Despite intensive chemotherapy and stem cell transplantation, long-term survival rates remain disappointingly low in acute myeloid leukemia (AML). Approximately 60% to 70% of patients aged 18 to 65 years will achieve a complete remission, but just 30.5% of these patients with AML have a 5-year or longer overall survival.1 The limitations of current therapies have spurred intense research into innovative immunotherapeutic approaches, particularly in the domain of adoptive cell therapy.
A subset of T lymphocytes, invariant natural killer T (iNKT) cells share characteristics of both conventional T cells and NK cells.2 In particular, NK cells possess a unique recognition mechanism that allows them to respond rapidly to infected or malignant cells without strict HLA restriction. This characteristic holds potential in treating patients with acute myeloid leukemia (AML), which remains a challenging hematologic malignancy.
In an interview with Targeted Therapies in Oncology, Caspian Oliai, MD, discussed the potential of the therapy and its potential advantages over chimeric antigen receptor (CAR) therapy, which could overcome some of the key limitations that have hindered progress in AML. Oliai is medical director of the UCLA Bone Marrow Transplantation Stem Cell Processing Center and clinical instructor at the David Geffen School of Medicine in California.
Combining Characteristics
“iNKT cells combine the best features of both T cells and natural killer cells. They have the intelligence and efficiency of T cells, plus the [same] potency and multiple mechanisms of action of killing as natural killer cells,” Oliai said.
“This dual functionality makes them particularly attractive for cancer immunotherapy. Although T cells typically kill through a single, antigen-specific mechanism, NK cells—and by extension, iNKT cells—can engage multiple killing pathways, including targeting cells that downregulate MHC molecules or upregulate stress ligands,” Oliai said. “This multimechanistic approach may help overcome antigen escape, a common cause of treatment failure in targeted therapies.”
In CD19-directed CAR T-cell therapy for acute lymphoblastic leukemia, for example, relapse often occurs due to the emergence of CD19- negative leukemic clones. Similarly, in AML, the heterogeneity of surface antigen expression and the lack of truly leukemia-specific targets have posed significant challenges. iNKT cells, with their inherent ability to kill through both antigen-dependent and independent pathways, may reduce the likelihood of such escape.3
CAR-iNKT Cells
CAR-iNKT cell therapy involves engineering iNKT cells to express chimeric antigen receptors that target specific AML-associated antigens. These cells are derived from healthy donors, expanded ex vivo, and infused into patients. Because iNKT cells are CD1d-restricted and do not cause graftvs-host disease (GVHD), they are suitable for allogeneic, off-the-shelf use.
Oliai highlighted several advantages of this approach. First, because the cells are derived from healthy donors, they can be mass-produced, dramatically reducing costs compared with autologous CAR-T products.
“The cost of CAR T-cell therapy is approximately $400,000 for a single dose,” he noted, “[whereas] the cost of CAR-iNKT cell therapy is estimated to be approximately 1% of that, or around $5,000 per dose.” This scalability could make the therapy accessible to a broader patient population.
Second, CAR-iNKT cells exhibit a highly active phenotype and are potent killers. Third, early preclinical data suggest a favorable safety profile, with reduced risks of cytokine release syndrome and GVHD compared with other allogeneic cell products. Finally, through HLA ablation, donor-derived iNKT cells can evade rejection, allowing for sustained persistence and activity.4
Adoptive Cell Therapy in AML
The review article “Beyond αβ T Cells: NK, iNKT, and γδT Cell Biology in Leukemic Patients and Potential for Off-the-Shelf Adoptive Cell T herapies for AML,” recently published in Frontiers in Immunology,5 provides a comprehensive overview of the immune cell types being explored for AML therapy. Kent et al emphasize that although αβ T cells have been the mainstay of adoptive cell therapy, their limitations in AML have motivated the investigation of alternative cell types.
