Jun 17, 2025

NK cell therapies represent a paradigm shift in cancer immunotherapy, combining safety, affordability, and versatility. With innovations in NK cell engineering and their implementation in combination therapies, NK cells hold promise for conquering solid tumors—a frontier where CAR-T cells have struggled. As clinical trials expand, the momentum for NK cells may soon transition these formidable cells from a "humble" innate immune player to a cornerstone of next-generation immunotherapy.

At AACR 2025, Dr. Katayoun Rezvani’s presentation, “Engineering NK Cells for Cancer Treatment: From Bench to Bedside,” definitely signaled great impetus for making these therapies a reality.

Dr. Rezvani is the VP and Head of the Institute for Cell Therapy at the MD Anderson Cancer Center, where she leads research and heads various clinical trials focused on developing and testing engineered NK cells. Currently, 12 clinical trials are ongoing at the institute evaluating NK cell therapies across over eleven cancer indications.

NK Cell vs. CAR-T Therapy Features

Natural Killer (NK) cells are emerging as a powerful alternative to CAR-T therapy, offering unique advantages. First and foremost, unlike clinically approved CAR-T cells, which are all currently autologous therapies or manufactured from a patient's own cells, NK cells do not cause graft-versus-host disease (GvHD), enabling "off-the-shelf" therapies. This NK cell intrinsic allogeneic potential translates to cost-effectiveness.

As Dr. Rezvani shared in her presentation, current manufacturing costs for NK cell therapies are dramatically lower than the cost of autologous CAR T cell therapies; “The cost of one of these doses for us is $600, which is significantly lower than what you pay for an autologous CAR-T product which is around $500,000 to $600,000.”

NK cell-based cancer immunotherapies also have a better safety profile, as they have minimal toxicity and do not induce cytokine release syndrome. Moreover, NK cells are naturally armed with innate tumor recognition via stress receptors and capable of mediating antibody-dependent cytotoxicity through their CD16 expression.

Despite these attributes, NK cells still face some challenges. Specifically, their persistence after infusion is limited. Additionally, similar to CAR-T cells, they are susceptible to inhibitory cues within the solid tumor microenvironment.

Therefore, various modifications have been adopted over time to arm CAR-NK cells, extending their survival after infusion and enabling them to mount multipronged attacks on tumors through the synergy of engineered receptors, antibodies, and cytokines for enhanced efficacy.

Advancing Engineered NK Cell Clinical Trials

Anti-CD19 and CD70 CAR NK Cells

Several key advances have enabled the development of effective NK cell-based cancer immunotherapies. Dr. Rezvani shared how her group has modified NK cells with a CAR construct targeting CD19, having a CD28 co-stimulatory domain, while also arming these cells with IL-15 expression. Clinical studies with this NK cell therapy have confirmed their safety. Dr. Rezvani emphasized that the treatment of 37 patients, all with relapsed and refractory lymphoid malignancies, showed 69% one-year overall survival and 32% one-year progression-free survival and stated that outcomes are “not that dissimilar to what you see with autologous CAR T cells in this particular setting.”

By digging deeper into the response rate variability within their patient population, the team zeroed in on the quality of the umbilical cord blood from which NK cells were derived. They found that NK cells derived from cord blood samples frozen within 24 hours of collection and having fewer than 80 million immature blood cells could support better responses (i.e., ~70% progression-free survival). Molecular characterization revealed that NK cells from optimal starting material did not show signs of hypoxic stress and rather upregulated transcripts relevant to NK cell functionality.

Overall, independently of the CAR construct engineered, whether it targets CD19 or CD70, Dr. Rezvani’s team found that NK cell performance was highly dependent on the quality of the starting material. Moreover, their studies also addressed a critical concern regarding the suitability of using a CAR construct having a CD28 co-stimulatory domain, as NK cells naturally do not express this molecule. Yet, they found this domain to support the best anti-tumor responses in preclinical studies using various animal tumor models, enabling the team to move forward to clinical evaluation.³

While these studies are ongoing, Dr. Rezvani shared compelling images demonstrating the dramatic reduction of tumor burden following CD70 directed CAR/IL-15 NK cell treatment in patients with relapsed and refractory disease (i.e., Hodgkin lymphoma and high-grade B-cell lymphoma). Some of these patients continue to progress to higher NK cell doses without any toxicities.

A significant finding of these studies is the persistence of infused NK cells in patients experiencing complete disease remission. A large number of CAR NK cells can be seen in the circulation of these patients, even four months after treatment. This is by far an improvement over the one to two weeks expected persistence for unmodified NK cells. In vitro evaluation of these cells by Rezvani’s team demonstrated that persistent NK cells are indeed functional and able to kill tumor cells.

Engineering NK Cells with T Cell Receptors

To expand the therapeutic potential of engineered NK cell therapies, Dr. Rezvani and colleagues turned their attention to T cell receptors (TCRs), which enable targeting tumor specific intracellular antigens or neoantigens. As a proof of concept, the team engineered NK cells to express a TCR specific for the tumor antigen NYESO, while also modifying these cells to express IL-15, ensuring their persistence.

