Natural Killer Cell Research: Hematological cancers

What Are They Looking At?

This is a Phase 1, first-in-human study, mainly focused on safety, with early signs of effectiveness also being explored.

The study is looking at:

• Whether CD19 t-haNK cells are safe
• What side effects occur
• Whether tumors show signs of shrinking or stabilizing
• Whether combining the cells with rituximab, with or without an immune-boosting drug, changes outcomes

Type of Cells Used

• Cell Type: Natural Killer (NK) cells
• Product Name: CD19 t-haNK
• Cell Category: CAR-NK cell therapy (not CAR-T)

These are immune cells designed to recognize and kill cancer cells.

Cell Source / Cell Markers / Cell Manufacturing

Source: Allogeneic (donor-derived), lab-grown cell line

Cell Line Origin: Derived from the NK-92 cell line

Not taken from the patient

The CD19 t-haNK cells are genetically engineered to express:

• CD19-targeted CAR
  helps the cells recognize CD19-positive B-cell lymphoma
• High-affinity CD16 (FcγRIIIa 158V)
  improves antibody-dependent cell killing when used with rituximab
• Endoplasmic-reticulum-retained IL-2 (ER-IL-2)
  supports cell survival and activity without giving IL-2 to the patient

No additional cell markers are listed in the study record.

Treatment Plan

Treatment happens in several stages:

Stage 1: Chemotherapy to prepare the immune system

• Participants first receive two chemotherapy drugs (cyclophosphamide and fludarabine).
• These drugs temporarily reduce existing immune cells to make room for the study cells.

Stage 2: CAR-NK cells on their own

• Participants receive CD19 t-haNK cells by themselves for 4 weeks.

Stage 3: Short rest, then chemotherapy again

• After a short break, participants receive the same two chemotherapy drugs again.

Stage 4: CAR-NK cells plus standard treatment

• Participants then receive CD19 t-haNK cells together with:

• Arm A: rituximab
• Arm B: rituximab plus N-803 (an immune-stimulating drug)

Stage 5: Additional combination treatment

• Participants may receive up to four more 4-week cycles of the combination treatment.
• These later cycles do not include more chemotherapy.

Drugs Used Alongside the Cells

• Cyclophosphamide (chemotherapy)
• Fludarabine (chemotherapy)
• Rituximab (anti-CD20 antibody)
• N-803 (also called Anktiva; IL-15 superagonist) — Arm B only

Study Design

• Phase 1
• Open-label (no blinding)
• Randomized 1:1 into two treatment arms
• No healthy volunteers
• No placebo or sham control

Time Frame

• Safety: within 30 days after each cell infusion
• Cancer response and survival measures: up to 12 months after first infusion

Primary Goal (Main Safety Measure)

The study mainly looks at how safe the treatment is, by monitoring:

• Side effects that happen after treatment
  (any new or worsening symptoms)
• Serious medical problems
  (events that require hospital care, are life-threatening, or medically significant)
• Important changes in blood tests and vital signs
  (such as blood counts, organ function, blood pressure, heart rate, or temperature)

Secondary Measures (Early Effectiveness)

Overall Response Rate (ORR)
whether tumors shrink or disappear

Assessed using LYRIC criteria, a lymphoma-specific response system

Other Measured Outcomes

• Progression-Free Survival (PFS)
  time until the cancer grows or returns
• Duration of Response (DoR)
  how long a response lasts once achieved
• Overall Survival (OS)
  time from treatment until death or last follow-up

Follow-up Schedule

• Participants are followed for safety after each infusion
• Cancer response and survival outcomes are tracked for up to 12 months

Procedure

Patients first received chemotherapy (fludarabine and cytarabine) to reduce leukemia burden and create space for the infused NK cells.

After chemotherapy, patients received repeated infusions of donor NK cells.

Delivery Method

• Intravenous infusion
• NK cells were given every other day
• Up to 6 infusions per patient

Cell Type & Source

• Haploidentical donor-derived natural killer (NK) cells
• Cells came from a partially matched family donor
• Cells were not genetically modified

Cell Preparation & Quality

Cells were expanded ex vivo using a specialised feeder-cell culture system.

