Immune System Booster for Non-Hodgkin's Lymphoma

Recruiting at 25 trial locations

Overseen By Nektar Recruitment

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Nektar Therapeutics

Must be taking: CAR-T cell therapy

Must not be taking: Corticosteroids, Immunosuppressants, IL-2/IL-15 agonists, others

Disqualifiers: Hepatitis, HIV, Autoimmune disorders, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate the safety and efficacy of NKTR-255 following CD19-directed chimeric antigen (CAR)-T cell therapy in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). NKTR-255 is an investigational IL-15 receptor agonist designed to boost the immune system's natural ability to fight cancer. T cells are infection fighting blood cells that can kill tumor cells. Chimeric antigen (CAR)-T cell product consists of genetically engineered T-cells, modified to recognize CD19, a protein on the surface of cancer cells. These CD19-specific T cells may help the body's immune system identify and kill CD19-positive cancer cells. Giving NKTR-255 following the treatment with CD19 CAR-T cell therapy may work better in treating large B-cell lymphoma than either drug alone.

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

The trial protocol does not specify if you need to stop your current medications. However, you cannot use therapeutic doses of corticosteroids or other systemic immunosuppressants within 7 days before leukapheresis or 72 hours before CAR-T cell infusion. Topical and inhaled steroids are allowed. It's best to discuss your specific medications with the trial team.

What data supports the idea that Immune System Booster for Non-Hodgkin's Lymphoma (also known as: NKTR-255, NKTR-255) is an effective treatment?

The available research shows that treatments using NKT cell-targeted vaccines, which are similar in approach to NKTR-255, have been effective in generating strong immune responses against B cell lymphoma. For example, one study found that combining a vaccine with an antibody treatment led to complete eradication of lymphoma in over 50% of mice, and these mice were resistant to the disease when exposed again later. Another study demonstrated that a single vaccination could significantly slow tumor growth and extend survival in mice. These results suggest that immune system boosters like NKTR-255 could be effective in treating Non-Hodgkin's Lymphoma by enhancing the body's immune response to fight the cancer. ^{1 2 3 4 5}

What safety data exists for the immune system booster treatment for Non-Hodgkin's Lymphoma?

The treatment, potentially known as NKTR-255, has been evaluated in various studies. In a phase 1 trial involving CAR-NKT cells for neuroblastoma, no dose-limiting toxicities were observed, and the treatment was considered safe with no significant adverse events attributed to the CAR-NKT cells. Another study involving NKG2D-CAR T cells in patients with AML/MDS and multiple myeloma reported no dose-limiting toxicities, cytokine release syndrome, or CAR T cell-related neurotoxicity. These findings suggest that similar immune-based treatments have been safely administered in clinical settings, although specific safety data for NKTR-255 in Non-Hodgkin's Lymphoma is not directly mentioned in the provided research. ^{1 2 3 6 7}

Is the treatment in the trial 'Immune System Booster for Non-Hodgkin's Lymphoma' a promising treatment?

Yes, the treatment is promising because immunotherapy has shown strong activity against aggressive forms of non-Hodgkin's lymphoma, like NK/T-cell lymphoma. It can help the immune system attack cancer cells more effectively, offering hope for better outcomes in patients who have limited options with traditional treatments. ^{8 9 10 11 12}

Research Team

Study Director

Principal Investigator

Nektar Therapeutics

Eligibility Criteria

Adults with relapsed/refractory large B-cell lymphoma who've had standard CAR-T cell therapy and specific chemotherapy. They must not have used certain immune therapies recently, have good organ function, and agree to contraception if of reproductive potential. Excluded are those with prior IL-15 agonist treatment, recent steroids or immunosuppression use, other CD19-directed CAR-T treatments, active infections like hepatitis/HIV, CNS lymphoma history, uncontrolled infections requiring IV drugs.

Inclusion Criteria

My lymphoma tests show CD19 presence or it's likely based on my cancer type.

