Dr Rezvani on Advancements and Challenges of NK Cell Therapy

In an interview with Targeted Oncology, Katy Rezvani, MD, PhD, vice president and head, Institute for Cell Therapy Innovation and Discovery, Department of Institute for Cell Therapy Innovation and Discovery, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the antitumor effectiveness of chimeric antigen receptor-natural killer (CAR-NK) cell therapy.

The focus of Rezvani's ongoing research is cell therapy, specifically harnessing NK cells as a platform for cellular engineering. This endeavor is built upon over a decade of dedicated work, driven by the belief that NK cells offer a compelling opportunity to significantly advance beyond the successes already achieved with CAR T cells. The underlying principle remains the same: redirecting the inherent specificity of immune cells toward a chosen target antigen on a cancer cell.

NK cells present several distinct and potentially transformative advantages, primarily relating to their use in an allogeneic (off-the-shelf) setting. Unlike T cells, allogeneic NK cells do not typically induce graft-vs-host disease (GVHD), a life-threatening complication that often restricts the use of allogeneic CAR T cells. This allows for the development of ready-to-use, "off-the-shelf" products that could dramatically shorten treatment timelines and reduce costs. Furthermore, NK cell therapies have so far demonstrated a generally more favorable safety profile compared to CAR T cells, often resulting in lower instances of severe cytokine release syndrome and neurotoxicity.

Initially, efforts concentrated on applying our CAR NK cells in the treatment of hematologic malignancies (blood cancers), where CAR T cells have had their most notable successes. Rezvani observed comparable efficacy, finding that the CAR NK cells could be highly effective against certain types of blood cancers, particularly lymphoid malignancies.

Rezvani and her team are now pivoting a significant portion of their research toward understanding how to apply CAR NK cell technology for the treatment of solid tumors. This category includes some of the most challenging cancers to treat, such as glioblastoma, pancreatic cancer, and ovarian cancer.

Treating solid tumors presents a formidable obstacle: the immensely hostile tumor microenvironment (TME). This environment is highly detrimental to the function and survival of immune cells. The hostility is multifaceted, encompassing:

1. Physical Barriers: The dense stroma and mass of the solid tumor itself act as a physical impediment, preventing sufficient immune cell infiltration.
2. Hypoxia: Low oxygen levels within the tumor, a condition known as hypoxia, severely impairs the metabolic activity and killing capacity of immune cells.
3. Acidity: Tumors often create an acidic environment, which is toxic to immune cells.
4. Immunosuppressive Molecules: The TME is saturated with various inhibitory signals and immunosuppressive molecules (like TGF-
   β and certain cytokines) released by cancer cells and other stromal cells, which actively shut down immune responses.

Given this hostile environment, a crucial question arose: How can we engineer NK cells to be resistant to the TME's suppressive effects, ensuring they maintain their potency and proliferative capacity once they successfully infiltrate the tumor mass?

This challenge is analogous to the work done on checkpoint inhibitors in T cell immunotherapy. Just as immune checkpoints (like PD-1 and CTLA-4) place brakes on T cell function, similar inhibitory pathways and checkpoints impact the functionality of NK cells. However, instead of pursuing a hypothesis-driven approach by individually targeting known checkpoints, Rezvani and her team decided to adopt an unbiased approach in their engineering efforts. The goal is to identify novel or systemic modifications that enhance the overall robustness and persistence of the CAR NK cells against the multiple stressors present within the solid tumor microenvironment.

Watch more with Dr Rezvani.

REFERENCE:

Bierderstädt A, Basar R, Park JM, et al. Genome-wide CRISPR screens identify critical targets to enhance CAR-NK cell antitumor potency. Cancer Cell. 2025 Aug 18:S1535-6108(25)00327-7. doi: 10.1016/j.ccell.2025.07.021. Online ahead of print.