NK cells, for example, have shown promise due to their ability to kill malignant cells without prior sensitization and their reduced risk of GVHD. Clinical trials using haploidentical NK cell infusions have demonstrated remission rates of up to 37.5% in patients with refractory AML. However, NK cells are short-lived and can become dysfunctional in the immunosuppressive tumor microenvironment.5
γδ T cells, another innate-like lymphocyte population, have also been studied for their MHC-independent cytotoxicity and antileukemic activity. Early-phase trials are ongoing to evaluate their safety and efficacy in AML, particularly in the posttransplant setting.5
iNKT cells occupy a unique niche within this spectrum. Like NK and γδ T cells, they function independently of classical HLA presentation and exhibit strong antitumor activity. Moreover, they have been shown to modulate immune responses in a way that may reduce GVHD while preserving graft-vs-leukemia effects.5
AML Treatment Timeline
Historically, AML treatment has relied on anthracycline- and cytarabine-based regimens, but since 2017, the treatment landscape has expanded to targeted therapies.6,7
Though not specific to a molecular or cellular target, CPX-351 demonstrated efficacy in patients with secondary AML or AML with myelodysplasia-related changes, and oral azacitidine (CC-486) improved survival in patients with NPM1- and/or FLT3-mutated AML, further supporting the ability to individualize therapy based on clinical characteristics in addition to cytogenetic or molecular features.7
Although consolidative hematopoietic cell transplantation in remission remains the only curative therapy for patients with AML, these new treatment options are a welcome addition to a therapeutic repertoire that has largely relied upon standard cytotoxic chemotherapy for the past 40 years. Despite these recent advances, cures remain elusive, and relapse is the most common cause of mortality.7
Clinical Translation and Future Directions
Although preclinical data have been encouraging, clinical experience with CAR-iNKT cells in AML is still in its infancy. Oliai acknowledged that no clinical data are yet available, as the therapy is still in the preclinical development phase. The work at UCLA, led by Lili Yang, PhD, a professor in the Department of Microbiology, Immunology & Molecular Genetics, has been supported by funding from the California Institute for Regenerative Medicine, following the passage of Proposition 14 in 2020.8
The next step is to initiate a phase 1 clinical trial, which is pending sufficient funding.
“The most expensive aspect of cellular therapies is creating the actual cell therapy from the donor to engineer it,” Oliai explained. “We’re trying our best to raise money through the private sector, through philanthropic donations.”
Once funding is secured, the trial will enroll patients with AML who have not had success with standard therapies—a population with limited options and poor prognosis, Oliai said.
To be eligible for the trial, patients must have relapsed or refractory AML and not be candidates for further chemotherapy or transplantation. Given that the 5-year survival for AML is approximately 30%, the potential patient pool is significant. “Basically, anyone who eventually relapses and progresses will be a candidate for this,” Oliai said.
Challenges and Opportunities
The development of any new cell therapy involves substantial challenges. Manufacturing complexity, regulatory hurdles, and funding constraints are significant barriers. Moreover, the biological challenges specific to AML, such as the lack of unique target antigens and the immunosuppressive bone marrow microenvironment, must be carefully addressed.
However, the potential benefits of CAR-iNKT therapy are substantial. Its off-the-shelf applicability, reduced cost, and multimechanistic killing capacity position it as a promising candidate for improving outcomes in AML.
Furthermore, the ability to use allogeneic cells without matching HLA types could eliminate delays in treatment initiation, which is critical in aggressive diseases such as AML.
Rapidly Evolving
The field of adoptive cell therapy is evolving rapidly, with researchers exploring beyond conventional αβ T cells to harness the unique properties of NK, γδ T, and iNKT cells. CAR-iNKT cell therapy represents an innovative approach that combines the antigen-specific targeting of CAR technology with the innate antitumor activity and safety profile of iNKT cells.
For community oncologists, staying informed about these emerging therapies is essential. As these technologies advance, they may soon become available in clinical trials and, eventually, in practice—offering new hope to patients with limited options.