CAR T-cell Therapy for Mesothelioma

Overseen By Adam Schoenfeld, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

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

Disqualifiers: Active malignancy, CNS metastases, Autoimmune, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest dose of a new treatment called MSLN-targeted CAR T-cell therapy, a type of immunotherapy, for individuals with mesothelioma, a cancer affecting the lung lining. Researchers are evaluating this treatment to assess its effects on the cancer and ensure patient safety. This marks the first human test of this therapy, which includes an anti-PD1 component that may help the immune system fight cancer. Ideal candidates for the trial are those previously treated for mesothelioma with cancer detectable on scans or evaluable by doctors. As a Phase 1 trial, participants will be among the first to receive this innovative treatment, aiding researchers in understanding its effects in humans.

Will I have to stop taking my current medications?

The trial requires that chemotherapy, targeted therapy, or radiotherapy be stopped at least 7 days before a procedure called leukapheresis, and at least 14 days before receiving T cells. Immunotherapy with CPI must be stopped at least 42 days before receiving T cells. If you're on these treatments, you will need to stop them for a certain period before participating.

Is there any evidence suggesting that MSLN-targeted CAR T-cell therapy is likely to be safe for humans?

Research has shown that MSLN-targeted CAR T-cell therapy has been tested in patients with pleural mesothelioma. One study found that the treatment had a manageable safety profile, indicating that side effects were not too severe. Another study confirmed the safety of these cells, showing they did not cause major harm to patients. These findings suggest that while some side effects may occur, they are generally tolerable.

Overall, early research appears promising in terms of safety. However, as this is a Phase 1 trial, the primary goal is to determine the safest dose and monitor any side effects. This trial phase involves closely observing the treatment's safety in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for mesothelioma?

Unlike the standard treatments for mesothelioma, which typically include surgery, chemotherapy, and radiation, the MSLN-targeted CAR T-cell therapy is unique because it uses genetically engineered T cells to specifically target and attack cancer cells. This approach involves modifying a patient's own immune cells to recognize and destroy mesothelin-expressing tumor cells, potentially leading to a more precise and effective treatment. Researchers are excited about this therapy because it offers a novel mechanism of action that could result in fewer side effects and improved outcomes compared to conventional therapies.

What evidence suggests that MSLN-targeted CAR T-cell therapy might be an effective treatment for mesothelioma?

Research has shown that a new treatment, mesothelin-targeted CAR T-cell therapy, holds promise for certain cancers. This therapy has successfully treated blood cancers, and there is hope it can also be effective for solid tumors like mesothelioma. In this trial, participants will receive MSLN-targeted CAR T-cell therapy, which uses CAR T cells to attack cancer cells with the protein mesothelin, often present in these tumors. Early results suggest that adding an anti-PD1 component might enhance the immune system's ability to fight cancer. Additionally, this treatment has demonstrated a manageable safety profile, which is crucial for its potential success. ^{2 3 5 6 7}

Who Is on the Research Team?

Roisin O'Cearbhaill, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults over 18 with mesothelioma who've had at least one treatment regimen, are not on high-dose steroids, and don't have other active cancers or certain heart/lung conditions. They must be in good physical condition (Karnofsky score ≥70%) and have a life expectancy of more than 4 months.

Inclusion Criteria

My mesothelioma affects both the lining of my abdomen and lungs, confirmed by tests.

I can finish palliative radiotherapy 2 days before starting lymphodepletion.

Your blood tests need to show a certain level of white blood cells and platelets, and your liver and kidney function need to be within a certain range.

Exclusion Criteria

I have had treatment for blood cancer or lymphoid malignancy in the last 5 years.

I am taking high doses of corticosteroids every day.

I am currently being treated for another cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Leukapheresis and Manufacturing

Patients undergo leukapheresis for the collection of PBMCs, followed by CAR T-cell manufacturing

4-6 weeks

Preconditioning

A preconditioning regimen of one dose of intravenous cyclophosphamide is administered 2-7 days before CAR T-cell infusion

1 week

Treatment

A single dose of M28z1XXPD1DNR CAR T cells is administered, followed by a minimum of 48 hours of hospital monitoring

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• MSLN-targeted CAR T-cell Therapy

Trial Overview The trial is testing different doses of MSLN-targeted CAR-T cells to find the safest dose for treating mesothelioma. It's the first time this therapy, which includes an anti-PD1 component, is being used in humans.

How Is the Trial Designed?

Group I: Engineered Autologous T Cells Experimental Treatment 2 Interventions

Following eligibility screening and enrollment, patients will undergo leukapheresis for the collection of peripheral blood mononuclear cells (PBMCs), to enable generation of M28z1XXPD1DNR. Following successful M28z1XXPD1DNR CAR T-cell manufacturing, patients will be reevaluated for eligibility. A preconditioning regimen of one dose of intravenous (IV) cyclophosphamide 1.5 g/m2 will be administered 2-7 days before the infusion. A single dose of M28z1XXPD1DNR CAR T cells will be instilled into the pleural cavity via a pleural catheter or through an interventional radiology-guided needle. All patients will be monitored in the hospital for a minimum of 48 h following the administration of CAR T cells.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Atara Biotherapeutics

Industry Sponsor

Trials

14

Recruited

740+

Published Research Related to This Trial

Anti-MSLN CAR-T-cell therapy has demonstrated a high safety profile in clinical trials, making it a promising option for treating solid tumors, although its efficacy remains limited.

Combining anti-MSLN CAR-T-cell therapy with standard treatments has shown significantly better outcomes than using the therapy alone, suggesting that combination strategies may enhance its effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Challenges of Anti-Mesothelin CAR-T-Cell Therapy. Zhai, X., Mao, L., Wu, M., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8563385/

A phase I trial of regional mesothelin-targeted CAR T-cell ... Chimeric antigen receptor (CAR) T-cell therapy induces durable and curative responses in patients with hematological malignancies, but attempts to treat solid ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06054308

Study Details | NCT06054308 | Mesothelin-targeted CAR-T ... Chimeric antigen receptor (CAR) T-cell therapy may represent a new paradigm in the treatment of pancreatic cancer. Mesothelin (MSLN) is a 40 kDa membrane ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.2534

Safety and efficacy of non-viral aPD1-MSLN JL-lightning– ... Non-viral aPD1-MSLN JL-Lightning-CAR-T cells demonstrated robust proliferative capacity, manageable safety profile, and significant anti-tumor potential.

4. nature.com nature.com/articles/s41591-023-02452-y

Mesothelin-targeting T cell receptor fusion construct ... Here we describe phase 1 results from an ongoing phase1/2 trial of gavo-cel in patients with treatment-refractory mesothelin-expressing solid tumors.

5. archivesofmedicalscience.com archivesofmedicalscience.com/Mesothelin-targeted-CAR-T-cells-for-adoptive-cell-therapy-of-solid-tumors,106265,0,2.html

Mesothelin-targeted CAR-T cells for adoptive cell therapy ... Significant progresses have been made in adoptive cell therapy with CAR-T cells for cancers, especially for hematological malignancies.

6. annalsofoncology.org annalsofoncology.org/article/S0923-7534(21)04599-3/fulltext

Mesothelin-targeted CAR (M28z1XXPD1DNR) with T-cell ... Clinical safety and systemic persistence of M28z1XXPD1DNR CAR T cells was investigated in 4 pleural mesothelioma patients (NCT04577326). Results. Following ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39548510/

Efficacy and safety of novel multiple-chain DAP-CAR-T ... Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and ...