NKX019 + Cyclophosphamide for Lupus Nephritis

Recruiting in Atlanta (>99 mi)

+11 other locations

Overseen By Nkarta Central Contact

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Nkarta, Inc.

Must be taking: Renin-angiotensin system blockers

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: Unknown

Duration: 4 weeks

21 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label, multi-center, non-randomized Phase 1 study to determine the safety and tolerability of NKX019 (allogeneic CAR NK cells targeting CD19) in participants with active lupus nephritis (LN).

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment NKX019 + Cyclophosphamide for Lupus Nephritis?

Research shows that natural killer (NK) cells, which are part of the immune system, play a role in lupus nephritis, a severe kidney inflammation in lupus patients. Although the exact role of NK cells in lupus nephritis is not fully understood, studies suggest that targeting these cells could potentially help manage the disease. ^{1 2 3 4 5}

Is NKX019 + Cyclophosphamide safe for humans?

The safety of cyclophosphamide, a drug used in the treatment, has been studied in lupus nephritis and is known to have some toxic effects, but it is generally considered effective. However, there is no specific safety data available for NKX019 or the combination of NKX019 with cyclophosphamide in humans. ^{6 7 8 9 10}

How is the treatment NKX019 + Cyclophosphamide unique for lupus nephritis?

NKX019 is a novel treatment using engineered natural killer (NK) cells that target CD19, a protein found on certain immune cells, which may help reduce inflammation in lupus nephritis. This approach is different from traditional treatments as it involves using modified immune cells to specifically target and potentially regulate the immune response in lupus nephritis. ^{1 2 3 4 5}

Research Team

David Shook, MD

Principal Investigator

Nkarta, Inc.

Eligibility Criteria

This trial is for adults with active lupus nephritis, a type of kidney inflammation due to autoimmune disease. Participants must meet certain health standards but specific inclusion and exclusion criteria are not listed.

Inclusion Criteria

Must have a negative SARS-CoV-2 test

I have lupus nephritis and have tried at least 2 treatments that didn't work.

I am between 18 and 65 years old.

Exclusion Criteria

My kidney function is reduced, with an eGFR of 45 ml/min/m2 or lower.

I have liver disease or abnormal liver tests.

I do not have HIV, Hepatitis B or C, active tuberculosis, antiphospholipid antibody syndrome, or a high-risk profile.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Participants receive single-agent lymphodepletion with cyclophosphamide

1 week

Treatment

Participants receive a three-dose cycle of NKX019

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days

Long-term follow-up

Participants are monitored for changes in SLEDAI-2K score and renal response

Up to 2 years

Treatment Details

Interventions

• NKX019

Trial Overview The study tests NKX019, a therapy involving immune cells (CAR NK) designed to target CD19, in combination with Cyclophosphamide, a chemotherapy drug. It's an early-phase trial to assess safety and how well patients tolerate the treatment.

Participant Groups

Group I: NKX019 - CAR NK cell therapy Experimental Treatment 2 Interventions

Phase 1: NKX019 plus cyclophosphamide

Who Is Running the Clinical Trial?

Nkarta, Inc.

Lead Sponsor

Trials

4

Recruited

300+

Findings from Research

This study is the first to characterize natural killer (NK) cells in kidney biopsies of patients with lupus nephritis (LN), revealing their presence in the kidney interstitium and peri-glomerular areas, but rarely in glomeruli.

Among the 12 SLE patients analyzed, NK cell numbers were reduced in four out of five patients after immunosuppressive therapy, indicating a potential link between NK cell activity and disease status, although the small sample size limits definitive conclusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kidney infiltrating NK cells and NK-like T-cells in lupus nephritis: presence, localization, and the effect of immunosuppressive treatment. Scheffschick, A., Fuchs, S., Malmström, V., et al.[2023]

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]

In patients with systemic lupus erythematosus (SLE), there is an increased expression of the NKG2D ligand MICA in the kidneys, indicating a potential role of NK cells in the disease's progression.