Preparation steps:

• Blood was collected from the donor
• Immune cells were processed to remove T cells (CD3⁺ cells)
• NK cells expanded for 14 days under GMP conditions

The cells were expanded using feeder cells (K562) designed to provide:

• Membrane-bound interleukin-21 (mbIL-21): It tells NK cells to grow, stay active, and keep their killing ability
• 4-1BB ligand (4-1BBL): An activation switch for Immune Cells, it turns them fully on.

Cell identity and tracking:

NK cells defined by expression of:

• CD56⁺
• CD16⁺/⁻
• CD3⁻

No genetic engineering of the NK cells themselves was performed.

Dosage

Dose levels:

• Low Dose: 1 million NK cells for every kilogram of body weight, per infusion
• High Dose: 10 Million NK cells for every kilogram of body weight, per infusion
• Up to 6 infusions

The treatment remained safe at all doses tested, and higher doses might still be possible in future studies.

Safety (Primary Endpoint)

Overall safety profile:

• Generally well tolerated
• No dangerous immune overreaction occurred
• Donor immune cells did not attack the patient’s body
• No serious side effects limited how much treatment could be given

Serious adverse events:

• None attributed to NK-cell infusion

Effectiveness (Exploratory Outcomes)

Remission:

• 7 of 12 patients (58.3%) achieved remission
• 4 complete remission (CR)
• 3 complete remission with incomplete blood count recovery (CRi)

Time to response:

• Median time to best response: 48 days

Bridge to transplant:

• 5 responding patients proceeded to haploidentical stem cell transplant
• Same donor used for NK cells and transplant

Survival:

• Overall (all patients): about 4 out of 10 patients were still alive one year later
• Patients whose leukemia responded to treatment: about 6 out of 10 were alive at one year
• Patients whose leukemia did not respond: none were alive at one year

Survival was strongly linked to whether the NK-cell treatment pushed the leukemia into remission.

How the Cells Worked

The researchers do not believe the NK cells turned into leukemia or bone marrow cells.

Instead, they believe the cells worked through direct immune killing and immune signalling:

• Donor NK cells recognised leukemia cells as abnormal
• NK cells directly killed leukemia cells
• NK cells expanded inside the patient after infusion
• NK cells released interferon-gamma (IFN-γ), confirming immune activation

In simple terms:

• The NK cells acted as a targeted immune attack
• They lowered the amount of leukemia in the body
• They opened a short window to allow stem cell transplant
• They did not give lasting immune protection on their own

What We Don’t Know (Limitations)

• Very small study (12 patients)
• No control or placebo group
• Phase I design focused on safety
• Long-term durability without transplant not established
• Optimal dosing and maintenance strategies not defined

Researchers’ Conclusion

This Phase I study shows that giving repeated doses of donor immune killer cells grown using a specialised mbIL-21 and 4-1BBL system is practical and appears safe in patients with advanced, hard-to-treat AML.

Procedure

Patients first received lymphodepleting chemotherapy to reduce existing immune cells and allow donor NK cells to function effectively:

• Fludarabine (days −5 to −3)
• Cyclophosphamide (days −5 to −3)

After chemotherapy:

• Patients received AFM13-NK cells by intravenous infusion on day 0
• This was followed by three weekly infusions of AFM13 alone on days 7, 14, and 21

Patients were followed for safety and outcomes for up to 2 years.

Delivery Method

• Intravenous (IV) infusion

Cell Type & Source

• Allogeneic natural killer cells
• Source: Umbilical cord blood donors
• Cells were not genetically modified
• Cells were physically bound with AFM13 before infusion

Cell Preparation & Quality

Only preparation steps explicitly stated in the study are included:

• NK cells were derived from umbilical cord blood
• Cells were expanded and cytokine-preactivated outside the body
• NK cells were pre-loaded with AFM13 before infusion

Cell identity and tracking:

• Donor-derived NK cells were tracked after infusion
• Specific surface marker definitions (for example CD56, CD16, CD3) were not explicitly listed in the registry or published abstract and are therefore not assumed here

No genetic engineering, CAR modification, or gene editing was performed.

