Using Natural Killer Cells to Treat Lymphoma: Challenges and New Treatment Options

Table of Contents

• Key Points
• Background: Why Lymphoma Treatment Needs New Options
• What Are Natural Killer Cells?
• How Lymphoma Suppresses Natural Killer Cells
• How Lymphoma Medications Affect Natural Killer Cells
• Natural Killer Cells as a Treatment for Lymphoma
• CAR-NK Cell Therapy in Lymphoma
• Clinical Implications: What This Means for Patients
• Limitations and Open Questions
• Recommendations and Future Directions
• Frequently Asked Questions
• Source Information

Key Points

• Natural killer (NK) cells can recognize and kill lymphoma cells without prior sensitization, but the tumor microenvironment often suppresses their activity.
• Lymphoma cells release factors like TGF-b and IL-10 and engage inhibitory receptors to impair NK cell function, leading to immune evasion.
• Standard lymphoma treatments have mixed effects: some chemotherapy suppresses NK cells, while rituximab and lenalidomide enhance NK cell-mediated cytotoxicity.
• Allogeneic NK cell transplantation and CAR-NK cell therapy are promising approaches, but challenges include cell persistence and donor availability.
• Combining NK cell therapy with standard treatments may improve outcomes, but further research is needed to optimize strategies and identify predictive biomarkers.

Background: Why Lymphoma Treatment Needs New Options

Lymphoma is a general category of blood cancers that start in abnormal lymphocytes (a type of white blood cell that is part of the immune system). Lymphomas are typically divided into two main groups: Hodgkin's lymphoma (HL) and non-Hodgkin lymphoma (NHL). Non-Hodgkin lymphoma is much more common than Hodgkin's lymphoma.

Among the subtypes of non-Hodgkin lymphoma, the most common are B-cell lymphomas. These include diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and mantle cell lymphoma. T-cell lymphomas and Hodgkin's lymphoma are less common, but they have important clinical subtypes with unique pathologic and clinical features.

Despite advances in chemotherapy and targeted therapy, the outlook for most patients with relapsed or refractory B-cell lymphoma remains unfavorable. Relapsed means the cancer has come back after treatment. Refractory means the cancer did not respond to treatment.

Standard first-line treatment regimens include R-CHOP, which stands for rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. These regimens have dramatically increased survival rates in B-cell lymphomas, particularly diffuse large B-cell lymphoma. However, these regimens have limited long-term benefits in patients with high-risk or advanced disease.

In addition, autologous stem cell transplantation (using the patient's own stem cells) is beneficial for some patients, but it is not an option in all cases. Resistance to treatment and relapse are also often seen in other types of lymphoma, such as some T-cell lymphomas and Hodgkin's lymphomas. These limitations highlight the need for more robust and individualized treatment approaches across the spectrum of lymphatic malignancies.

Cell-based immunotherapy has revolutionized cancer treatment by leveraging immune system cells to identify and destroy tumor cells. Among the diverse cell-based immunotherapeutic strategies, the use of natural killer (NK) cells has emerged as a promising therapeutic approach in lymphoma.

As innate immune effectors, NK cells possess distinctive properties that make them attractive candidates for immunotherapy. Most importantly, they can recognize and eliminate tumor cells without prior sensitization. This means NK cells do not need to be exposed to a specific threat before they can attack it. NK cells play a critical role in immune surveillance against tumor development and viral infections.

NK cells possess a delicate balance of activating and inhibitory receptors. This balance allows them to distinguish between healthy cells and cells that exhibit altered self-characteristics, such as infected or malignant cells.

However, in the context of lymphoma, abnormalities within the tumor microenvironment can suppress NK cell activity. This compromises the ability of NK cells to effectively target and eliminate tumor cells. Researchers are therefore exploring strategies to enhance NK cell function and overcome immunosuppressive mechanisms. These strategies include targeting immunosuppressive factors, modulating cytokine levels, and overcoming NK cell exhaustion.

By understanding the complex interplay between NK cells and the lymphoma microenvironment, novel immunotherapeutic strategies can be developed. These strategies aim to improve anti-tumor responses and enhance NK cell-mediated immunity in lymphoma.

What Are Natural Killer Cells?

