NKX019 for Lupus

Overseen By Anca D Askanase, MD, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Columbia University

Must be taking: RAAS blockers

Must not be taking: Immunoglobulin therapy

Disqualifiers: Renal dialysis, Liver disease, COPD, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 90

6 Participants Needed

Trial Summary

What is the purpose of this trial?

Primary objective: Safety and tolerability of NKX019, administered after lymphodepletion (LD). Secondary objectives: * Assess clinical activity of NKX019 in subjects with systemic lupus erythematosus (SLE) with or without active lupus nephritis (LN) * Characterize pharmacokinetics (PK) of NKX019 * Characterize immunogenicity of NKX019

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that prior therapies for SLE should be stopped at least 4 weeks before starting lymphodepletion. Additionally, any medications prohibited in the study protocol must not be taken.

What data supports the effectiveness of the treatment NKX019 for Lupus?

Research shows that natural killer (NK) cells, which are part of the immune system, have impaired function in lupus patients. Treatments that enhance NK cell function, like NKX019, may help improve the immune response in lupus by targeting these dysfunctional cells. ^{1 2 3 4 5}

Is NKX019 safe for use in humans?

Research on NK cells equipped with CARs, like NKX019, shows they are generally safe and do not cause graft-versus-host disease (a condition where donor cells attack the recipient's body). Studies indicate that these cells have a lower toxicity profile compared to similar therapies, and safety measures are in place to limit potential side effects. ^{6 7 8 9 10}

How is the treatment NKX019 for Lupus different from other treatments?

NKX019 is unique because it uses genetically modified natural killer (NK) cells with a chimeric antigen receptor (CAR) targeting CD19, which enhances their ability to attack specific cells without causing graft-versus-host disease, making it a promising off-the-shelf therapy option. ^{7 9 10 11 12}

Research Team

Anca D Askanase, MD, MPH

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for individuals with Systemic Lupus Erythematosus (SLE), a chronic autoimmune disease. Participants should have active symptoms and may or may not have lupus nephritis, which affects the kidneys. The full eligibility criteria are not provided, but typically include specific health requirements and no recent treatments that could interfere with the study.

Inclusion Criteria

Negative SARS-CoV-2 test

I am not pregnant, will not have sex or will use birth control correctly until 1 year after my last treatment dose.

I have signed the consent form and can follow the study schedule.

Exclusion Criteria

Any other acute or chronic medical or psychiatric condition, or known laboratory abnormality that, in the Investigator's opinion is expected to increase the risk associated with study participation or NKX019 administration, interfere with the informed consent process, compliance with the study requirements, make the subject inappropriate for entry into this study, require concomitant use of any medication that is listed as prohibited while on study, or indicate clinically significant drug or alcohol abuse within 2 years prior to screening

I have not had an infection requiring antibiotics in the last 30 days.

I have previously received cellular therapy, such as CAR-T.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Active Treatment

Subjects receive cyclophosphamide lymphodepletion followed by NKX019 infusion to determine safety and preliminary efficacy

4 weeks

Weekly visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Visits every 90 days

Extended Follow-up

Continued monitoring of disease assessments and safety

2 years

Treatment Details

Interventions

• Cyclophosphamide
• NKX019

Trial Overview The trial is testing NKX019, a type of cell therapy targeting CD19 to treat SLE. It's given after 'lymphodepletion' using low doses of Cyclophosphamide to prepare the body. The study will check how safe it is, its effects on lupus symptoms, how long it stays in the body (PK), and if it causes any immune response against itself.

Participant Groups

Group I: NKX019 infusion Experimental Treatment 2 Interventions

Subjects with SLE will receive cyclophosphamide LD followed by NKX019.

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

Findings from Research

In a study involving 191 patients with systemic lupus erythematosus (SLE) and other autoimmune diseases, 23% of SLE patients had autoantibodies against killer immunoglobulin-like receptors (KIRs), which are crucial for NK cell function.

These anti-KIR autoantibodies were linked to reduced NK cell activity, increased disease activity, and a higher risk of developing lupus nephritis, suggesting that impaired NK cell function may contribute to disease severity in SLE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autoantibodies to Killer Cell Immunoglobulin-Like Receptors in Patients With Systemic Lupus Erythematosus Induce Natural Killer Cell Hyporesponsiveness. Segerberg, F., Lundtoft, C., Reid, S., et al.[2020]

In patients with systemic lupus erythematosus (SLE), natural killer (NK) cells show significant dysfunction, characterized by altered expression of CD38, SLAMF1, and SLAMF7, which affects their ability to kill plasma cells.

Targeting SLAMF7 and CD38 on SLE NK cells with specific antibodies can enhance their function, suggesting potential new therapeutic strategies to improve NK cell activity and reduce the accumulation of antibody-producing cells in SLE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Restoration of NK Cell Cytotoxic Function With Elotuzumab and Daratumumab Promotes Elimination of Circulating Plasma Cells in Patients With SLE. Humbel, M., Bellanger, F., Fluder, N., et al.[2021]

In a study of systemic lupus erythematosus (SLE) patients, a subset showed increased levels of proliferating NK cells (marked by Ki67), which correlated with more severe disease and active nephritis, suggesting a potential role for NK cells in SLE pathology.

The study indicates that the cytokine interleukin-15 may drive the proliferation of these NK cells, highlighting a possible therapeutic target for managing SLE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natural killer cell expression of Ki67 is associated with elevated serum IL-15, disease activity and nephritis in systemic lupus erythematosus. Hudspeth, K., Wang, S., Wang, J., et al.[2020]

In patients with systemic lupus erythematosus (SLE), there is a significant reduction in the levels and cytotoxicity of natural killer (NK) cells compared to healthy controls, particularly in those with lupus nephritis and thrombocytopenia.