Dosage

NK-cell dose levels tested:

• 1,000,000 NK cells per kilogram of body weight
• 10,000,000 NK cells per kilogram of body weight
• 100,000,000 NK cells per kilogram of body weight

The highest dose (100,000,000 cells per kilogram of body weight) was selected as the recommended Phase II dose.

Patients received:

• One NK-cell infusion per cycle
• Between 2 and 4 treatment cycles

Safety (Primary Endpoint)

Overall safety profile:

• Well tolerated across all dose levels
• No cytokine release syndrome (CRS)
• No neurotoxicity
• No graft-versus-host disease

Dose-limiting toxicities:

• None reported that prevented dose escalation

Effectiveness (Secondary Outcomes)

Overall response rate (ORR): 92.9%
This means almost 9 out of 10 patients had their cancer shrink or disappear.

Complete response (CR): 66.7%
About 2 out of 3 patients had no detectable cancer after treatment.

NK-cell behaviour:

Donor NK cells:

• Reached their highest level in the blood 1 day after infusion
• Stayed in the body for up to about 3 weeks
• Were able to travel to the tumour sites, where the cancer was located

Survival:

Median follow-up: 20 months
Patients were monitored for nearly two years on average.

2-year event-free survival: 26.2%
About 1 in 4 patients had no cancer progression or relapse two years after treatment.

2-year overall survival: 76.2%
About 3 out of 4 patients were still alive two years after treatment.

Long-term remission:

• 11 patients stayed in complete remission for 14 to 40 months
• Some patients received additional “consolidation” treatment, while others did not

In simple terms:
This treatment caused the cancer to shrink or disappear in most patients, worked with surprisingly few serious side effects, and helped a smaller group of patients stay cancer-free for a long time.

How the Cells Worked

The researchers believe the therapy worked through immune mechanisms:

• AFM13 physically linked NK cells to CD30-positive lymphoma cells
• NK cells directly killed tumour cells
• NK cells briefly expanded after infusion
• NK cells migrated to tumour sites

In simple terms:

• The antibody acted as a targeting bridge
• The NK cells acted as the killers
• The immune effect was strong but temporary

What We Don’t Know (Limitations)

• No control or comparison group
• Phase I/II design focused on safety and early efficacy
• NK-cell persistence was temporary
• Long-term disease control without additional therapy is unclear

Researchers’ Conclusion

This Phase I/II study shows that cord-blood–derived NK cells pre-loaded with the bispecific antibody AFM13 can be safely administered to patients with heavily pretreated CD30-positive lymphomas.

The treatment produced exceptionally high response rates with minimal immune-related toxicity, even in patients who had exhausted standard therapies.

The researchers conclude that this approach should be studied further in larger, controlled clinical trials and represents a promising non–genetically engineered NK-cell immunotherapy strategy.

Procedure

• Patients first received standard autologous stem cell transplantation
• After recovery, patients received repeated infusions of their own NK cells
• Each patient received three escalating NK-cell doses given at weekly intervals

Delivery Method

• Intravenous infusion

Cell Type & Source

• Autologous natural killer (NK) cells
• Cells were collected from the patient’s own blood
• Cells were not genetically modified

Cell Preparation & Quality

The patient’s NK cells were taken out of the body and grown in a highly controlled medical laboratory, where they were stimulated to multiply and switch into an active, cancer-killing state.

This process was done using certified pharmaceutical-grade standards (GMP), inside a sealed, automated machine that grows the cells without using helper “feeder” cells, reducing contamination risk and improving consistency.

Culture and expansion conditions reported in the study:

• Serum-free CellGro SCGM culture medium
  A liquid nutrient solution that keeps immune cells alive and supports their growth in a controlled, clinical-grade environment.
• Interleukin-2 (IL-2) at 500 IU/mL
  A natural immune signaling protein that tells NK cells to grow, stay active, and maintain their cancer-killing function.
• OKT3 (anti-CD3 antibody) at 10 ng/mL
  This is an antibody used to activate supporting immune cells during preparation, helping create conditions that stimulate NK cell expansion.
• 5% human AB serum
  This is a purified human blood component added to support cell health and stability during growth.
• 0.1% Pluronic F68
  This is a protective agent that helps prevent physical damage to cells while they are growing in a bioreactor.
• Expansion performed for approximately 20 days in a closed Wave bioreactor system