Natural killer cells are a type of CD16+CD56+ cytotoxic lymphocyte that belongs to the innate immune system. Cytotoxic means they can kill other cells. Lymphocytes are a type of white blood cell. The markers CD16 and CD56 are proteins on the surface of these cells that help identify them.

NK cells have the ability to induce apoptosis (programmed cell death) even in the absence of antibodies and major histocompatibility complexes. Major histocompatibility complexes are proteins that help the immune system recognize cells as "self" or "foreign."

NK cells recognize tumor antigens through killer-cell immunoglobulin-like receptors (KIRs). These receptors have either inhibitory or activating functions, depending on the intracytoplasmic region of the receptor. The intracytoplasmic region is the part of the receptor inside the cell.

The presence and behavior of NK cells can be altered at the site where lymphoma begins. Lymphomas develop complex interactions with the immune system, including alterations in the microenvironment where lymphomas develop. These alterations impact NK cell function and behavior.

Multiple modifications occur in the lymphoma microenvironment. These include changes in immunoregulatory cells, the cytokine milieu (the mix of signaling molecules), stromal cells, expression of activating and inhibitory receptors, and functional NK cells.

Variations in NK cells within the lymphoma microenvironment differ based on the particular subtype of lymphoma. Classic Hodgkin's lymphoma (cHL) is characterized by a potent immunosuppressive tumor microenvironment (TME) that inhibits NK cells. The immunosuppressive nature of the TME in classic Hodgkin's lymphoma specifically inhibits the proliferation and activity of NK cells. This contributes to the tumor immune-escape mechanisms.

This deficiency of NK cells begins at the tumor site and progresses systemically in patients with advanced disease or adverse prognostic factors. Several facets of classic Hodgkin's lymphoma account for this effect on NK cells.

Locally, malignant Reed-Sternberg cells and cells from the tumor microenvironment express ligands for inhibitory receptors on NK cells. These ligands include Human Leukocyte Antigen (HLA)-E, HLA-G, and programmed death-ligand 1. The secretion of chemokines and cytokines mediates the systemic immunosuppression. These include soluble interleukin (IL)-2 receptor (sCD25), transforming growth factor-beta (TGF-b), IL-10, CXCL9, and CXCL10.

Generally in the lymphoma spectrum, the lymphoma microenvironment often contains regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). These cells suppress NK cell activity and impair their antitumor functions. This leads to immune evasion by lymphoma cells.

Besides immunoregulatory cells, stromal cells in the lymphoma microenvironment, such as cancer-associated fibroblasts (CAFs), secrete factors that suppress NK cell function. They may also contribute to the formation of a physical barrier. This barrier limits NK cell infiltration into the tumor site.

In addition to cells, the presence of certain cytokines within the lymphoma microenvironment influences NK cell behavior. Elevated levels of transforming growth factor-beta (TGF-b) and IL-10 inhibit NK cell function. This impairs their cytotoxicity and cytokine production.

The well-characterized inhibitory effect of TGF-b on the effector functions and cytotoxic activity of NK cells has been demonstrated. It has been shown that the IL-10 signaling pathway can be promoted to inhibit the TGF-b-induced suppression of NK cell cytotoxic function.

NK cells also express an array of activating and inhibitory receptors that regulate their activity. In lymphomas, the expression of these receptors on NK cells can be altered. This affects their ability to recognize and kill tumor cells. For example, the downregulation of NKG2D receptor ligands on lymphoma cells impairs NK cell activation.

Notably, prolonged exposure to the lymphoma microenvironment leads to NK cell exhaustion or dysfunction. This exhaustion is characterized by reduced cytotoxicity, impaired cytokine production, and altered receptor expression. Exhausted NK cells exhibit decreased responsiveness to stimulation and diminished tumor-killing capacity.

Understanding the complex interplay between NK cells and the lymphoma microenvironment is crucial for developing novel immunotherapeutic strategies. These strategies aim to enhance NK cell function and improve anti-tumor responses.

How Lymphoma Suppresses Natural Killer Cells

Despite the importance of NK cells in the immune response against cancer cells, lymphomas employ various mechanisms to evade or suppress NK cell activity. The most common suppressive factors are tumor-derived soluble factors. These factors are released by lymphoma cells and have immunosuppressive effects on NK cells.

These factors include cytokines, chemokines, and growth factors, such as TGF-b and IL-10. These molecules inhibit the activity of NK cells and impair their cytotoxic functions.