I agree to use birth control if I can become pregnant.

My organs, including my bone marrow, kidneys, liver, lungs, and heart, are working well.

Exclusion Criteria

Presence of any indwelling line or drain

I have had a solid organ transplant.

Use of investigational agents or devices within specified timeframes

Treatment Details

Interventions

• NKTR-255

Trial Overview The trial tests NKTR-255's effectiveness in enhancing the body's immune response after CD19-directed CAR-T cell therapy in patients with stubborn large B-cell lymphoma. It compares different doses of NKTR-255 against a placebo to see if it improves cancer-fighting outcomes.

Participant Groups

Group I: Stage 1 NKTR-255 at 3.0/6.0 μg/kg Experimental Treatment 1 Intervention

In this arm of Stage 1 (Phase 2 of the study), patients will be dosed with 3.0 μg/kg NKTR-255 in Cycle 1 (C1) and continue in Cycle 2 and subsequent cycles (C+) with 6.0 μg/kg NKTR-255 (hereinafter referred to as 3.0/6.0 µg/kg NKTR-255). NKTR-255 will be administered intravenously approximately 14 days after CD19-directed CAR-T cell infusion. Patients will be dosed every 3 weeks for up to 7 cycles or 5 months, whichever is earlier, in the absence of disease progression or unacceptable toxicity. The dose regimen for Stage 2 (Phase 3 of the study) will be selected based on the results of Stage 1 as reviewed by the Data Monitoring Committee (DMC) and the study team.

Group II: Stage 1 NKTR-255 at 3.0 μg/kg Experimental Treatment 1 Intervention

In this arm of Stage 1 (Phase 2 of the study), NKTR-255 will be dosed at 3.0 μg/kg. NKTR-255 will be administered intravenously approximately 14 days after CD19-directed CAR-T cell infusion. Patients will be dosed every 3 weeks for up to 7 cycles or 5 months, whichever is earlier, in the absence of disease progression or unacceptable toxicity. The dose regimen for Stage 2 (Phase 3 of the study) will be selected based on the results of Stage 1 as reviewed by the Data Monitoring Committee (DMC) and the study team.

Group III: Stage 1 NKTR-255 at 1.5 µg/kg Experimental Treatment 1 Intervention

In this arm of Stage 1 (Phase 2 of the study), NKTR-255 will be dosed at 1.5 µg/kg. NKTR-255 will be administered intravenously approximately 14 days after CD19-directed CAR-T cell infusion. Patients will be dosed every 3 weeks for up to 7 cycles or 5 months, whichever is earlier, in the absence of disease progression or unacceptable toxicity. The dose regimen for Stage 2 (Phase 3 of the study) will be selected based on the results of Stage 1 as reviewed by the Data Monitoring Committee (DMC) and the study team.

Group IV: Placebo Placebo Group 1 Intervention

Placebo is commercially available 0.9% Sodium Chloride Solution for Injection (USP). Placebo will be administered intravenously approximately 14 days after CD19-directed CAR-T cell infusion. Placebo will be infused every 3 weeks for up to 7 cycles or 5 months, whichever is earlier.

Who Is Running the Clinical Trial?

Nektar Therapeutics

Lead Sponsor

Trials

59

Recruited

9,900+

Howard W. Robin

Nektar Therapeutics

Chief Executive Officer since 2007

B.S. in Accounting and Finance from Fairleigh Dickinson University

Dr. Dimitry Nuyten

Nektar Therapeutics

Chief Medical Officer since 2022

MD

Findings from Research

A therapeutic vaccine using α-galactosylceramide (α-GalCer) loaded onto irradiated tumor cells significantly inhibited tumor growth and prolonged survival in a mouse model of B-cell lymphoma, highlighting its potential efficacy in boosting antitumor immunity.