Activated NK cell phenotype observed in the final product included:

• CD56 (bright expression in a major subset)
• CD16
• Ki67 (marker of proliferation)
• HLA-DR (activation marker)

After infusion, the NK cells circulating in the bloodstream showed:

• They remained detectable for up to four weeks
• They displayed high levels of activation markers such as NKG2D and 2B4, which are linked to cancer recognition
• They released increased amounts of granzyme B, a substance used by immune cells to kill abnormal cells

Dosage

• Three escalating doses per patient
• Weekly administration

Reported dose levels:

• Dose 1: 5,000,000 NK cells per kilogram of body weight
• Dose 2: 50,000,000 NK cells per kilogram of body weight
• Dose 3: up to 100,000,000 NK cells per kilogram of body weight

Safety (Primary Endpoint)

Overall safety profile

• Generally well tolerated
• No dangerous immune overreaction was observed during or after treatment
• No severe adverse events attributed to NK cell infusion

Notable adverse event

• Herpes zoster (shingles) reactivation occurred in early patients
• Managed with antiviral treatment
• Later patients received preventive antiviral prophylaxis

Effectiveness (Exploratory Outcomes)

Disease markers

• Patients who had measurable signs of myeloma in their blood showed lower levels after receiving the NK cell treatment

Minimal residual disease (MRD)

• Several patients had fewer remaining cancer cells detectable four weeks after the final NK cell infusion

Immune activity

• After each treatment, there were clear increases in granzyme B, a cancer-killing substance, and it was still detectable in bone marrow samples weeks later

Survival

• On average, patients went about 34 months without their disease getting worse, and all treated patients were still alive at long-term follow-up

How the Cells Worked

The researchers do not suggest that NK cells turned into bone marrow or myeloma cells.

Instead, the findings support immune-mediated activity:

• Activated NK cells persisted in circulation for weeks
• NK cells released cytotoxic molecules such as granzyme B
• These findings are consistent with immune killing of abnormal cells

In simple terms:

• The NK cells stayed active after infusion
• They showed biological signs of cancer-killing function
• They may have helped reduce remaining myeloma after transplant

What We Don’t Know (Limitations)

• Very small study (6 treated patients)
• No control or comparison group
• Designed primarily for safety and feasibility
• Cannot prove direct causation between NK cells and cancer cell death

Researchers’ Conclusion

This study shows that repeated infusions of a patient’s own activated and expanded NK cells, produced using a defined GMP culture system, are feasible and appear safe after autologous stem cell transplantation in multiple myeloma.

The study demonstrated immune activation and early signs of disease reduction, supporting further investigation of autologous NK cell therapy in larger, controlled clinical trials.

Procedure

• Patients first received lymphodepleting chemotherapy (fludarabine and cyclophosphamide)
• This was followed by a single infusion of CAR-NK cells
• Three escalating dose levels were evaluated

Delivery Method

• Intravenous infusion

Cell Type & Source

• Allogeneic natural killer (NK) cells
• Cells were derived from donor umbilical cord blood
• Cells were not taken from the patient
• Cells were genetically engineered prior to infusion

Cell Preparation & Quality

The donor NK cells were processed and expanded in a controlled laboratory environment before being infused.

Reported preparation steps:

• NK cells were isolated from cord blood
• Cells were cultured with engineered K562 feeder cells and interleukin-2 (IL-2)
  K562 feeder cells are lab-grown helper cells that provide activation signals to help NK cells grow and become more potent
  IL-2 is an immune signaling protein that keeps NK cells alive, expanding, and functionally active during culture
• Cells were genetically modified using a retroviral vector to express:

• An anti-CD19 chimeric antigen receptor (CAR)
  This allows the cells to specifically recognize and target CD19-positive cancer cells.
• Interleukin-15 (IL-15) to support survival and persistence
  This helps the cells stay alive and active in the body for longer after infusion.
• Inducible caspase-9, a built-in safety switch to allow elimination of the cells if needed
  This is a safety feature that lets doctors switch the cells off if serious side effects occur