The interaction between inhibitory receptors expressed on NK cells and their corresponding ligands on lymphoma cells represents another mechanism that suppresses NK cell activity. Inhibitory receptors recognize specific ligands on target cells. Lymphoma cells can upregulate the expression of ligands for these inhibitory receptors, such as Major Histocompatibility Complex class I molecules.

These ligands engage with inhibitory receptors like KIRs and NKG2A. This engagement transmits inhibitory signals to the NK cells and dampens their cytotoxicity against lymphoma cells.

In addition, immunoregulatory cells, such as Tregs and MDSCs, often exist in the lymphoma microenvironment and also suppress NK cell function. These cells produce immunosuppressive molecules and inhibit NK cell activity. This prevents effective anti-tumor responses.

Furthermore, extracellular matrix components and stromal cells in the lymphoma microenvironment, such as cancer-associated fibroblasts (CAFs), secrete factors and remodel the extracellular matrix. This creates a physical barrier that hampers NK cell infiltration into the tumor site. This limited access to malignant lymphocytes imposes spatial constraints that impede NK cell recognition and subsequent mediated cytotoxicity.

Metabolic reprogramming derived from lymphoma cells also leads to alterations in the tumor microenvironment that affect NK cell function. For example, increased consumption of nutrients and competition for resources within the microenvironment impair the NK cell metabolism and compromise their effector functions.

Immune checkpoint molecules, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), expressed in NK cells are upregulated in the lymphoma microenvironment. Engagement of these checkpoints by their ligands on lymphoma cells leads to NK cell exhaustion and functional suppression.

These immune checkpoint molecules are negative regulators of T-cell and NK cell function. They limit the amplitude of T cell and NK cell activation. The blockade of immune checkpoints, such as PD-1 and CTLA-4, has shown promising results in enhancing antitumor immunity and producing durable clinical responses.

Moreover, genetic and epigenetic changes within lymphoma cells contribute to NK cell suppression. These alterations affect the expression of molecules involved in NK cell recognition and activation. This impairs the ability of NK cells to effectively target and eliminate lymphoma cells.

It has been observed that promoter methylation or hypermethylation of tumor suppressor genes, miRNA expression or methylation level, and Long noncoding RNA (LncRNA) expression were associated with lymphoma disease progression.

How Lymphoma Medications Affect Natural Killer Cells

The treatment of lymphoma relies heavily on medication. Treatment varies depending on the type and stage of lymphoma, as well as individual patient factors. Common types of medication used in lymphoma treatment include chemotherapy, monoclonal antibodies, immunomodulatory drugs, and targeted therapies.

Chemotherapy

Some chemotherapy agents have suppressive effects on NK cell function. Investigations have been conducted on the effects of the chemotherapy agents commonly used in lymphoma treatment on NK cell proliferation and cytotoxicity.

The findings indicate that NK cell activation is modulated by chemotherapy-induced DNA damage and DNA damage response pathways. This leads to alterations in the NK cell phenotype and impaired cytotoxicity.

Research has been carried out on the impact of various chemotherapy drugs, such as cyclophosphamide and methotrexate, on the ability of NK cells to destroy cancer cells. These investigations have focused on the role of a protein called NKG2D ligand in mediating this process.

The findings have shown that specific chemotherapy agents cause a decrease in the expression of NKG2D ligands on lymphoma cells. As a result, NK cells have a reduced ability to recognize and eliminate these cancer cells.

Moreover, both dendritic cells (DCs) and NK cells were treated with chemotherapy such as ifosfamide. When this happened, dendritic cells were able to overcome the negative effect of ifosfamide on NK cytotoxic function. It has been reported that ifosfamide treatment of dendritic cells resulted in a reduction in indirect dendritic cell stimulation of NK cell proliferation via T cells and T cell-derived IL-2. While the negative impact on NK cytotoxic function can be overcome by dendritic cells, the restoration of NK cell interferon-gamma (IFN-g) production is not as effective.

Monoclonal Antibodies

While chemotherapy may have suppressive effects on NK cell function, monoclonal antibody therapies enhance NK cell-mediated cytotoxicity. Rituximab is an anti-CD20 chimeric monoclonal antibody. It targets the CD20 protein found on the surface of B cells, including malignant B cells in some lymphomas.

