T-Cell Therapy for Breast Cancer

Recruiting at 7 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Anticonvulsants, Corticosteroids, Immunosuppressants, others

Disqualifiers: CNS metastases, Seizure disorder, Autoimmune diseases, Cardiac disease, others

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

Compensation: Varies

Number of Visits: 10

Duration: 2 days

186 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop chemotherapy, targeted therapy, or radiotherapy at least 14 days before receiving T-cells, and any prior immunotherapy must be completed more than a month before the T-cell infusion. If you are on daily systemic corticosteroids or other immunosuppressive agents, you will need to stop those as well.

What data supports the effectiveness of the treatment AP1903, Cyclophosphamide, Cytoxan, Neosar, Endoxan, Mesothelin-targeted T cells for breast cancer?

Research shows that mesothelin-targeted T cells, a type of immune cell therapy, have shown promise in treating other cancers like ovarian cancer by targeting a protein called mesothelin, which is found on many cancer cells. This suggests potential effectiveness for breast cancer, as similar mechanisms may apply. ^{1 2 3 4 5}

Is T-cell therapy targeting mesothelin safe for humans?

Research on T-cell therapy targeting mesothelin, used in various cancer treatments, shows that it can cause changes to tissues where mesothelin is present, but these studies are mostly in animal models. Human trials have evaluated safety, but specific safety data for breast cancer is not detailed in the available research. ^{3 6 7 8 9}

How is the T-Cell Therapy for Breast Cancer using Mesothelin-targeted T cells different from other treatments?

This treatment is unique because it uses genetically engineered T cells to specifically target mesothelin, a protein over-expressed in many cancers, including breast cancer. These T cells are designed to recognize and attack cancer cells, potentially offering a more targeted and effective approach compared to traditional therapies. ^{2 3 4 6 9}

What is the purpose of this trial?

The purpose of this study is to test the safety of different doses of specially prepared T cells collected from the blood. The investigators want to find a safe dose of these modified T cells for patients who have metastatic HER2-negative breast cancer.

Research Team

Shanu Modi, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with advanced HER2-negative breast cancer who've had at least one chemo treatment and whose disease has progressed. They must have finished any previous treatments, including immunotherapy, certain days before getting T-cells and agree to use contraception. People can't join if they're on daily steroids, have autoimmune diseases, are pregnant or breastfeeding, or have untreated brain metastases.

Inclusion Criteria

I finished chemotherapy at least a week ago.

I finished chemotherapy, targeted therapy, or radiotherapy at least 14 days ago and any immunotherapy over a month ago.

My breast cancer diagnosis was confirmed through a biopsy.

Exclusion Criteria

Pregnancy or lactation

I have not taken antibiotics for an infection in the last 7 days.

I have an autoimmune or antibody-mediated disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment

Leukapheresis for harvesting PBMCs and administration of cyclophosphamide

1 week

1 visit (in-person)

Treatment

Infusion of mesothelin-targeted T cells and inpatient monitoring

2 days

1 visit (in-person, inpatient)

Follow-up

Participants are monitored weekly as outpatients for safety and effectiveness

8 weeks

8 visits (in-person)

Long-term follow-up

Participants are monitored for long-term safety and effectiveness

2 years

Treatment Details

Interventions

• AP1903
• Cyclophosphamide
• Mesothelin-targeted T cells

Trial Overview The study tests different doses of modified T cells targeting mesothelin in patients with metastatic breast cancer to find a safe level. Patients will receive Cyclophosphamide followed by the engineered T cells and AP1903 as part of the treatment process.

Participant Groups

Group I: T-cell infusion Experimental Treatment 3 Interventions

A single blood volume leukapheresis for harvesting of PBMCs will be performed, As the transduced T cells will be frozen, the timing of leukapheresis is not defined \& can vary from patient to patient. Subsequently, a single dose of mesothelin-targeted T cells will be infused via intravenous catheter or central line (i.e., mediport). Patients will be monitored in the hospital and discharged home after a minimum of 48 hours. Patients will be monitored closely as outpatients for the next 2 months. Patients will be followed weekly as outpatients for the first 8 weeks after treatment. All patients will be hydrated intravenously, premedicated with acetaminophen \& diphenhydramine, \& administered cyclophosphamide at 1.5 g/m2 2 to 7 days (Day -7 to Day -2) before administration of mesothelin-targeted T cells.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

Two types of mesothelin-directed CAR T cells were tested in mouse models of ovarian cancer, showing that while M28z CAR T cells improved survival, they did not achieve lasting tumor control, whereas MBBz CAR T cells led to long-term remission in some cases.

The study revealed that the tumor microenvironment negatively affects CAR T cell persistence due to the upregulation of inhibitory pathways, highlighting the need for strategies to enhance CAR T cell effectiveness in ovarian cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mesothelin-Specific CAR T Cells Target Ovarian Cancer. Schoutrop, E., El-Serafi, I., Poiret, T., et al.[2021]

The study developed fully human anti-mesothelin CAR T cells that effectively target and kill mesothelin-expressing tumors, demonstrating strong cytolytic functions and the ability to produce proinflammatory cytokines in vitro.

In a xenogenic model of human ovarian cancer, the transfer of these human CAR T cells led to significant tumor regression, even in the presence of high levels of soluble mesothelin, suggesting they can overcome challenges related to transgene immunogenicity seen with mouse-derived CARs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor. Lanitis, E., Poussin, M., Hagemann, IS., et al.[2021]

Meso3 CAR T cells, targeting the membrane-proximal region of mesothelin, showed superior activation and cytokine production compared to meso1 CAR T cells, indicating a more effective immune response against cancer cells.

In animal models, meso3 CAR T cells demonstrated stronger antitumor effects in gastric and ovarian cancers, suggesting that this approach could be a more effective immunotherapy for treating mesothelin-positive solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor. Zhang, Z., Jiang, D., Yang, H., et al.[2021]

References

1. Poland pubmed.ncbi.nlm.nih.gov

Mesothelin-targeted CAR-T cells for adoptive cell therapy of solid tumors. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy. [2023]

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

Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. [2023]

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

Mesothelin-Specific CAR T Cells Target Ovarian Cancer. [2021]

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

Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor. [2021]

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

Therapeutic effiacy of T cells expressing chimeric antigen receptor derived from a mesothelin-specific scFv in orthotopic human pancreatic cancer animal models. [2022]

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

Mesothelin as a biomarker for targeted therapy. [2020]

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

Novel Humanized Mesothelin-Expressing Genetically Engineered Mouse Models Underscore Challenges in Delivery of Complex Therapeutics to Pancreatic Cancers. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor. [2021]