Reported characteristics of the final cell product

• CAR expression was confirmed on infused NK cells
• Very low levels of contaminating T cells were present
• No expansion of contaminating T cells was observed after infusion

Dosage

• Single infusion per patient

Planned dose levels:

• 100,000 CAR-NK cells per kilogram of body weight
• 1,000,000 CAR-NK cells per kilogram of body weight
• 10,000,000 CAR-NK cells per kilogram of body weight

One patient received a lower dose than planned due to limited cell availability

Safety (Primary Endpoint)

• No cytokine release syndrome (CRS)
• No neurotoxicity
• No graft-versus-host disease
• No intensive care admissions related to CAR-NK toxicity
• One patient was admitted to intensive care for progressive lymphoma and later died
• Inflammatory cytokines such as interleukin-6 did not increase above baseline levels

Effectiveness (Exploratory Outcomes)

• 8 of 11 patients showed a clear treatment response, meaning their cancer measurably improved
• 7 patients reached complete remission, with no detectable signs of cancer
• Most responses happened within 30 days after the cells were given
• CAR-NK cells increased in number after infusion and were still detectable for up to 12 months, showing they survived in the body

Cell Behavior in the Body

CAR-NK cells:

• Increased in number soon after they were given
• Remained present at low levels over time
• Were found in the blood, bone marrow, and lymph nodes
• Patients who responded had a larger early increase in CAR-NK cells

How the Cells Worked

The researchers claimed, the findings support immune-mediated anti-cancer activity:

• CAR-NK cells recognized CD19-positive cancer cells
• The cells expanded in the body after infusion rather than disappearing quickly
• CAR-NK cells trafficked to disease sites such as lymph nodes
• The inclusion of IL-15 in the CAR construct may have supported cell survival and persistence

In simple terms:

• The engineered NK cells stayed alive longer than typical NK cells
• They reached cancer sites
• Their behavior was consistent with immune-based cancer cell killing

What We Don’t Know (Limitations)

• Very small study (11 treated patients)
• No control or comparison group
• Some patients received additional therapies after day 30
• Long-term durability of CAR-NK responses cannot be fully isolated

Researchers’ Conclusion

This study shows that CAR-NK cells made from donor cord blood and designed to target CD19 can be given safely to patients with advanced blood cancers, leading to strong treatment responses without the severe immune side effects often seen with CAR-T therapy.

The results support further study of CAR-NK cells as a ready-to-use immune treatment in larger clinical trials.

Procedure

• Patients first received lymphodepleting chemotherapy
• This was followed by infusion of CAR-NK cells
• Some patients received weight-based doses, others a flat dose

Delivery Method

• Intravenous infusion

Cell Type & Source

• Allogeneic natural killer (NK) cells
• Cells were derived from donated umbilical cord blood units
• Cells were not taken from the patient

Cell Preparation & Quality

The NK cells were processed and expanded in a controlled laboratory environment and genetically modified before infusion.

Genetic Engineering

The NK cells were engineered to express:

• Anti-CD19 chimeric antigen receptor (CAR)
  Allows the NK cells to recognize and target B-cell cancers that carry a marker called CD19.
• Interleukin-15 (IL-15)
  Supports survival and persistence of NK cells in the body.
• Inducible caspase-9 (iC9) safety switch
  Allows the cells to be eliminated if serious toxicity occurs.

Cord Blood Quality Factors Studied

The researchers later found that better results were linked to two cord blood quality factors:

• The cord blood was frozen within 24 hours of collection
• The cord blood came from a healthy situation, with fewer stressed or damaged blood cells, which helped the NK cells work better

These factors were used to define “optimal” versus “sub-optimal” cord blood units.