Studies suggest that rituximab enhances NK cell-mediated cytotoxicity through the CD16 signaling pathway. This pathway is involved in antibody-dependent cellular cytotoxicity (ADCC). ADCC is a process where antibodies attach to target cells and help immune cells kill them.

Rituximab-mediated binding to CD20 on lymphoma cells triggers NK cell activation and ADCC. This ultimately results in the targeted elimination of malignant cells. The results of a meta-analysis confirmed that NK cell-mediated cytotoxicity against lymphoma cells through ADCC is significantly enhanced by rituximab treatment. This contributes to improved clinical outcomes.

Immunomodulatory Drugs

Between 2012 and 2014, research focused on immunomodulatory medications in lymphoma, including lenalidomide. Lenalidomide has immunomodulatory effects, including the activation and enhancement of NK cell function. It stimulates NK cell activity and cytokine production, potentially contributing to antitumor immune responses.

Lenalidomide treatment increases CD20 expression on lymphoma cells. This leads to enhanced NK cell-mediated lysis of tumor cells. Lenalidomide also enhances NK cell activity, including increased cytotoxicity and IFN-g production. It also modulates cytokine production by ovarian cancer cells.

These studies provide evidence that lenalidomide can activate and enhance NK cell function, contributing to antitumor immune responses in lymphoma treatment. The immunomodulatory effects of lenalidomide and its potential contribution to antitumor immune responses in lymphoma treatment are supported by these findings.

Furthermore, recent studies suggest that the combination of lenalidomide and rituximab may have complementary mechanisms of action. This unique combination is characterized by immune enhancement, not immunosuppression.

This benefit was demonstrated in the Phase III AUGMENT trial. The AUGMENT trial evaluated rituximab with or without lenalidomide in relapsed rituximab-sensitive follicular lymphoma. The trial found a significant progression-free survival benefit with the combination.

Results demonstrated that lenalidomide has synergy with anti-CD20 antibodies such as obinutuzumab and rituximab. This synergy occurs via reconstitution of a functional immune synapse, improved NK cell function, and greater antibody-dependent cellular cytotoxicity.

In animal models and in vitro studies, the effect of rituximab in combination with lenalidomide on ADCC and direct apoptosis was assessed in B-cell lymphoma. The results showed that the lenalidomide and rituximab combination therapy enhanced ADCC and direct apoptosis in B-cell lymphoma. Multiple phase II studies showed that lenalidomide and rituximab therapy achieves clinical synergy in treatment-naive, relapsed, and refractory settings.

Targeted Therapy

Unlike chemotherapy, which can affect both cancerous and healthy cells, targeted therapies are more selective in their action and can minimize damage to healthy cells. They specifically target molecules or pathways involved in the immunosuppressive microenvironment. They can be used alone or in combination with other treatments, such as chemotherapy or immunotherapy.

Various targeted therapies, such as kinase inhibitors, are now used in the treatment of specific lymphoma subtypes. These include venetoclax, duvelisib, copanlisib, polatuzumab vedotin, and ibrutinib. Venetoclax, duvelisib, and copanlisib inhibit some factors that are involved in the growth and survival of cancer cells.

Similarly, ibrutinib disrupts B-cell receptor (BCR) signaling by inhibiting Bruton's tyrosine kinase (BTK). This impairs the essential growth and survival mechanisms of malignant B cells. By inhibiting this signaling pathway, ibrutinib helps to slow down or stop the growth of lymphoma cells.

Brentuximab vedotin and polatuzumab vedotin target proteins found on the surface of some lymphoma cells. These targeted therapies may indirectly facilitate NK cell activation by disrupting tumor-mediated immune evasion pathways. They also reduce the overall suppressive burden within the microenvironment.

Recent studies have investigated the potential of various inhibitors to enhance NK cell-mediated cytotoxicity against lymphoma cells. One study found that Bruton's tyrosine kinase (BTK) inhibitors, such as ibrutinib, can enhance NK cell-mediated cytotoxicity. This occurs by targeting signaling pathways involved in immune evasion and tumor cell survival. BTK, an essential component of the B-cell receptor pathway, has emerged as a novel target in the treatment of B-cell malignancies.

In addition, selinexor, a selective inhibitor of the nuclear export protein exportin-1 (XPO1), enhances NK cell activation against malignant B cells via downregulation of HLA-E. The NKG2A:HLA-E axis is a novel immune checkpoint target. It has been found that selinexor sensitizes lymphoma cells to NK cell-mediated killing via disruption of this interaction.

