NK Cell Therapy + Mogamulizumab for T-Cell Lymphoma/Leukemia

Overseen By Thomas Needham

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: John Reneau

Must not be taking: Immunosuppressants, Live-virus vaccines

Disqualifiers: Active CNS lymphoma, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: 3

Duration: 12 weeks

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial is to find out the best dose, possible benefits and/or side effects of third-party natural killer cells in combination with mogamulizumab in treating patients with cutaneous T-cell lymphoma or adult T-cell leukemia/lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Immunotherapy with third-party natural killer cells, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Mogamulizumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving third-party natural killer cells in combination with mogamulizumab may kill more cancer cells.

Will I have to stop taking my current medications?

The trial requires that all cancer therapies, including radiation, topical steroids, and chemotherapy, be stopped at least 1 week or 3 half-lives before starting the study, except for certain corticosteroids. Participants can continue medications for other conditions if there is evidence of T-cell lymphoma progression while on these medications.

What data supports the effectiveness of the drug mogamulizumab for T-cell lymphoma/leukemia?

Mogamulizumab has shown promising results in treating adult T-cell leukemia/lymphoma (ATL) and other T-cell lymphomas, with studies indicating it is effective and well-tolerated in patients with relapsed or refractory conditions. It has been approved in Japan for ATL and demonstrated significant improvement in progression-free survival for other T-cell lymphomas, suggesting its potential utility in these aggressive cancers. ^{1 2 3 4 5}

Is NK Cell Therapy + Mogamulizumab safe for humans?

Natural killer (NK) cells have shown a proven safety profile in cancer treatments, and they are considered safer than some other cell therapies. Mogamulizumab, also known as Poteligeo, is a medication used for certain types of cancer and has been evaluated for safety in humans, though specific safety data for the combination with NK cells is limited. ^{6 7 8 9 10}

How is the NK Cell Therapy + Mogamulizumab treatment different from other treatments for T-Cell Lymphoma/Leukemia?

This treatment is unique because it combines mogamulizumab, a monoclonal antibody that targets a specific receptor on cancer cells, with natural killer (NK) cells, which are immune cells that help destroy cancer cells. Mogamulizumab enhances the body's immune response at lower doses, and the addition of NK cells aims to further boost the immune system's ability to fight the cancer. ^{2 4 5 11 12}

Research Team

John C Reneau, MD, PhD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

Adults over 18 with relapsed or refractory cutaneous T-cell lymphoma or adult T-cell leukemia/lymphoma, who've had at least one prior systemic therapy. Participants must have adequate organ function and performance status, not be pregnant, and free from severe allergies to monoclonal antibodies or certain infections. Those with a history of other cancers may join if they've been disease-free for two years.

Inclusion Criteria

Absolute neutrophil count >= 1000/mm^3

I can understand and willingly sign a consent form.

Able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria

Any illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety

My lymphoma has spread to my brain or spinal cord.

I am experiencing moderate to severe symptoms from a transplant reaction.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive mogamulizumab IV, fludarabine IV, and cyclophosphamide IV, followed by NK cell infusion every 2 weeks for six infusions total

12 weeks

Multiple visits for infusions

Follow-up

Participants are monitored for safety and effectiveness after treatment

28-35 days

Follow-up visits every 3 months for 2 years

Long-term follow-up

Participants are monitored for progression free survival and overall survival

Up to 2 years

Treatment Details

Interventions

• Mogamulizumab
• Third-Party Natural Killer Cells

Trial Overview The trial is testing the combination of third-party natural killer cells and mogamulizumab to determine the best dose and assess potential benefits/side effects in treating specific lymphomas that are resistant to standard treatments. It's an early-phase study exploring how this immunotherapy can help control cancer growth.

Participant Groups

Group I: Treatment (mogamulizumab, chemotherapy, NK cells) Experimental Treatment 6 Interventions

Patients receive mogamulizumab IV over 60 minutes on day -7 and fludarabine IV and cyclophosphamide IV on days -5 to -3. Patients receive NK cell infusion on day 0. Patients then receive mogamulizumab IV over 60 minutes on days 0, 7, 14, and 28, then every 2 weeks thereafter in the absence of disease progression or unacceptable toxicity.

