In the realm of cellular therapy, CAR-NK technology is spearheading a new wave of treatment possibilities. Given the current state of cellular therapy in China, advancing technologies like CAR-NK has become crucial. At the 12th Lu Daopei Hematology Forum, Hematology Frontier had the privilege of inviting Dr. Wenbin Qian from The Second Affiliated Hospital Zhejiang University School of Medicine to provide an in-depth analysis of the benefits and challenges of CAR-NK therapy, explore future research directions, and discuss new chapters in cellular therapy.

Hematology Frontier: You have profound insights into the development of cellular therapy policies and the implementation of clinical research. Under the current regulatory policies for cellular therapy in China, how do you balance innovation with safety to promote the development of CAR-NK and other cellular therapies?

Dr. Wenbin Qian: Innovation holds a pivotal role in medical research and treatment. It is not only essential to avoid reliance on existing technologies and to prevent falling behind the global frontier, but it also serves as the key driving force for the autonomous development and advancement of China’s medical community. Given the rapid advancements in global medical science and technology, Chinese researchers must actively engage in innovative practices, exploring the unknown with independence and leading the way.

Taking CAR-NK therapy as an example, this emerging therapy is currently in its nascent and exploratory stages, with a broad development prospect but also accompanied by many challenges and uncertainties. In this context, the first priority is emphasizing the importance of regulation in investigator-initiated clinical trials, as it forms the cornerstone for ensuring patient safety and maintaining clinical research ethics. Ensuring that every step in the development and clinical research of CAR-NK therapy is conducted within a rigorous and scientific regulatory framework is the premise for its healthy development.

Secondly, comprehensive preclinical research data is essential for evaluating the therapy’s clinical efficacy and formulating subsequent research plans. These data should not only objectively and thoroughly reflect the potential efficacy of CAR-NK therapy but also deeply analyze its safety issues, laying a solid foundation for clinical translation. On this basis, investigator-initiated trials (IIT) become a crucial platform for validating and promoting the therapy. They can stimulate the generation of innovative academic results and accelerate the translation of these results into clinical applications, ultimately benefiting patients.

Moreover, policy support is also indispensable for the research and clinical development of innovative cellular therapies like CAR-NK. Establishing a regulatory system that is both stringent and flexible, coupled with policy measures that encourage innovation, can inspire the creative potential of researchers, reduce the risks associated with innovation, and create a favorable external environment for the rapid development of cellular therapies.

Finally, for innovative therapies that demonstrate good efficacy and safety in IITs, we should actively explore and establish efficient translation mechanisms to ensure that these results can quickly be applied clinically, benefiting a broader patient population. This requires not only continuous efforts at the research level but also strengthened collaboration in industrial translation and market access, jointly promoting the progress and development of medical science and technology in China and globally.

Hematology Frontier: What potential advantages does CAR-NK cell therapy have over CAR-T cell therapy in treating lymphoma? How might the introduction of CAR-NK cell therapy affect the treatment landscape?

Dr. Wenbin Qian: Autologous CAR-T cell therapy involves a complex production process and regulatory system, leading to high costs and limited accessibility. Additionally, this therapy has shown significant side effects in some patients, particularly with high incidences of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Severe CRS occurs in approximately 20% to 30% of patients, while ICANS of grade 3 or higher occurs in about 10% to 15% of cases. Due to the challenges in accessibility and the limitations of personalized treatment products, the large-scale clinical application of CAR-T therapy is currently somewhat restricted.

In contrast, CAR-NK cell therapy exhibits superior safety characteristics, with a lower risk of severe side effects such as CRS and ICANS. Additionally, its production costs are relatively lower, suggesting broader future accessibility. As an off-the-shelf cellular therapy product, CAR-NK offers greater convenience and consistency in quality control and regulation, making it a promising new strategy for widespread cellular therapy application. Given the biological differences between NK cells and T cells, CAR-NK also holds the potential to overcome resistance to CAR-T therapy and may even be used in combination with CAR-T and other innovative therapies to further enhance treatment outcomes.