The study also provides preliminary evidence suggesting an association between NK cell activity and clinical response to selinexor. These data indicate that NK cells may contribute to the therapeutic efficacy of selinexor. This potentially provides a rationale for its synergistic use with NK cell-targeted therapies in lymphoma treatment.

Natural Killer Cells as a Treatment for Lymphoma

NK cells are crucial in host immunity against cancer, but cancers develop mechanisms to escape NK cell attack or induce defective NK cells. NK cell-based cancer immunotherapy aims to overcome NK cell paralysis using several approaches.

These approaches include expanded allogeneic NK cells, stable allogeneic NK cell lines, and genetic modification of fresh NK cells or NK cell lines. Allogeneic means the cells come from a donor rather than the patient.

Therapeutic NK cells can be derived from various sources. These include peripheral blood cells, cord blood cells, stem cells, or even induced pluripotent stem cells (iPSCs). A variety of stimulators can be used for large-scale production in laboratories or good manufacturing practice facilities. These stimulators include soluble growth factors, immobilized molecules or antibodies, and other cellular activators.

In the first approach, expanded allogeneic NK cells are not inhibited by self-histocompatibility antigens like autologous NK cells. This makes them suitable for adoptive cellular immunotherapy. In the second approach, stable allogeneic NK cell lines are more practical for quality control and large-scale production. Thirdly, genetic modification of fresh NK cells or NK cell lines to highly express cytokines, Fc receptors, and/or chimeric tumor-antigen receptors is another approach.

In the context of lymphoma, the objective of NK cell therapy revolves around exploiting the inherent anti-tumor attributes possessed by these cells. The specific aim is to selectively target and eradicate lymphoma cells. The implementation of this therapy entails the introduction of ex vivo expanded and activated NK cells into the patient's system. These NK cells may be autologous (derived from the patient themselves) or allogeneic (derived from a donor).

The ultimate goal lies in bolstering the immune response against lymphoma cells, thereby promoting regression of the tumor. Clinical trials investigating allogeneic NK cell therapies in patients with relapsed or refractory hematologic malignancies, including those with B-cell lymphoma, have supported the significant anti-tumor activity of these cells. These therapies may provide a superior safety profile, as they are associated with a lower incidence of cytokine release syndrome.

The article presents a table outlining diverse therapeutic strategies utilizing natural killer cell therapy for lymphoma:

• Allogeneic NK Cell Transplantation: Infusion of NK cells from a healthy donor. Advantages include reduced risk of graft-versus-host disease (GvHD). Challenges include donor availability and compatibility.
• Autologous NK Cell Infusion: Infusion of the patient's own NK cells. Advantages include lower risk of immune rejection. Challenges include limited NK cell numbers and quality.
• CAR-NK Cell Therapy: Genetic engineering of NK cells to express CARs. Advantages include enhanced specificity and potency. Challenges include optimization of CAR design and manufacturing.
• Combination Therapies: Co-administration of NK cell therapy with other treatments. Advantages include synergistic effects for improved outcomes. Challenges include identifying optimal combination strategies.
• Cytokine Stimulation: Administration of cytokines (e.g., IL-2, IL-15). Advantages include promotion of NK cell proliferation and cytotoxicity. Challenges include potential systemic side effects.
• Antibody Stimulation: Administration of antibodies (e.g., anti-CD20). Advantages include enhancement of NK cell-mediated antibody-dependent cytotoxicity (ADCC). Challenges include resistance or downregulation of target antigens.
• Gene Editing Techniques: CRISPR/Cas9-mediated gene editing in NK cells. Advantages include improved persistence and resistance to immunosuppression. Challenges include off-target effects and safety concerns.

The intention behind combination approaches is to amplify the effectiveness of standard treatments while concurrently enhancing the immune response against lymphoma. Standard therapeutic modalities include chemotherapy, radiation therapy, or targeted therapies. The article also references tables outlining selected clinical studies using allogeneic NK cells in lymphoma and preclinical data supporting their potential efficacy.