Mogamulizumab is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Poteligeo for:

• Mycosis fungoides
• Sézary syndrome

Approved in United States as Poteligeo for:

• Mycosis fungoides
• Sézary syndrome

Approved in Canada as Poteligeo for:

• Mycosis fungoides
• Sézary syndrome

Approved in Japan as Poteligeo for:

• Adult T-cell leukemia-lymphoma
• Cutaneous T-cell lymphoma

Who Is Running the Clinical Trial?

John Reneau

Lead Sponsor

Trials

4

Recruited

90+

Findings from Research

Mogamulizumab is an FDA-approved monoclonal antibody that targets the CCR4 receptor, showing significant improvement in progression-free survival for patients with relapsed or refractory mycosis fungoides or Sézary syndrome compared to vorinostat.

While mogamulizumab offers a new treatment option for T-cell lymphomas, it is associated with serious adverse events such as infusion reactions and increased risk of graft-versus-host disease in certain settings, highlighting the need for careful patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mogamulizumab: An Anti-CC Chemokine Receptor 4 Antibody for T-Cell Lymphomas. Moore, DC., Elmes, JB., Shibu, PA., et al.[2020]

Mogamulizumab, an anti-CCR4 receptor antibody, shows promising antitumor activity in treating aggressive T-cell neoplasms like adult T-cell leukemia/lymphoma (ATL) at lower doses compared to other monoclonal antibodies.

Clinical trials indicate that mogamulizumab is effective and well tolerated in patients with relapsed/refractory ATL, leading to its recent regulatory approval in Japan and ongoing evaluations in the U.S. and Europe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mogamulizumab for the treatment of adult T-cell leukemia/lymphoma. de Lartigue, J.[2017]

In a study of 13 patients with cutaneous T-cell lymphoma (CTCL), mogamulizumab treatment led to significant reductions in T cells, with a 57% decrease in total CD3+ T cells and up to 75% in aberrant T cell populations after four treatment cycles.

The reduction in aberrant T cells was noticeable after just one dose of mogamulizumab, indicating its potential effectiveness, although no clear correlation was found between the decrease in aberrant T cells and treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of mogamulizumab on the aberrant T cell population in the peripheral blood - A monocentric retrospective analysis. Gosmann, J., Bielefeld, A., Schmitz, FJ., et al.[2023]

Mogamulizumab, a monoclonal antibody targeting CC chemokine receptor 4, demonstrated significant efficacy in a patient with refractory peripheral T-cell lymphoma (PTCL) who had relapsed after autologous stem cell transplantation.

The treatment with mogamulizumab was well-tolerated, showing no severe adverse events, highlighting its potential as a novel therapeutic option for difficult-to-treat PTCL cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mogamulizumab treatment of refractory peripheral T-cell lymphoma following autologous stem cell transplantation: A case report. Fujita, Y., Nakaya, A., Fujita, S., et al.[2020]

Recent clinical trials have shown that the combination of VCAP-AMP-VECP and mogamulizumab significantly improves complete response rates in aggressive adult T-cell leukemia (ATL), with a higher response rate of 52% compared to 33% for VCAP-AMP-VECP alone.

Mogamulizumab has demonstrated promising efficacy for relapsed ATL and peripheral T-cell lymphomas (PTCLs), indicating its potential as a new treatment option for these challenging malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disease-oriented treatment of T/NK-cell lymphomas. Tobinai, K.[2017]

In a study involving 30 patients with advanced leukemia, the use of CTLA4Ig before donor lymphocyte infusion (DLI) led to a significant increase in mature NK cells, which are important for fighting leukemia, while also reducing the risk of acute graft-versus-host disease (GVHD) and nonrelapse mortality (NRM).

The overall survival rate at 18 months was 79%, indicating that CTLA4Ig primed DLI not only enhances NK cell activity but also supports better outcomes in leukemia treatment with fewer side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA4Ig Primed Donor Lymphocyte Infusion: A Novel Approach to Immunotherapy after Haploidentical Transplantation for Advanced Leukemia. Jaiswal, SR., Bhakuni, P., Joy, A., et al.[2020]

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]

CAR-T cell therapy has shown success in treating blood cancers but is limited by risks like graft-versus-host disease and lengthy production times.

