CAR T-Cell Therapy for Esophageal Cancer

Recruiting at 6 trial locations

Overseen By Geoffrey Ku, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Pregnancy, HIV, Active hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 3-4 weeks

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for esophageal cancer using a patient’s own T cells (a type of white blood cell) to combat the disease. In the lab, researchers modify the T cells to target and destroy cancer cells in individuals with a specific type of esophageal cancer that has spread to the stomach lining. This study may suit those whose esophageal cancer has returned or spread and who have not responded well to previous treatments. Participants will have their T cells collected and modified, then receive the M28z1XXPD1DNR CAR treatment over several weeks. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial requires that you complete any systemic therapy at least 7 days before leukapheresis, and immune checkpoint inhibitor therapy must be completed at least 14 days before leukapheresis. You should discuss your current medications with the study team to ensure compliance with these requirements.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the M28z1XXPD1DNR CAR T-cell therapy is being tested for safety in people with certain types of cancer. Earlier studies indicated some promise, but the treatment remains in the early stages of testing. Researchers are primarily assessing its safety for humans.

In these studies, patients seem to tolerate the therapy well. However, since the treatment is still in the first phase of testing, information on possible side effects is limited. Participants might experience side effects, as with any new treatment. These studies aim to identify potential side effects and assess their severity.

Prospective trial participants should discuss any concerns with a doctor, who can provide more detailed information on what to expect. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for esophageal cancer, which often include chemotherapy and radiation, M28z1XXPD1DNR CAR T-cell therapy offers a novel approach by harnessing the patient's own immune cells to fight cancer. This therapy is unique because it targets mesothelin, a protein commonly found on the surface of certain cancer cells, enabling a more precise attack on the tumor. Additionally, CAR T-cell therapy has the potential to provide longer-lasting protection against cancer recurrence by training the immune system to recognize and destroy cancer cells. Researchers are excited about this treatment because it represents a personalized and potentially more effective option for patients with mesothelin-positive esophagogastric adenocarcinoma with peritoneal carcinomatosis.

What evidence suggests that this treatment might be an effective treatment for esophageal cancer?

Research has shown that M28z1XXPD1DNR CAR T-cell therapy could be promising for treating esophageal cancer. This treatment targets a protein called mesothelin, often found in large amounts in some cancer cells. In earlier studies, this therapy proved more effective when administered directly into the abdominal cavity. When tested on cells from gastroesophageal adenocarcinoma (a type of esophageal cancer), the modified T cells effectively located and attacked the cancer cells. These results suggest that the therapy might be effective for patients with mesothelin-positive esophagogastric adenocarcinoma with peritoneal carcinomatosis, which is the focus of this trial. Participants in this trial will receive this targeted CAR T-cell therapy. ^{2 4 5 6 7}

Who Is on the Research Team?

Geoffrey Y. Ku

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals with certain types of cancer affecting the lining of organs, esophagus, or stomach. Participants must have T cells that can be collected and modified in a lab. Specific eligibility details are not provided but typically include factors like age, health status, and prior treatments.

Inclusion Criteria

My doctor expects me to live for at least 4 more months.

I am fully active or can carry out light work.

At least 1 measurable or evaluable lesion per RECIST 1.1

Exclusion Criteria

I have an autoimmune disease treated within the last year.

Baseline pulse oximetry <90% on room air at the screening time point

Deemed to be noncompliant by the study team for administration of a high-risk treatment agent and for close follow-up after treatment as required by the protocol

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Leukapheresis and CAR T-cell Modification

Participants undergo leukapheresis to collect T cells, which are then modified to become MSLN-targeted CAR T cells

3-4 weeks

Treatment

Participants receive MSLN-targeted CAR T-cell therapy administered through the peritoneal cavity

3-4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events

Up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• M28z1XXPD1DNR CAR

Trial Overview The study tests a new therapy where patients' own T cells are engineered to target cancer cells expressing mesothelin (MSLN). These modified T cells (M28z1XXPD1DNR CAR) are then given back to the patient to help fight the cancer.

