Gemcitabine + NK Cells +/- Naxitamab for Breast Cancer

Overseen By Amanda Kabetso

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Margaret Gatti-Mays

Must not be taking: Systemic steroids

Disqualifiers: Active brain metastases, Autoimmune disease, Uncontrolled illness, others

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

Compensation: Varies

Number of Visits: 3

Duration: Up to 1 year

42 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received chemotherapy, investigational agents, or radiation within 3 weeks prior to enrollment, and certain medications like systemic steroids must be discontinued more than 2 weeks before starting the trial.

What data supports the effectiveness of the treatment Gemcitabine + NK Cells +/- Naxitamab for Breast Cancer?

Research shows that engineered natural killer (NK) cells can enhance anti-tumor activity and improve outcomes in cancer treatments. In particular, NK cells derived from stem cells have shown strong tumor-killing abilities and can work well with other therapies to boost the immune response against tumors. ^{1 2 3 4 5}

Is the combination of Gemcitabine and NK cells safe for humans?

Research shows that combining Gemcitabine with natural killer (NK) cells is generally well-tolerated in humans, with no severe adverse events reported in a study involving patients with advanced gastric or colorectal cancer. This suggests that the treatment is generally safe, although individual responses may vary. ^{1 2 6 7 8}

What makes the treatment with Gemcitabine, NK Cells, and Naxitamab unique for breast cancer?

This treatment is unique because it combines Gemcitabine, a chemotherapy drug, with NK cells (a type of immune cell) and Naxitamab, an antibody, to potentially enhance the immune system's ability to attack cancer cells. This approach leverages the immune-boosting effects of NK cells and the targeted action of Naxitamab, which is not a standard treatment for breast cancer. ^{9 10 11 12 13}

What is the purpose of this trial?

This phase Ib/II trial tests the safety, best dose and how well gemcitabine and ex vivo expanded allogenic universal donor TGFBi NK cells with or without naxitamab work for the treatment of patients with GD2 expressing, HER2 negative breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Gemcitabine is a chemotherapy drug that blocks the cells from making deoxyribonucleic acid (DNA) and may kill cancer cells. TGFBi NK cells are manufactured cells that are a part of your natural immunity. NK cells can recognize missing or incorrect proteins on tumor cells and then eliminate these tumor cells and TGFBi NK cells are created to be able to better kill the tumor cells. Naxitamab is a monoclonal antibody that targets GD2, which is a protein or sugar present on tumor cells but not very commonly found on normal cells. This antibody helps draw the attention of the immune system to the tumor cells that have GD2 to help attack the tumor cells. Giving gemcitabine and TGFBi NK cells with or without naxitamab may kill more tumor cells in patients with metastatic GD2 expressing, HER2 negative breast cancer.

Research Team

Margaret E Gatti-Mays, MD MPH

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with metastatic, GD2 expressing, HER2 negative breast cancer who've had at least one prior treatment. They must understand the study and consent to it, have good organ function and performance status, resolved any previous therapy side effects to a mild level, and agree to use effective contraception. Excluded are those with certain allergies, recent other cancers or treatments, brain metastases, severe heart conditions or infections.

Inclusion Criteria

You have enough infection-fighting white blood cells in your body.

You must have at least 100,000 platelets per microliter of blood.

My breast cancer is HER2 negative, possibly GD2 positive, and I have a sample of the tumor.

Exclusion Criteria

Any other condition, which would, in the opinion of the principal investigator the subject is a poor candidate for the clinical trial or would jeopardize the subject or the integrity of the data obtained

I haven't had chemotherapy, investigational drugs, or radiation in the last 3 weeks.

I do not have cancer that has spread to my brain or the membranes around my brain and spinal cord.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive gemcitabine and TGFBi NK cells with or without naxitamab. Treatment cycles repeat every 28 days for up to 1 year.

Up to 1 year

Multiple visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

1 year

Every 3 months

Treatment Details

Interventions

• Gemcitabine
• Naxitamab
• Universal Donor Expanded TGF-beta-imprinted NK Cells

Trial Overview The trial tests gemcitabine (a chemotherapy drug) combined with lab-grown NK cells that boost immune response against cancer cells. It also examines the addition of naxitamab—a monoclonal antibody targeting specific proteins on tumor cells—to this combination in patients whose tumors express a particular protein called GD2.

Participant Groups

Group I: Arm IV (Gemcitabine, naxitamab, TGFBi x2) Experimental Treatment 6 Interventions

Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle followed by naxitamab IV over 30-60 minutes on days 1, 4, and 8 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 and 18 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.

Group II: Arm III (Gemcitabine naxitamab, TGFBi) Experimental Treatment 6 Interventions

Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle followed by naxitamab IV over 30-60 minutes on days 1, 4, and 8 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.

