- Correspondence
- Open access
- Published:
Novel natural killer cell-based therapies for hematologic and solid malignancies: latest updates from ASCO 2024
Journal of Hematology & Oncology volume 17, Article number: 57 (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.
Data availability
No datasets were generated or analysed during the current study.
Abbreviations
- CAR:
-
Chimeric antigen receptor
- CIT:
-
Chemoimmunotherapy
- CR:
-
Complete remission
- EGFR:
-
Epidermal growth factor receptor
- FL:
-
Follicular lymphoma
- MZL:
-
Marginal zone lymphoma
- IV:
-
Intravenously
- ICI:
-
Immune checkpoint inhibitor
- KIR3DL2:
-
Killer cell immunoglobulin like receptor 3DL2
- LAG-3:
-
Lymphocyte-activation gene 3
- MLA:
-
Mesonephric-like adenocarcinoma
- NBL:
-
Neuroblastoma
- NHL:
-
Non-Hodgkin lymphoma
- NK:
-
Natural killer
- NKG2A:
-
NK cell lectin-like receptor subfamily C member 1
- ORR:
-
Objective response rate
- OS:
-
Overall survival
- PR:
-
Partial response
- PFS:
-
Progression-free survival
- Q3W:
-
Once every 3 weeks
- R/R:
-
Relapsed or refractory
- TROP2:
-
Trophoblast cell-surface antigen 2
- TGFbi:
-
TGFb-induced suppression
- UD:
-
Universal donor
- WT:
-
Wide type
References
Lamers-Kok N, Panella D, Georgoudaki AM, Liu H, Özkazanc D, Kučerová L, et al. Natural killer cells in clinical development as non-engineered, engineered, and combination therapies. J Hematol Oncol. 2022;15(1):164.
Ranalli MA, Shah N, Skeens M, Streby KA, Lamb M, Cole LA, et al. Preliminary experience of ex-vivo expanded allogeneic universal donor TGFβi NK cell infusions in combination with irinotecan, temozolomide, and dinutuximab in patients with relapsed or refractory neuroblastoma: the Allo - STING trial. J Clin Oncol. 2024;42(16suppl):10005.
Kim HR, Saavedra O, Cervantes A, Lugowska IA, Oberoi A, El-Khoueiry AB et al. Preliminary results from the phase 2 study of AFM24 in combination with atezolizumab in patients with EGFR wild-type (EGFR-WT) non-small cell lung cancer (NSCLC). J Clin Oncol. 2024;42(16_suppl):2522.
Le NT. A phase I study to evaluate the safety and tolerability of JCXH-211 (a self-replicating mRNA encoding IL-12) intratumoral injection in patients with malignant solid tumors: results from the phase Ia dose escalation. J Clin Oncol. 2024;42(16suppl):2539.
Lee J, Cho EC, Lee JL, Lee JY, Ma WW, Adjei AA, et al. A first-in-human, phase 1/2a study of GI-102 (CD80-IL2v3) in patients with advanced or metastatic solid tumors: initial results from dose escalation. J Clin Oncol. 2024;42(16suppl):2598.
Gong J, Shen L, Zang A, Zhou H, Tang J, Liu D, et al. A phase I open-label study of a novel IL-2Rβ/γ cytokine agonist, LTC004, in patients with advanced or metastatic solid tumors. J Clin Oncol. 2024;42(16suppl):2652.
Porcu P, Bagot M, Ram-Wolff C, Kim YH, Huen A, Dalle S, et al. Lacutamab in patients with relapsed and/or refractory mycosis fungoides: results from the TELLOMAK phase 2 trial. J Clin Oncol. 2024;42(16suppl):7082.
Browning S, Li F, Parker TL, Bar N, Anderson T, Stevens E, et al. Open-label, single-arm phase Ib/II study of immune combination therapy with elotuzumab and belantamab mafodotin in patients with relapsed refractory multiple myeloma. J Clin Oncol. 2024;42(16suppl):7559.
Yang J, Song Y, Zhou K, Li Z, Zhang M, Jing H, et al. Preliminary results from a phase I study of IMM0306 in patients with relapsed or refractory CD20-positive B-cell non-hodgkin’s lymphoma. J Clin Oncol. 2024;42(16suppl):7060.
Timmerman J, Lavie D, Johnson NA, Avigdor A, Peter B, Andreadis C, et al. A phase 1/2 study of favezelimab in combination with pembrolizumab for heavily pretreated anti–PD-1–refractory classical Hodgkin lymphoma (cHL): an updated analysis. J Clin Oncol. 2024;42(16suppl):7056.
Acknowledgements
We are thankful to many specialists in the field whose seminal works are not cited due to space constraints. We would like to express my gratitude to all those who helped us during the writing of this review.
Funding
This work was supported by grants from the Natural Science Foundation of China (grant no. 81400107 and 82350104), and Zhejiang Medical and Health Science and Technology Project (2022RC154).
Author information
Authors and Affiliations
Contributions
X.G., L.Z., X.H., B.Z., Z.T., and W.Q. were the principal investigators. X.G. drafted the manuscript. L.Z., H.X., W.L., and W.L. prepared the tables. All authors participated in the process of drafting and revising the manuscript. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Gong, X., Zhang, L., He, X. et al. Novel natural killer cell-based therapies for hematologic and solid malignancies: latest updates from ASCO 2024. J Hematol Oncol 17, 57 (2024). https://doi.org/10.1186/s13045-024-01575-0
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s13045-024-01575-0