How Is the Trial Designed?

Group I: Participants with Mesothelin-Positive Esophagogastric Adenocarcinoma with Peritoneal Carcinomatosis Experimental Treatment 1 Intervention

Participants will be diagnoses with Mesothelin-Positive Esophagogastric Adenocarcinoma with Peritoneal Carcinomatosis

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

In a phase 3 trial involving 596 patients with advanced esophageal squamous cell carcinoma, the addition of camrelizumab to chemotherapy significantly improved overall survival (15.3 months vs. 12.0 months with placebo) and progression-free survival (6.9 months vs. 5.6 months with placebo).

The treatment was associated with a similar rate of severe adverse events (grade 3 or higher) between the camrelizumab-chemotherapy group (63.4%) and the placebo-chemotherapy group (67.7%), indicating that the combination therapy is relatively safe while providing better efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. Luo, H., Lu, J., Bai, Y., et al.[2022]

In a study of 64 patients with esophageal squamous cell carcinoma (ESCC), PD-L1 expression was found in 54.7% of pre-treatment samples, and high levels of PD-L1 were linked to a poorer prognosis, indicating its potential as a prognostic marker.

After concurrent chemoradiation therapy (CCRT), there was a trend of decreased PD-L1 expression in patients who responded to treatment, suggesting that changes in PD-L1 levels may reflect treatment response in ESCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Change in PD-L1 and CD8 Expression after Chemoradiotherapy for Esophageal Squamous Cell Carcinoma. Chen, WC., Wu, CC., Chen, YH., et al.[2022]

EphA2 is significantly overexpressed in esophageal squamous cell carcinoma (ESCC) tissues, making it a promising target for CAR T cell therapy.

EphA2.CAR-T cells demonstrated superior ability to kill ESCC cells in vitro compared to regular T cells, showing a dose-dependent response and increased production of cytokines like TNF-α and IFN-γ, indicating their potential effectiveness in immunotherapy for ESCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EphA2 chimeric antigen receptor-modified T cells for the immunotherapy of esophageal squamous cell carcinoma. Shi, H., Yu, F., Mao, Y., et al.[2022]

In a systematic review of 5595 patients from 10 clinical trials, PD-1 blockade therapies for advanced esophageal cancer showed high rates of treatment-related adverse events (TRAEs), with 88% experiencing any grade of TRAEs and 24% experiencing grade 3 or higher TRAEs when treated with PD-1 blockade alone.

When compared to chemotherapy, PD-1 blockade therapies had similar rates of all grade TRAEs (RR 0.96) and lower rates of grade 3 or higher TRAEs (RR 0.75), suggesting that PD-1 blockade may be a safer option for patients with advanced esophageal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profile of treatment-related adverse events of PD-1 blockade-based therapies in advanced esophageal cancer: A systematic review and meta-analysis. Luo, Y., Yao, Y., Wu, P., et al.[2023]

A systematic review of 11 studies involving 3451 patients showed that PD-1 inhibitors significantly improve median overall survival in patients with advanced esophageal and gastroesophageal junction cancers compared to standard treatments.

The use of PD-1 blockade is associated with an acceptable safety profile, indicating it is well tolerated, and its potential in the adjuvant setting suggests further advancements in treatment options for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 inhibitors in esophageal cancer: a systematic review of the oncological outcomes associated with PD-1 blockade and the evolving therapeutic paradigm. Whooley, J., Alazzawi, M., Donlon, NE., et al.[2022]

A systematic review of 11 randomized controlled trials involving patients with esophageal cancer (EPC) and gastroesophageal junction cancer (GEJC) found that immune checkpoint inhibitors (ICIs) have a similar risk of severe treatment-related adverse events (trAEs) compared to chemotherapy, with a risk ratio of 0.764.