Group III: Arm II (Gemcitabine, TGFBi x2) Experimental Treatment 5 Interventions

Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 and 18 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.

Group IV: Arm I (Gemcitabine, TGFBi) Experimental Treatment 5 Interventions

Patients receive gemcitabine intravenously (IV) over 30 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients receive TGFBi NK cells IV over 10-30 minutes on day 16 of cycle 1. Patients undergo CT scan and blood sample collection and may undergo MRI throughout the study.

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

Approved in European Union as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in United States as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Canada as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Japan as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Who Is Running the Clinical Trial?

Margaret Gatti-Mays

Lead Sponsor

Trials

1

Recruited

40+

Findings from Research

NK-CAR-iPSC-NK cells, engineered with a specific CAR construct, show enhanced anti-tumor activity against ovarian cancer compared to traditional T-CAR-expressing NK cells and non-CAR NK cells, indicating their potential as a more effective immunotherapy.

In an ovarian cancer model, NK-CAR-iPSC-NK cells not only inhibited tumor growth and improved survival rates but also exhibited similar in vivo activity to T-CAR T cells while demonstrating lower toxicity, making them a promising 'off-the-shelf' option for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity. Li, Y., Hermanson, DL., Moriarity, BS., et al.[2019]

The study developed a new method to create high-quality natural killer (NK) cells from induced pluripotent stem cells (iPSCs), which can be produced in large quantities and used as an 'off-the-shelf' immunotherapy option.

These iPSC-derived NK cells not only directly kill tumors but also enhance the effectiveness of existing checkpoint inhibitor therapies, like PD-1 blockade, by recruiting T cells and increasing inflammatory responses against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti-PD-1 therapy. Cichocki, F., Bjordahl, R., Gaidarova, S., et al.[2022]

Tumor-infiltrating NK (TI-NK) cells are strong independent biomarkers for predicting pathologic complete response (pCR) to neoadjuvant anti-HER2 antibody treatment in HER2-positive breast cancer, as shown in two patient cohorts totaling 113 participants.

The presence of TI-NK cells is also associated with longer disease-free survival (DFS), and tumor HLA class I expression can help stratify patients by relapse risk, providing additional prognostic information.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NK Cell Infiltrates and HLA Class I Expression in Primary HER2+ Breast Cancer Predict and Uncouple Pathological Response and Disease-free Survival. Muntasell, A., Rojo, F., Servitja, S., et al.[2021]

The study developed allogeneic CAR-NK cells that target pancreatic ductal adenocarcinoma (PDAC) by enhancing their ability to induce cancer cell death through specific receptors (FRα and DR4), showing improved tumor-selective apoptosis.

This approach suggests that using engineered NK cells could provide a safer and more effective treatment option for solid tumors like PDAC, potentially benefiting a larger number of patients with tailored therapies based on their tumor profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationally designed redirection of natural killer cells anchoring a cytotoxic ligand for pancreatic cancer treatment. Lee, YE., Ju, A., Choi, HW., et al.[2021]

A pilot study demonstrated that reprogramming tumor-sensitized immune cells from breast cancer patients can enhance their ability to fight tumors, particularly against HER-2/neu, by expanding activated CD25+ NKT and NK cells.

The study suggests that using a combination of bryostatin 1, ionomycin, and specific interleukins (IL-2, IL-7, IL-15) can effectively overcome immune suppression caused by myeloid-derived suppressor cells (MDSCs), making this approach a promising strategy for adoptive cellular therapy in breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells. Payne, KK., Zoon, CK., Wan, W., et al.[2021]

A study involving 23 patients with disseminated carcinomas showed that combining cytokine-activated killer (CAK) cell infusion therapy with gemcitabine resulted in long-term stable disease, indicating potential effectiveness in treating metastatic cancers.

In vitro experiments revealed that gemcitabine treatment increased the expression of NKG2D ligands on cancer cells, enhancing the cytotoxic effect of CAK cells, suggesting a synergistic mechanism that improves treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NKG2D-directed cytokine-activated killer lymphocyte therapy combined with gemcitabine for patients with chemoresistant metastatic solid tumors. Morisaki, T., Hirano, T., Koya, N., et al.[2022]

In a study of 109 patients with advanced non-small cell lung cancer (NSCLC), combining pembrolizumab with allogeneic NK cell therapy resulted in significantly longer overall survival (15.5 months) compared to pembrolizumab alone (13.3 months).

Patients receiving multiple courses of NK cell therapy showed even greater survival benefits, with a median overall survival of 18.5 months, highlighting the potential of NK cell infusion to enhance the efficacy of anti-PD-1 treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus allogeneic NK cells in advanced non-small cell lung cancer patients. Lin, M., Luo, H., Liang, S., et al.[2021]

The combination of expanded natural killer (NK) cells with IgG1 antibodies in patients with advanced gastric or colorectal cancers was well tolerated, showing no severe adverse events during the trial involving 9 participants.