CAR-NK Cell Therapy in Lymphoma

Chimeric Antigen Receptors (CARs) are genetically engineered to recognize and bind to antigens on the cell surface. Receptors allow cells to recognize specific targets, for example, tumor cells, and trigger potent cytotoxic activity against them. CARs are usually designed to bind to particular antigens on the surface of cancer cells and therefore provide targeted therapies against tumors.

While the earliest cancer treatments were mainly based on CAR-T cell therapy, recent studies have also proposed CAR-NK cell therapy (CAR-engineered NK cells) as a promising candidate for tumor treatment.

These treatments make use of NK cells, which already have the innate ability to recognize and eradicate cancer cells. By using CAR technology, the cells are engineered to recognize and eliminate specific tumor antigens.

These cells, due to their unique features, do not require HLA matching and possess allogeneic potential. This means they can effectively target cancer cells. Furthermore, CAR-NK cells have the ability to exert potent antitumor effects without inducing severe toxicities.

Clinical Implications: What This Means for Patients

The findings in this review have several important implications for patients with lymphoma. First, allogeneic NK cell transplantation has shown promise in specific subtypes of lymphoma. This approach offers a reduced risk of graft-versus-host disease, improved response rates, prolonged remissions, and increased overall survival.

Graft-versus-host disease is a condition where donated immune cells attack the patient's healthy tissues. A reduced risk of this complication is a significant advantage for patients considering cell therapy.

Second, combining NK cell therapy with standard treatments such as chemotherapy or immune checkpoint inhibitors holds potential for synergistic effects. Synergistic means the combined effect is greater than the sum of the individual effects. This combination approach could improve outcomes for patients who do not respond well to standard treatments alone.

Third, medications already used in lymphoma treatment have varying effects on NK cells. Some chemotherapy agents suppress NK cell function, while monoclonal antibodies like rituximab and immunomodulatory drugs like lenalidomide enhance NK cell activity. Understanding these effects helps doctors choose treatment combinations that maximize anti-tumor activity.

Fourth, targeted therapies such as ibrutinib and selinexor may enhance NK cell-mediated cytotoxicity. This provides additional rationale for combining these agents with NK cell-targeted therapies.

However, addressing challenges such as cell persistence, the immunosuppressive tumor microenvironment, and optimal delivery methods is crucial to improve efficacy. Cell persistence means how long the infused NK cells survive and remain active in the patient's body.

Limitations and Open Questions

The review identifies several challenges that limit the effectiveness of NK cell therapy in lymphoma. These challenges must be addressed to improve treatment outcomes.

• Cell persistence: Infused NK cells may not survive long enough in the patient's body to produce a lasting anti-tumor effect.
• Immunosuppressive tumor microenvironment: The lymphoma microenvironment contains factors that suppress NK cell function, limiting their ability to attack cancer cells.
• Optimal delivery methods: The best way to deliver NK cells to patients has not been fully determined.
• Donor availability and compatibility: Allogeneic NK cell transplantation depends on finding suitable donors.
• Limited NK cell numbers and quality: Autologous NK cell infusion is limited by the number and quality of NK cells that can be collected from the patient.
• CAR design and manufacturing: CAR-NK cell therapy requires optimization of CAR design and manufacturing processes.
• Identifying optimal combination strategies: The best combinations of NK cell therapy with other treatments have not been established.
• Potential systemic side effects: Cytokine stimulation can cause side effects throughout the body.
• Resistance or downregulation of target antigens: Lymphoma cells may develop resistance to antibody stimulation or lose the target antigens that antibodies recognize.
• Off-target effects and safety concerns: Gene editing techniques such as CRISPR/Cas9 may cause unintended changes in NK cells.

Further investigations are required to gain a better understanding of NK cell-mediated responses. Researchers also need to refine genetic engineering approaches, identify predictive biomarkers, and optimize combination strategies. Predictive biomarkers are biological markers that can help predict which patients will respond to treatment.

Recommendations and Future Directions

Continued research and clinical trials will play a vital role in optimizing cell therapy and expanding treatment options for lymphoma patients. The authors recommend several areas of focus for future work.

1. Gain a better understanding of NK cell-mediated responses in lymphoma.
2. Refine genetic engineering approaches to improve NK cell therapy.
3. Identify predictive biomarkers to determine which patients will benefit most from NK cell therapy.
4. Optimize combination strategies that pair NK cell therapy with standard treatments.
5. Address challenges such as cell persistence, the immunosuppressive tumor microenvironment, and optimal delivery methods.