Having found in preclinical models of multiple myeloma that these NYESO-TCR-IL-15 engineered NK-cells had similar anti-tumor activity as their NYESO-TCR-T cells counterparts, the team was able to initiate clinical studies. About clinical outcomes in a patient with relapsed and refractory multiple myeloma, Dr. Rezvani shared, “30 days after receiving the cells the bone marrow is completely normal. This patient is now seven months out and continues to be in deep complete remission.”

Targeting Solid Tumors with Engineered NK Cells

Engineering NK cells with tumor-targeting receptors, such as CARs and TCRs, extends their tumor-killing capabilities. Moreover, by engineering them to express cytokines, such as IL-15, it is possible to extend their persistence. Lastly, NK cells can be further modified to overcome tumor inhibitory signals.

Various inhibitory mechanisms in the solid tumor microenvironment reduce the cytotoxic potential of NK cells, requiring innovative engineering approaches. The Rezvani group has focused in evaluating various strategies, including inducing the expression of new cytokines and targeting new checkpoint inhibitory pathways in NK cells.

For instance, they have found that NK cells engineered to express IL-21 have improved metabolic fitness and tumor-killing capacity when compared to those expressing IL-15 in glioblastoma models.⁴ This finding is helping propel another NK cell therapy to the clinic, additionally engineered with two CAR constructs targeting IL-13Ra and EGFRvIII for glioblastoma patients.

The group has also focused in understanding the functional role of the transcription factor cAMP response element modulator (CREM) in NK cells. In a separate presentation, Dr. Hind Rafei, a member of the Rezvani research team, shared her findings on the role of CREM as a regulatory checkpoint of CAR and IL-15 signaling in engineered NK cells.⁵

Among her findings, Dr. Rafei, shared that the expression of CREM is upregulated in engineered NK cells by both CAR activation and IL-15 expression. Moreover, CAR/IL-15 NK cells with high CREM expression also had induced exhaustion markers.

By knocking out CREM from CAR/IL-15 NK cells, Dr. Rafei demonstrated both in vitro and in vivo the critical inhibitory roles of CREM in CAR/IL-15 NK cells’ cytotoxicity, cytokine production, resistance to tumor-induced immunosuppression, proliferation, capacity for tumor-infiltration and persistence.⁵ These findings provide yet another tool for CRISPR/Cas9-mediated editing of NK cells to achieve improved efficacy against solid tumors.

Future Outlook

The future of NK cell cancer immunotherapies shines brightly as innovations from Dr. Rezvani’s team at MD Anderson bridge preclinical discovery and clinical translation, tackling historically intractable cancers. By iterating between bench and bedside, her lab continues to optimize cord blood-derived NK cells for off-the-shelf therapies by setting standards for starting material, and decoding transcriptomic/epigenetic drivers of NK cell fitness. Their NK cell engineering strategies, such as ectopic CD28 signaling to amplify cytotoxicity and TCR-like receptors to target intracellular antigens (e.g., NY-ESO-1), are breaking barriers across tumor indications.

Preclinical breakthroughs, like IL-21 engineering to induce metabolic resilience and memory-like NK cells in glioblastoma models, are now advancing to the clinic. CRISPR screens are uncovering novel checkpoints (e.g., CREM) that, when disrupted, enhance persistence and tumor control.

With 12 trials spanning hematologic and solid cancers—including bispecific-armed NK cells achieving 95% response rates in refractory Hodgkin lymphoma—Rezvani’s work exemplifies a translational flywheel: clinical insights fueling mechanistic studies, which in turn refine next-gen designs.

As challenges like the fitness of NK cells to survive the immunosuppressive tumor microenvironment and persistence are systematically addressed, NK therapies, scalable at 1/1000th the cost of autologous CAR-T cell manufacturing, are poised to democratize access and redefine outcomes for solid tumors.

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References

• 1. Peng, L., Sferruzza, G., Yang, L. et al. CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors. Cell Mol Immunol 21, 1089–1108 (2024). https://doi.org/10.1038/s41423-024-01207-0
• 2. Daher M, Melo Garcia L, Li Y, Rezvani K. CAR-NK cells: the next wave of cellular therapy for cancer. Clin Transl Immunology. 2021 Apr 28;10(4):e1274. doi: 10.1002/cti2.1274
• 3. Acharya S, et al. CD28 Costimulation Augments CAR Signaling in NK Cells via the LCK/CD3ζ/ZAP70 Signaling Axis. Cancer Discov. 2024 Oct 4;14(10):1879-1900. doi: 10.1158/2159-8290.CD-24-0096
• 4. Shanley M, et al. Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD. Cancer Cell. 2024 Aug 12;42(8):1450-1466.e11. doi: 10.1016/j.ccell.2024.07.007
• 5. Hind Rafei, et al. CREM is a regulatory checkpoint of CAR and IL-15 signaling in NK cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1): Abstract nr 6396.Cancer Res (2025) 85 (8_Supplement_1): 6396. https://doi.org/10.1158/1538-7445.AM2025-6396