Preliminary results indicated that this therapy could induce anti-tumor activity, with 4 out of 6 evaluable patients achieving stable disease and some showing a decrease in tumor size, alongside enhanced immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of adoptive transfer of expanded natural killer cells in combination with IgG1 antibody in patients with gastric or colorectal cancer. Ishikawa, T., Okayama, T., Sakamoto, N., et al.[2018]

In HER2-positive breast cancer patients, combining taxanes like docetaxel with trastuzumab enhances the effectiveness of the treatment by increasing the activity of natural killer (NK) cells, which are crucial for antibody-dependent cellular cytotoxicity (ADCC).

The study found that taxane treatment up-regulates NKG2D receptor expression on NK cells, leading to a 15-40% increase in trastuzumab-mediated ADCC, particularly benefiting patients with lower baseline immune activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Taxanes enhance trastuzumab-mediated ADCC on tumor cells through NKG2D-mediated NK cell recognition. Di Modica, M., Sfondrini, L., Regondi, V., et al.[2022]

Tafasitamab, a monoclonal antibody targeting CD19, effectively induces antitumor activity in non-Hodgkin's lymphoma through antibody-dependent cellular cytotoxicity (ADCC), particularly when combined with immune effector cells like γδ T and MG4101 NK cells.

In preclinical models, combining tafasitamab with allogeneic MG4101 NK cells significantly improved survival rates, showing a 1.7- to 4.1-fold increase in lifespan compared to monotherapy, suggesting that enhancing immune cell presence could boost the efficacy of tafasitamab in treating lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tafasitamab mediates killing of B-cell non-Hodgkin's lymphoma in combination with γδ T cell or allogeneic NK cell therapy. Her, JH., Pretscher, D., Patra-Kneuer, M., et al.[2022]

Infusing expanded autologous NK cells alongside trastuzumab in patients with HER2-positive tumors was well tolerated, with no maximum tolerated dose reached, indicating a favorable safety profile for this combination therapy.

While no objective responses were observed, 6 out of 19 patients experienced stable disease for at least 6 months, suggesting potential antitumor activity, particularly in a patient with a specific CD16 variant who had a partial response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers. Lee, SC., Shimasaki, N., Lim, JSJ., et al.[2021]

The soluble MIC (sMIC) produced by tumors reprograms Natural Killer (NK) cells to secrete pro-tumorigenic cytokines, reducing their ability to kill cancer cells, which contributes to poorer outcomes in cancer patients.

Targeting sMIC with antibodies can restore NK cell function and enhance their anti-tumor effects, suggesting that co-targeting sMIC could improve the effectiveness of NK cell-based cancer immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-derived NKG2D ligand sMIC reprograms NK cells to an inflammatory phenotype through CBM signalosome activation. Dhar, P., Basher, F., Ji, Z., et al.[2022]

Immunomodulatory drugs (IMiDs) are effective in treating multiple myeloma and myelodysplastic syndrome, showing benefits such as antitumor and immunostimulating effects, particularly on natural killer (NK) cells.

While some cancer treatments can enhance the immune response against tumors, they may also impair NK cell function depending on the dosage and duration of treatment, highlighting the need for careful management in therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel immune modulators used in hematology: impact on NK cells. Krieg, S., Ullrich, E.[2021]

References

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

Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity. [2019]

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

iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti-PD-1 therapy. [2022]

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

NK Cell Infiltrates and HLA Class I Expression in Primary HER2+ Breast Cancer Predict and Uncouple Pathological Response and Disease-free Survival. [2021]

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

Rationally designed redirection of natural killer cells anchoring a cytotoxic ligand for pancreatic cancer treatment. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells. [2021]

6. Greece pubmed.ncbi.nlm.nih.gov

NKG2D-directed cytokine-activated killer lymphocyte therapy combined with gemcitabine for patients with chemoresistant metastatic solid tumors. [2022]

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

Pembrolizumab plus allogeneic NK cells in advanced non-small cell lung cancer patients. [2021]

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

Phase I clinical trial of adoptive transfer of expanded natural killer cells in combination with IgG1 antibody in patients with gastric or colorectal cancer. [2018]

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

Taxanes enhance trastuzumab-mediated ADCC on tumor cells through NKG2D-mediated NK cell recognition. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Tafasitamab mediates killing of B-cell non-Hodgkin's lymphoma in combination with γδ T cell or allogeneic NK cell therapy. [2022]

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

Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers. [2021]

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

Tumor-derived NKG2D ligand sMIC reprograms NK cells to an inflammatory phenotype through CBM signalosome activation. [2022]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Novel immune modulators used in hematology: impact on NK cells. [2021]