The study found that the differentiation of hematopoietic stem cells (HSCs) into NK cells is impaired in SLE patients, which may contribute to the overall immune system dysregulation associated with the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impaired differentiation and cytotoxicity of natural killer cells in systemic lupus erythematosus. Park, YW., Kee, SJ., Cho, YN., et al.[2009]

Patients with active systemic lupus erythematosus (SLE) show a decreased absolute count of natural killer (NK) cells, but their relative frequencies remain unchanged, indicating a potential alteration in NK cell dynamics during disease activity.

NK cells from SLE patients exhibit unique phenotypic changes and lower cytotoxicity, yet they can produce significant amounts of interferon-gamma (IFNγ), which may disrupt the balance between innate and adaptive immunity in SLE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenotype and function of natural killer cells in systemic lupus erythematosus: excess interferon-γ production in patients with active disease. Hervier, B., Beziat, V., Haroche, J., et al.[2017]

Natural killer (NK) cells are a significant barrier to the successful engraftment of donor bone marrow in transplantation, as depleting NK cells improved donor stem cell survival and allowed for the acceptance of lower doses of donor marrow.

Blocking the LFA-1 molecule reduced NK cell-mediated killing of donor cells, suggesting that targeting NK alloreactivity could enhance the success of costimulation blockade strategies in clinical transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NK cells mediate costimulation blockade-resistant rejection of allogeneic stem cells during nonmyeloablative transplantation. Kean, LS., Hamby, K., Koehn, B., et al.[2023]

Engineered cord blood-derived natural killer (NK) cells, modified with CAR-CD19 and IL-15, showed effective targeting and killing of leukemia cells in laboratory tests and improved survival in a mouse model of lymphoma.

This approach not only enhances the efficacy of NK cells in treating cancers but also includes a safety mechanism (the iC9 suicide gene) to eliminate the cells if necessary, reducing the risk of adverse effects like graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Liu, E., Tong, Y., Dotti, G., et al.[2021]

Ex vivo manipulation of NK cells for adoptive transfer reduces their ability to migrate to the bone marrow due to decreased expression of the CXCR4 receptor, which is crucial for homing to this area.

Genetically engineering NK cells to express a gain-of-function variant of CXCR4 (CXCR4R334X) enhances their migration towards bone marrow, improving their potential effectiveness in treating leukemia and myeloma without compromising their function or viability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced Bone Marrow Homing of Natural Killer Cells Following mRNA Transfection With Gain-of-Function Variant CXCR4R334X. Levy, E., Reger, R., Segerberg, F., et al.[2020]

Chimeric antigen receptor (CAR) NK-cell therapy is being explored as a promising treatment for hematologic malignancies, particularly targeting the CD19 protein.

This approach is advantageous because NK cells do not cause graft-versus-host disease, allowing for their potential off-the-shelf use in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Equipping NK Cells with CARs. [2019]

A new feeder-free culture method allows for the efficient genetic modification and expansion of peripheral blood-derived NK cells, maintaining their natural responsiveness while enhancing their proliferative capacity.

CAR.CD19-NK cells show significantly improved antileukemic activity against B-cell precursor ALL compared to unmodified NK cells, with similar effectiveness to CAR-T cells but with a lower risk of toxicity in animal models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia. Quintarelli, C., Sivori, S., Caruso, S., et al.[2021]

Transducing natural killer (NK) cells with chimeric receptors targeting CD19 significantly enhances their ability to kill leukemic cells, overcoming resistance caused by inhibitory HLA types.

The addition of the 4-1BB costimulatory molecule to the chimeric receptor further boosts NK cell activation and cytokine production, suggesting a promising strategy to improve the efficacy of allogeneic hematopoietic transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Imai, C., Iwamoto, S., Campana, D.[2022]

Transfecting CAR-encoding mRNA into primary natural killer (NK) cells is feasible, with optimal CAR expression achieved after 3 days of IL15 stimulation, resulting in over 80% expression and enhanced targeting of CD19+ cancer cells.

Adaptive NK cells, which have specific markers like NKG2C and CD57, showed superior effectiveness in killing CD19+ tumor cells, indicating that the diversity of NK cell subsets is crucial for optimizing CAR-based cancer immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors. Oei, VYS., Siernicka, M., Graczyk-Jarzynka, A., et al.[2019]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Autoantibodies to Killer Cell Immunoglobulin-Like Receptors in Patients With Systemic Lupus Erythematosus Induce Natural Killer Cell Hyporesponsiveness. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Restoration of NK Cell Cytotoxic Function With Elotuzumab and Daratumumab Promotes Elimination of Circulating Plasma Cells in Patients With SLE. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Natural killer cell expression of Ki67 is associated with elevated serum IL-15, disease activity and nephritis in systemic lupus erythematosus. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Impaired differentiation and cytotoxicity of natural killer cells in systemic lupus erythematosus. [2009]

5. United States pubmed.ncbi.nlm.nih.gov

Phenotype and function of natural killer cells in systemic lupus erythematosus: excess interferon-γ production in patients with active disease. [2017]

6. United States pubmed.ncbi.nlm.nih.gov

NK cells mediate costimulation blockade-resistant rejection of allogeneic stem cells during nonmyeloablative transplantation. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Enhanced Bone Marrow Homing of Natural Killer Cells Following mRNA Transfection With Gain-of-Function Variant CXCR4R334X. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Equipping NK Cells with CARs. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors. [2019]