The vaccine's effectiveness relied on the activation of NKT cells, NK cells, and CD8 T cells, with a notable increase in IFN-γ production, suggesting that targeting NKT cell ligands could be a promising strategy for immunotherapy in hematologic cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma. Mattarollo, SR., West, AC., Steegh, K., et al.[2021]

The study developed a therapeutic vaccine using A20 lysate and an NKT cell agonist, α-galactosylceramide, which provided long-term immune protection against aggressive B cell lymphoma in a murine model, primarily through CD8 T cell responses.

Key immune biomarkers, such as the strength of the germinal center reaction and the Th1 type humoral response, were identified as predictors of long-term survival, highlighting the potential for this vaccine to be a simple and effective treatment option for B lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A simple, clinically relevant therapeutic vaccine shows long-term protection in an aggressive, delayed-treatment B lymphoma model. Pradhan, P., Leleux, J., Liu, J., et al.[2019]

An autologous lymphoma vaccine that activates NKT cells was shown to generate effective tumor-specific immunity in mice, leading to significant tumor regression and resistance to tumor rechallenge.

The study identified that conventional CD4(+) T cells, rather than CD8(+) T cells, were crucial for mediating this antitumor immunity, suggesting a targeted approach for developing immunotherapies against human lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An NKT-mediated autologous vaccine generates CD4 T-cell dependent potent antilymphoma immunity. Chung, Y., Qin, H., Kang, CY., et al.[2022]

In patients receiving anti-CD20 antibodies and cytotoxic chemotherapy for lymphomas, a third dose of the BNT162b2 vaccine improved CD4+Th1+T cell responses, indicating a potential benefit for enhancing immune response in severely immunosuppressed individuals.

However, the effect on CD8+ T cell responses was only marginal, suggesting that while the booster dose can help some aspects of the immune response, it may not be as effective for all T cell types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-SARS-CoV-2 cellular response after 2 and 3 doses of BNT162b2 mRNA vaccine in lymphoma patients receiving anti-CD20 antibodies. Gressens, SB., Wiedemann, A., Déchenaud, M., et al.[2023]

Combining α-galactosylceramide (α-GalCer)-loaded tumor cell vaccination with an anti-4-1BB antibody significantly improved survival rates in mice with B cell lymphoma, with over 50% of treated mice completely eradicating their tumors.

The enhanced immune response was linked to the expansion of CD8+ T cells and the development of immunological memory, as 'cured' mice remained resistant to lymphoma re-challenge 80 days later, suggesting a durable anticancer immunity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NKT cell-targeted vaccination plus anti-4-1BB antibody generates persistent CD8 T cell immunity against B cell lymphoma. Kobayashi, T., Doff, BL., Rearden, RC., et al.[2021]

In a phase 1 trial involving three children with relapsed or resistant neuroblastoma, engineered NKT cells showed promising safety, with no dose-limiting toxicities observed after infusion, despite some hematologic adverse events linked to pre-treatment conditioning.

One patient experienced a significant anti-tumor response, with regression of bone metastatic lesions, indicating that CAR-NKT cells can effectively target tumors and expand in the body after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis. Heczey, A., Courtney, AN., Montalbano, A., et al.[2023]

The phase I study involving 12 subjects with acute myeloid leukemia or relapsed/refractory multiple myeloma demonstrated that NKG2D-CAR T cells were safe, with no dose-limiting toxicities or significant adverse events observed, indicating a favorable safety profile for this treatment approach.

While no objective tumor responses were achieved, there were transient improvements in hematologic parameters in one AML patient, suggesting potential for disease stability, but further modifications to enhance CAR T-cell expansion and effectiveness may be necessary for better clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma. Baumeister, SH., Murad, J., Werner, L., et al.[2021]

Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive form of lymphoma associated with Epstein-Barr virus, primarily affecting patients in East Asia and Latin America, and current treatments have limited effectiveness for advanced cases.