Murine models of SLE showed that NK cells in the kidneys have a more mature and activated phenotype during lupus nephritis, suggesting that these cells may contribute to the immunopathogenesis of SLE and could be targeted for therapeutic strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NKG2D ligand overexpression in lupus nephritis correlates with increased NK cell activity and differentiation in kidneys but not in the periphery. Spada, R., Rojas, JM., Pérez-Yagüe, S., et al.[2019]

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]

Low-dose cyclophosphamide (LCYC) is an effective induction therapy for lupus nephritis, showing similar response rates to mycophenolate mofetil (MMF) and better than high-dose cyclophosphamide (HCYC) based on a meta-analysis of 11 randomized controlled trials involving 1212 patients.

LCYC also has the highest probability of reducing the risk of serious infections compared to MMF and HCYC, making it a safer option for patients undergoing treatment for lupus nephritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy and safety of low-dose and high-dose cyclophosphamide as induction therapy for lupus nephritis: a network meta-analysis. Bae, SC., Lee, YH.[2020]

High-dose cyclophosphamide (HDCyC) and rituximab were found to be the most effective treatments for lupus nephritis (LN) in a study of 222 patients, with renal response rates of 90.3% and 90.9%, respectively.

Rituximab showed particular effectiveness in patients with relapsing disease, achieving a 100% renal response rate, while the study also noted that high-dose cyclophosphamide was associated with a higher incidence of infections compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclophosphamide Versus Mycophenolate Versus Rituximab in Lupus Nephritis Remission Induction: A Historical Head-to-Head Comparative Study. Goswami, RP., Sircar, G., Sit, H., et al.[2022]

Current treatments for lupus nephritis, like corticosteroids and cyclophosphamide, are effective but come with significant side effects, highlighting the need for safer, targeted therapies.

New therapeutic strategies are being developed to specifically interrupt the disease process, such as blocking co-stimulatory molecules and targeting cytokines, which could lead to more effective and less toxic treatments for lupus nephritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel approaches in the treatment of lupus nephritis. Illei, GG., Czirják, L.[2019]

In a study involving (NZB x NZW)F(1) (B/W) mice, the combination of cyclophosphamide (CTX) and CTLA4Ig significantly reduced proteinuria and improved survival rates in mice with advanced renal disease, outperforming either treatment alone.

This combination therapy not only delayed the onset of kidney issues in mice with mild disease but also achieved a remarkable reversal of proteinuria in 71% of mice with advanced nephritis, marking a significant advancement in treatment for lupus nephritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutting edge: reversal of murine lupus nephritis with CTLA4Ig and cyclophosphamide. Daikh, DI., Wofsy, D.[2019]

High-dose corticosteroids are the standard initial treatment for severe inflammation in lupus nephritis, but long-term management often requires additional therapies to address underlying immune system issues.

New treatment options for lupus nephritis include novel immunosuppressive agents and combination therapies, which may improve efficacy and reduce toxicity compared to traditional treatments like cyclophosphamide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress in the treatment of proliferative lupus nephritis. Balow, JE., Austin, HA.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Kidney infiltrating NK cells and NK-like T-cells in lupus nephritis: presence, localization, and the effect of immunosuppressive treatment. [2023]

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

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

3. 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]

4. England pubmed.ncbi.nlm.nih.gov

NKG2D ligand overexpression in lupus nephritis correlates with increased NK cell activity and differentiation in kidneys but not in the periphery. [2019]

5. 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]

6. Germany pubmed.ncbi.nlm.nih.gov

Comparative efficacy and safety of low-dose and high-dose cyclophosphamide as induction therapy for lupus nephritis: a network meta-analysis. [2020]

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

Cyclophosphamide Versus Mycophenolate Versus Rituximab in Lupus Nephritis Remission Induction: A Historical Head-to-Head Comparative Study. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Novel approaches in the treatment of lupus nephritis. [2019]

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

Cutting edge: reversal of murine lupus nephritis with CTLA4Ig and cyclophosphamide. [2019]

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

Progress in the treatment of proliferative lupus nephritis. [2019]