CAR-NK cell therapies offer a promising alternative as they can be produced as off-the-shelf products, potentially providing a safer and more efficient treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-NK for tumor immunotherapy: Clinical transformation and future prospects. Wang, W., Jiang, J., Wu, C.[2020]

A study of 441 patients with aggressive B-cell lymphomas revealed that a homozygous deletion of the NKG2C gene is linked to a three-fold increase in prevalence among patients compared to healthy controls, and is associated with poorer outcomes, including significantly reduced progression-free survival (PFS).

The presence of the HLA-E*01:01 allele was found to be more common in B-NHL patients and correlated with higher rates of complete remission, suggesting that genotyping for NKG2C and HLA-E could help identify risk levels and predict responses to immunotherapy in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic Variants of the NKG2C/HLA-E Receptor-Ligand Axis Are Determinants of Progression-Free Survival and Therapy Outcome in Aggressive B-Cell Lymphoma. Wagner, B., Dührsen, U., Hüttmann, A., et al.[2020]

Chimeric antigen receptor (CAR) T cells have shown great success in treating B-lymphoid cancers, but their production is costly and they can cause significant toxicity, limiting their use to specialized centers.

Natural killer (NK) cells present a promising alternative for cancer treatment due to their strong antitumor activity, safety in allogeneic settings, and potential for off-the-shelf availability, making them a viable option for broader cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive cell therapy using engineered natural killer cells. Rezvani, K.[2022]

Pretransplantation use of mogamulizumab (Mog) in patients with aggressive adult T-cell leukemia/lymphoma (ATLL) significantly increased the risk of severe acute graft-versus-host disease (GVHD) and refractoriness to treatment, indicating potential safety concerns.

Patients who received Mog before allogeneic hematopoietic stem-cell transplantation (allo-HSCT) had a higher one-year nonrelapse mortality rate (43.7% vs. 25.1%) and lower overall survival (32.3% vs. 49.4%) compared to those who did not, suggesting that Mog may negatively impact clinical outcomes in this setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pretransplantation Anti-CCR4 Antibody Mogamulizumab Against Adult T-Cell Leukemia/Lymphoma Is Associated With Significantly Increased Risks of Severe and Corticosteroid-Refractory Graft-Versus-Host Disease, Nonrelapse Mortality, and Overall Mortality. Fuji, S., Inoue, Y., Utsunomiya, A., et al.[2021]

Natural killer (NK) cells are being explored as a promising strategy to enhance anti-cancer therapies, particularly in their ability to target and kill tumor cells while also producing important immune signals like interferon gamma.

Despite advances in NK cell therapy, challenges remain in treating NK leukemias and lymphomas, which are rare but difficult to manage due to the lack of effective treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments in anti-tumor efficacy and malignant transformation of human natural killer cells. VanDeusen, JB., Caligiuri, MA.[2019]

References

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

Mogamulizumab: An Anti-CC Chemokine Receptor 4 Antibody for T-Cell Lymphomas. [2020]

2. Spain pubmed.ncbi.nlm.nih.gov

Mogamulizumab for the treatment of adult T-cell leukemia/lymphoma. [2017]

3. Germany pubmed.ncbi.nlm.nih.gov

The effect of mogamulizumab on the aberrant T cell population in the peripheral blood - A monocentric retrospective analysis. [2023]

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

Mogamulizumab treatment of refractory peripheral T-cell lymphoma following autologous stem cell transplantation: A case report. [2020]

5. Japan pubmed.ncbi.nlm.nih.gov

Disease-oriented treatment of T/NK-cell lymphomas. [2017]

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

CTLA4Ig Primed Donor Lymphocyte Infusion: A Novel Approach to Immunotherapy after Haploidentical Transplantation for Advanced Leukemia. [2020]

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. Ireland pubmed.ncbi.nlm.nih.gov

CAR-NK for tumor immunotherapy: Clinical transformation and future prospects. [2020]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Genetic Variants of the NKG2C/HLA-E Receptor-Ligand Axis Are Determinants of Progression-Free Survival and Therapy Outcome in Aggressive B-Cell Lymphoma. [2020]

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

Adoptive cell therapy using engineered natural killer cells. [2022]

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

Pretransplantation Anti-CCR4 Antibody Mogamulizumab Against Adult T-Cell Leukemia/Lymphoma Is Associated With Significantly Increased Risks of Severe and Corticosteroid-Refractory Graft-Versus-Host Disease, Nonrelapse Mortality, and Overall Mortality. [2021]

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

New developments in anti-tumor efficacy and malignant transformation of human natural killer cells. [2019]