Phenotype and Functional Markers Reported

NK cell activity and cancer-killing ability were checked by measuring:

• How long the NK cells stayed in the bloodstream (qPCR)
• How much energy the NK cells could produce
• Whether the NK cells switched on genes used to kill cancer cells (such as perforin and granzyme pathways)

Dosage

• Multiple dose levels were tested

Reported doses included:

• Weight-based dosing up to 10 million cells/kg
• Flat dose of 800 million CAR-NK cells

Safety (Primary Endpoint)

• No graft-versus-host disease observed
• No brain or nervous system side effects were seen
• One patient had a mild, flu-like immune reaction
• Temporary drops in blood cell levels occurred, as normally expected after chemotherapy

Effectiveness (Primary and Secondary Endpoints)

Overall response rate

• ~49% showed improvement by day 30
• ~49% still showed improvement by day 100

Complete response rate

• ~27% had no detectable cancer by day 30
• ~38% had no detectable cancer after one year

Survival

• ~68% of patients were alive one year later
• ~32% were alive without their cancer getting worse after one year

Cell Persistence and Immune Activity

• CAR-NK cells expanded and remained detectable in the bloodstream
• Patients with better responses had higher CAR-NK cell levels and longer persistence of infused cells

Why Some Patients Did Better

Patients receiving CAR-NK cells from optimal cord blood units showed:

• Higher response rates
• Better one-year survival
• Lower signs of immune cell stress

Sub-optimal cord blood was associated with:

• NK cells had less energy to do their job
• NK cells showed signs of stress and low oxygen exposure
• Cancer was harder for the immune cells to control

How the Cells Worked

• CAR-NK cells persisted and expanded after infusion
• Cells showed enhanced metabolic and cytotoxic function
• Tumor control was linked to immune killing, not cell replacement

In simple terms:

• The NK cells survived in the body
• They stayed biologically active
• They killed cancer cells through immune mechanisms

What We Don’t Know (Limitations)

• No control or comparison group
• Small patient numbers
• Heterogeneous cancer types
• Long-term durability beyond one year still uncertain

Researchers’ Conclusion

This study shows that CAR-NK cells made from donated cord blood and designed to target CD19 can be safely given to people with advanced B-cell cancers.

The treatment showed real anti-cancer effects with few side effects, and results depended heavily on how healthy and well-handled the cord blood was, supporting further testing of ready-made CAR-NK cell therapies in larger studies.

Procedure

Patients first received lymphodepleting chemotherapy:

• Fludarabine
• Cyclophosphamide

This was followed by three infusions of NKX019:

• Day 0
• Day 7
• Day 14

Each cycle lasted 28 days.

Delivery Method

• Intravenous infusion

Cell Type & Source

• Allogeneic natural killer (NK) cells
• Cells were taken from healthy donors, not from the patient
• Cells were cryopreserved and given as an off-the-shelf product

Cell Preparation & Genetic Engineering

The NK cells were genetically modified before infusion to express:

• Anti-CD19 chimeric antigen receptor (CAR)
  Allows NK cells to recognize and attack CD19-positive B-cell cancers.
• CD3 zeta (CD3ζ) signaling domain
  Triggers immune activation when the cancer cell is recognized.
• OX40 costimulatory domain
  Enhances activation and function of the NK cells.
• Membrane-bound interleukin-15 (IL-15)
  Supports NK cell survival and persistence after infusion.

No additional safety switches or surface marker selection methods were reported in the provided data.

Dose Levels Tested

• 300 million CAR-NK cells per dose
• 1 billion CAR-NK cells per dose
• 1.5 billion CAR-NK cells per dose

Each dose level was given three times per cycle.

The recommended Phase 2 dose (RP2D) was:

• 1.5 billion CAR-NK cells × 3 doses

Safety (Primary Endpoint)

• No serious side effects that limited how much treatment could be given
• No dangerous immune overreaction (cytokine release syndrome)
• No brain or nervous system side effects
• No immune attack against the patient’s own body (graft-versus-host disease)
• No patients had to stop treatment because of NKX019

Other Findings

• 84% experienced grade 3–4 low blood counts, attributed to lymphodepleting chemotherapy
• One grade 3 infection reported
• ~26% experienced short-lasting fever within 8 hours of infusion, resolving quickly

Effectiveness (Preliminary)

• Responses were seen mainly in B-cell non-Hodgkin lymphoma
• Response rates increased with higher dose levels
• 8 patients achieved a complete response
• Some patients with indolent lymphoma relapsed after more than 6 months

Limited Responses in Leukemia

• One patient with CLL had stable disease
• No clear responses in other leukemia cases

