a median duration of 14.4 weeks, the objective response rate (ORR) was 26.7%, and no unexpected toxicities were observed compared to each single agent. It demonstrates that this combination is well-tolerated and shows a manageable safety profile in these patients.

Cytokine-based NK cell activation

The safety and tolerability of JCXH-211, a self-replicating mRNA encoding IL-12, were assessed in patients with malignant solid tumors in a phase I study [4]. Patients were administrated across three dose levels, and grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 10% of patients. It reveals a favorable safety profile, and antitumor activities in the heavily pretreated late-stage patients.

Another phase I/IIa study [5] evaluated GI-102, a novel CD80-IgG4-IL2V3 fusion protein driving robust proliferation and activation of NK cells, in patients with advanced or metastatic solid tumors. The ORR was 17.4%, and grade ≥ 3 TRAEs were found in 15.6% of patients. It shows that GI-102 is well tolerated with meaningful monotherapy activity in patients who failed on standard of care.

LTC004, a novel IL-2Rβ/γ cytokine agonist designed to minimize toxicity with improved potency, was assessed in patients with advanced or metastatic solid tumors [6]. No dose-limiting toxicities was observed. The ORR was 5.9%, and the disease control rate was 58.8%. It demonstrates encouraging anti-tumor efficacy and is well tolerated in patients enrolled.

NK cell activation by immune checkpoint inhibitor (ICI)

Lacutamab, an ICI targeting killer cell immunoglobulin-like receptor 3DL2 (KIR3DL2), was assessed in patients with R/R mycosis fungoides. With a median follow-up of 11.8 months, the ORR was 22.4%, and the median progression-free survival (PFS) was 10.2 months. Grade ≥ 3 TRAEs were observed in 3.7% of patients [7]. It substantiates the promising clinical efficacy of lacutamab, with a favorable safety and tolerability profile among these patients.

Elotuzumab is a signaling lymphocytic activation molecule family member 7 (SLAMF7) checkpoint inhibitor. A phase Ib/II trial [8] evaluated the combination of elotuzumab and belantamab mafodotin in patients with R/R myeloma. The PR was 40%, and grade ≥ 3 TRAEs occurred in 30% of patients. It shows an encouraging safety profile and a promising preliminary efficacy.

IMM0306, which activates NK cells via blockade of CD47-SIRPa interaction and FcɣR engagement, achieved an ORR of 30.3% in patients with R/R CD20-positive B-cell non-Hodgkin’s lymphoma [9]. The median PFS was 10.58 months, and grade ≥ 3 TRAEs occurred in 68.8% of patients. It indicates that IMM0306 is well-tolerated and has promising preliminary anti-tumor activity especially in patients with R/R follicular lymphoma and marginal zone lymphoma.

Of note, dual ICI with pembrolizumab (a PD-1 inhibitor) and favezelimab (a lymphocyte-activation gene 3 inhibitor) was evaluated in patients with anti-PD-1-naive R/R classical Hodgkin’s lymphoma [10]. With a median follow-up of 36.9 months, the ORR was 83%. The median PFS was 19.4 months, and 24-month overall survival rate was 93%. Grade ≥ 3 TRAEs occurred in 23% of patients. It demonstrates sustained antitumor activity and manageable safety in patients studied.

In conclusion, 2024 ASCO Annual Meeting underscored substantial advancements in NK cell-based therapies, including adoptive transfer of modified NK cells, NK cell engagers, cytokine- and ICI-based NK activation (Tables 1 and 2) strategies, highlighting their potential to revolutionize tumor treatment and offering optimism for patients with R/R tumors.

Table 1 Advancements of NK cell transfer, NK cell engagers and Cytokine-based NK cell activation for hematologic and solid tumors

Table 2 Advancements of NK cell activation immune checkpoint inhibitor for hematologic and solid tumors