Immunotherapy, including strategies targeting PD-1/PD-L1 and CTLA-4, as well as CAR T cell therapy, shows promise in improving outcomes for NKTCL patients, highlighting the need for novel treatment approaches in this challenging disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances and challenges of immunotherapies in NK/T cell lymphomas. He, L., Chen, N., Dai, L., et al.[2023]

Extranodal NK/T-cell lymphoma (ENKTCL) is a highly aggressive form of non-Hodgkin's lymphoma with poor prognosis and limited efficacy from traditional chemoradiotherapy.

Recent advancements in immunotherapy have shown promising results in treating ENKTCL, suggesting a potential shift in treatment strategies for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Advances in immunotherapy of extranodal NK/T cell lymphoma]. Hao, DQ., Li, LQ., Li, MC., et al.[2020]

The study found that overexpression of the IL-2 receptor α (IL-2Rα) in NKTCL cells leads to increased cell proliferation and resistance to chemotherapy drugs like gemcitabine and doxorubicin, indicating a mechanism of chemoresistance in this aggressive lymphoma.

LMP1 was shown to activate the MAPK/NF-κB pathway, which in turn up-regulates IL-2Rα levels, suggesting that targeting IL-2Rα could be a promising therapeutic strategy for improving treatment outcomes in patients with NKTCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-2Rα up-regulation is mediated by latent membrane protein 1 and promotes lymphomagenesis and chemotherapy resistance in natural killer/T-cell lymphoma. Wang, L., Bi, XW., Zhu, YJ., et al.[2020]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can lead to long-term survival in about 48.6% of patients with relapsed/refractory natural killer/T-cell lymphomas (NKTCL), based on a study of 135 patients over a median follow-up of 4.8 years.

The timing of the transplant and the patient's condition at the time of transplantation significantly affect progression-free survival, with shorter intervals between diagnosis and transplant and not being in complete or partial remission associated with poorer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem cell transplantation for NK/T-cell lymphoma: an international collaborative analysis. Berning, P., Schmitz, N., Ngoya, M., et al.[2023]

Natural killer (NK)/T-cell lymphomas are aggressive cancers commonly found in Asian and South American populations, with Epstein-Barr virus (EBV) infection present in all cases, making EBV DNA levels a useful marker for assessing lymphoma load and treatment response.

Standard treatment for early-stage nasal NK/T-cell lymphoma involves non-anthracycline asparaginase-based regimens combined with radiotherapy, while advanced cases require asparaginase-containing regimens and may benefit from allogeneic stem cell transplantation, highlighting the need for tailored therapeutic approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How we treat NK/T-cell lymphomas. Tse, E., Zhao, WL., Xiong, J., et al.[2023]

References

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

NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma. [2021]

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

A simple, clinically relevant therapeutic vaccine shows long-term protection in an aggressive, delayed-treatment B lymphoma model. [2019]

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

An NKT-mediated autologous vaccine generates CD4 T-cell dependent potent antilymphoma immunity. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Anti-SARS-CoV-2 cellular response after 2 and 3 doses of BNT162b2 mRNA vaccine in lymphoma patients receiving anti-CD20 antibodies. [2023]

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

NKT cell-targeted vaccination plus anti-4-1BB antibody generates persistent CD8 T cell immunity against B cell lymphoma. [2021]

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

Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis. [2023]

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

Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma. [2021]

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

Advances and challenges of immunotherapies in NK/T cell lymphomas. [2023]

9. China pubmed.ncbi.nlm.nih.gov

[Advances in immunotherapy of extranodal NK/T cell lymphoma]. [2020]

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

IL-2Rα up-regulation is mediated by latent membrane protein 1 and promotes lymphomagenesis and chemotherapy resistance in natural killer/T-cell lymphoma. [2020]

11. England pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem cell transplantation for NK/T-cell lymphoma: an international collaborative analysis. [2023]

12. England pubmed.ncbi.nlm.nih.gov

How we treat NK/T-cell lymphomas. [2023]