Cell Persistence and Immune Activity

• CAR-NK cells were measurable in the bloodstream after infusion
• Higher doses led to higher peak CAR-NK cell levels
• Patients with complete responses had much higher CAR-NK levels in blood
• No link was found between cancer response and elevated inflammatory cytokines

How the Cells Worked

• The CAR-NK cells entered the bloodstream after infusion
• Higher circulating cell levels were linked to better tumor responses
• Cancer control appeared to be driven by direct immune cell activity rather than excessive immune inflammation

In simple terms:

• The cells reached the blood
• They stayed detectable for a period of time
• Patients with more cells in circulation tended to respond better

What We Don’t Know Yet (Limitations)

• Results are preliminary and based on a small number of patients
• No comparison or control group
• Long-term durability of responses is not yet known
• Expansion cohorts are still ongoing

Researchers’ Conclusion

This early-stage study shows that NKX019, a donor-derived CAR-NK cell treatment designed to target CD19, can be given safely to adults with advanced B-cell cancers.

Early results so far suggest the treatment can help control non-Hodgkin lymphoma and appears generally safe, supporting continued enrollment and further testing in larger patient groups.

Procedure

Patients received lymphodepleting chemotherapy before FT596 infusion:

• Cyclophosphamide
• Fludarabine

FT596 was then administered:

• As monotherapy (Regimen A), or
• In combination with rituximab (Regimen B)

Patients who tolerated treatment and benefited could receive additional cycles.

Delivery Method

• Intravenous infusion

Cell Type & Source

• Allogeneic natural killer cells
• Cells derived from a single induced pluripotent stem cell (iPSC) master cell line
• Cells were not taken from the patient

Cell Preparation & Engineering

FT596 is a ready-made natural killer (NK) cell treatment made by first reprogramming adult cells into stem cells, genetically modifying those stem cells, and then turning them into NK cells before use.

Genetic Modifications Reported

The NK cells were engineered to express:

• CD19 chimeric antigen receptor (CAR)
  Allows the NK cells to recognize and attach to B-cell cancers that carry the CD19 marker.
• High-affinity, non-cleavable CD16 Fc receptor
  Helps the NK cells kill cancer cells more effectively when antibody drugs like rituximab are used.
• Interleukin-15 / IL-15 receptor fusion
  Helps the NK cells stay alive and active in the body without needing extra immune-boosting drugs.

No additional surface phenotype markers were reported in the published clinical results.

Dosage

• Multiple dose levels tested during escalation
• Maximum tolerated dose was not reached

Recommended Phase 2 dose (RP2D)

• 1.8 billion cells
• Administered as three doses per treatment cycle

Safety (Primary Endpoint)

• No neurotoxicity observed
• No problems with the brain or nervous system were seen

Cytokine Release Syndrome (CRS)

• A short-term immune reaction that can cause flu-like symptoms such as fever
• It happened in only a few patients and was mild

• Dose-limiting toxicities were infrequent
• Serious side effects that would force doctors to stop treatment were rare

Effectiveness (Exploratory Endpoints)

Cancer responses were seen in:

• Slow-growing B-cell lymphomas
• Fast-growing B-cell lymphomas

• Responses were strong and long-lasting
• The treatment also worked in some patients who had already received CAR-T therapy

Cell Persistence and Pharmacokinetics

The study checked whether FT596 cells were still in the blood by measuring:

• How much FT596 DNA was present compared with the patient’s own DNA (% chimerism)

How the Cells Worked

• FT596 NK cells recognized cancer cells through CD19 targeting
• Combination with rituximab enhanced immune-mediated killing via CD16
• IL-15 signaling supported continued NK cell activity

In simple terms:

• The cells acted as immune attackers
• They did not replace tissue
• Cancer control occurred through immune cell killing

What We Don’t Know (Limitations)

• No randomized control group
• Early-phase study focused on safety and dosing
• Results for CLL and obinutuzumab arms have not been published

Researchers’ Conclusion

This Phase 1 study shows that FT596, a ready-made CAR-NK cell treatment made from lab-grown stem cells, can be safely given to patients whose B-cell lymphoma has returned or not responded to treatment.

However, further trials have been terminated, with a restructure happening within Fate Therapeutics.