For patients, these recommendations mean that new and better treatment options may become available as research progresses. Patients with relapsed or refractory lymphoma, particularly those who have limited options with standard treatments, may benefit from clinical trials investigating NK cell therapies.

Patients interested in NK cell therapy should discuss clinical trial opportunities with their healthcare team. The field is rapidly evolving, and new findings continue to emerge.

Frequently Asked Questions

What are natural killer cells and how do they fight lymphoma?

Natural killer (NK) cells are a type of white blood cell that belong to the innate immune system. They can recognize and kill tumor cells without needing prior exposure to them. In lymphoma, NK cells can induce programmed cell death in cancer cells, but the tumor environment often suppresses their activity.

How does lymphoma suppress natural killer cells?

Lymphoma cells release soluble factors such as TGF-b and IL-10 that inhibit NK cell function. They also express ligands that engage inhibitory receptors on NK cells, and recruit regulatory T cells and myeloid-derived suppressor cells. Together, these mechanisms impair NK cell cytotoxicity and allow the cancer to evade immune attack.

Do common lymphoma medications affect natural killer cells?

Yes, they can have varying effects. Some chemotherapy agents, such as cyclophosphamide and methotrexate, can reduce NK cell function by decreasing NKG2D ligands on lymphoma cells. In contrast, monoclonal antibodies like rituximab and immunomodulatory drugs like lenalidomide enhance NK cell-mediated cytotoxicity. Targeted therapies such as ibrutinib and selinexor may also boost NK cell activity.

What is CAR-NK cell therapy and how does it work?

CAR-NK cell therapy involves genetically engineering NK cells to express chimeric antigen receptors (CARs) that recognize specific tumor antigens. This enhances their ability to target and kill lymphoma cells. CAR-NK cells do not require HLA matching and may have allogeneic potential, meaning they can be used in more patients without causing severe toxicities.

What are the main challenges with NK cell therapy for lymphoma?

Key challenges include limited persistence of infused NK cells, an immunosuppressive tumor microenvironment that inhibits NK cell function, and difficulty finding suitable donors for allogeneic transplants. Other issues are optimizing delivery methods, CAR design, and combination strategies, as well as managing potential side effects from cytokine stimulation and gene editing.

Are there clinical trials for NK cell therapy in lymphoma?

Yes, clinical trials have investigated allogeneic NK cell therapies in patients with relapsed or refractory hematologic malignancies, including B-cell lymphoma. These trials have shown significant anti-tumor activity and a lower incidence of cytokine release syndrome. Patients interested in NK cell therapy should discuss clinical trial opportunities with their healthcare team.

What does the future hold for NK cell therapy in lymphoma?

Researchers recommend refining genetic engineering, identifying predictive biomarkers, and optimizing combination strategies with standard treatments. Addressing challenges like cell persistence and the immunosuppressive microenvironment is crucial. As research progresses, new and better treatment options may become available, particularly for patients with relapsed or refractory lymphoma who have limited standard options.

When should a patient with relapsed or refractory lymphoma seek a second opinion about NK cell therapy?

A second opinion is worth considering when lymphoma has relapsed or is refractory, since the outlook for most patients in that setting remains unfavorable and standard regimens have limited long-term benefit in high-risk or advanced disease. It can also help when autologous stem cell transplantation is not an option, or when a patient wants to know whether a clinical trial of allogeneic NK cell transplantation or CAR-NK cell therapy is appropriate. A review of pathology, prior treatment and donor options supports that discussion. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Harnessing the power of natural killer cells in Lymphoma immunotherapy: Overcoming challenges and enhancing treatment options.

Authors: Roshandel E, Lasemi MV, Mehravar M, Salimi M, Majidi M, Mohammadali F, Seraji HR, Hajifathali A.

Author affiliations: Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran; Department of Hematology and Oncology, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Note: Elham Roshandel and Maryam Vahdat Lasemi are co-first authors.

Publication details: Hematology, Transfusion and Cell Therapy, 2026;48(3):106352. Published by Elsevier España, S.L.U. on behalf of Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. This is an open access article under the CC BY license.

DOI: https://doi.org/10.1016/j.htct.2026.106352

Article history: Received 11 December 2024; Accepted 30 November 2025.

This patient-friendly article is based on peer-reviewed research.