As a result, CAR-NK cell therapy is gradually gaining widespread attention in the international medical community. Currently, there are over a hundred clinical studies on CAR-NK being conducted globally, with China actively participating in dozens of related studies. Although the clinical application prospects of CAR-NK therapy are not yet fully clear, its numerous advantages suggest that CAR-NK therapy could become an effective complement or a new treatment option to CAR-T therapy, offering more significant benefits to clinical patients.

Hematology Frontier: In your clinical practice, how do you evaluate and monitor the efficacy and safety of CAR-NK cell therapy in lymphoma patients?

Dr. Wenbin Qian: Based on comprehensive evaluations from existing IITs and dose-escalation clinical studies, CAR-NK cell therapy has demonstrated significant advantages in safety, providing patients with a more reassuring treatment option. In terms of efficacy evaluation, CAR-NK cell therapy’s unique mechanism offers a faster tumor-killing speed compared to CAR-T, which typically means the evaluation time point is one month post-treatment, following internationally accepted evaluation standards. PET-CT is currently the mainstream detection method.

However, it is important to note that while CAR-NK therapy shows good short-term safety and efficacy, long-term efficacy and safety still require close monitoring and evaluation. Therefore, like CAR-T therapy, CAR-NK therapy also requires an all-encompassing management strategy to ensure patients receive comprehensive and detailed monitoring throughout the treatment process.

Looking to the future, to better understand the long-term efficacy and safety of CAR-NK therapy, we need to conduct long-term follow-up of all patients currently participating in related clinical studies. This initiative will not only help accumulate valuable clinical data, providing a scientific basis for further optimization and promotion of CAR-NK therapy but will also offer strong support for clinical decision-making, ultimately benefiting more cancer patients.

Hematology Frontier: Regarding the resistance mechanisms to CAR-NK cell therapy in treating lymphoma, what key issues do you believe future research should focus on?

Dr. Wenbin Qian: Although CAR-NK therapy has many advantages, it also has significant limitations, the foremost being its relatively limited cell proliferation capacity, which directly results in insufficient persistence in the body, becoming a key factor limiting its efficacy. Therefore, in clinical applications, achieving optimal treatment outcomes often requires a larger number of CAR-NK cells, necessitating the development of an efficient ex vivo expansion system to meet treatment demands. Additionally, reducing the host’s immune rejection of CAR-NK cells, particularly the occurrence of host-versus-graft (HVG) responses, is also a critical aspect of enhancing CAR-NK efficacy.

To overcome the limitation of restricted in vivo proliferation of CAR-NK cells, future research should actively explore strategies to enhance their proliferative capacity through structural modifications. One promising direction is equipping CAR-NK cells with specific cytokines, such as IL-15 or IL-18, to improve treatment efficacy. These efforts not only hold the potential to break through the current limitations of CAR-NK therapy but also pave new paths in the field of tumor immunotherapy. As research deepens and technology continues to advance, we look forward to CAR-NK therapy showing broader application prospects in the future, bringing hope and benefits to more patients.

Expert Profile

Dr. Wenbin Qian

• Professor, Chief Physician, PhD Supervisor
• Director of Hematology, Second Affiliated Hospital of Zhejiang University School of Medicine
• Director of the Biological Therapy Center, Second Affiliated Hospital of Zhejiang University School of Medicine
• Member, Hematology Physician Branch, Chinese Medical Doctor Association
• Standing Member, Tumor Hematology Committee, Chinese Anti-Cancer Association
• Standing Member, Hematologic Tumor Committee, Chinese Anti-Cancer Association
• Member, Lymphoma Committee, Chinese Anti-Cancer Association
• Vice Chair, Lymphoma Committee, Chinese Geriatrics Society
• Member, Lymphocyte Disease Group, Infection Group, Chinese Society of Hematology
• Chair, Hematology Branch, Zhejiang Medical Association
• Vice President, Hematology Physician Branch, Zhejiang Medical Association
• Vice Chair, Hematology and Lymphoma Committee, Zhejiang Anti-Cancer Association