While ICIs were associated with a higher incidence of immune-related adverse events (irAEs) compared to chemotherapy (7.35% vs. 2.25%), the overall rates of these events were considered low and manageable, highlighting the importance of monitoring for specific adverse effects in patients receiving ICIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment- and immune-related adverse events of immune checkpoint inhibitors in esophageal or gastroesophageal junction cancer: A network meta-analysis of randomized controlled trials. Zheng, J., Huang, B., Xiao, L., et al.[2023]

In a review of five clinical trials involving 1970 patients, second-line PD-1 inhibitors significantly improved overall survival (OS) and objective response rate (ORR) in advanced esophageal squamous cell carcinoma (ESCC) compared to conventional chemotherapy, particularly in patients with positive PD-L1 status.

PD-1 inhibitors also demonstrated a better safety profile, with lower incidences of severe treatment-related adverse events (TRAEs) compared to chemotherapy, although they did not show significant improvements in progression-free survival (PFS) or disease control rate (DCR).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 inhibitors versus chemotherapy as second-line treatment for advanced esophageal squamous cell carcinoma: a meta-analysis. Zhu, X., Shanzhou, Q., Li, D., et al.[2022]

The study established 14 patient-derived xenograft (PDX) models of esophageal squamous cell carcinoma (ESCC), which maintained the original patient characteristics and biological diversity, making them valuable for research.

These PDX models are effective tools for investigating the molecular mechanisms of ESCC and for testing new therapeutic strategies, addressing the need for improved treatment options in a cancer type with a low 5-year survival rate of 15-25%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A method for establishing a patient-derived xenograft model to explore new therapeutic strategies for esophageal squamous cell carcinoma. Jiang, Y., Wu, Q., Yang, X., et al.[2022]

In a study of 47 patients with advanced or metastatic esophageal cancer, next-generation sequencing (NGS) identified 227 mutated genes, with TP53 being the most frequently mutated, which is linked to important cancer processes like immune response and cell survival.

Patients receiving NGS-guided treatments had significantly better outcomes, including a 72.22% objective remission rate and improved overall survival and progression-free survival, highlighting the effectiveness of precision therapy in managing esophageal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics and response to next-generation sequencing-guided therapy in locally advanced or metastatic esophageal cancer. Ma, Y., Li, W., Chen, S., et al.[2023]

CD276 is highly expressed in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) tissues, making it a promising target for CAR-T cell therapy.

CD276-targeting CAR-T cells effectively killed ESCC tumor cells in laboratory and animal models, leading to tumor regression and improved survival, suggesting their potential for clinical application in treating ESCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting CD276 by CAR-T cells induces regression of esophagus squamous cell carcinoma in xenograft mouse models. Xuan, Y., Sheng, Y., Zhang, D., et al.[2021]

Definitive chemoradiotherapy (CRT) is a safe and effective treatment for patients with clinical T1N0M0 esophageal adenocarcinoma, showing a 3-year overall survival rate of 78% and disease-specific survival rate of 81% based on a study of 28 patients.

While 25% of patients experienced acute grade 3 adverse events, the treatment was well-tolerated overall, and CRT provided a viable alternative for patients who could not undergo surgery due to medical comorbidities or personal choice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-institutional Evaluation of Curative Intent Chemoradiotherapy for Patients With Clinical T1N0 Esophageal Adenocarcinoma. Deng, W., Jethwa, KR., Gonuguntla, K., et al.[2022]

Enhanced MUC1-CAR-T cells demonstrated strong antitumor activity and prolonged survival in both in vitro and in vivo models, indicating their potential effectiveness against esophageal cancer.

The study utilized long-term co-culture and mouse xenograft models to confirm that these enhanced CAR-T cells can effectively target and eliminate esophageal tumors, suggesting a promising new treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK-STAT Domain Enhanced MUC1-CAR-T Cells Induced Esophageal Cancer Elimination. Zhang, H., Zhao, H., He, X., et al.[2022]

In a phase 1b study involving 20 patients with locally advanced esophageal squamous cell carcinoma, the combination of concurrent chemoradiotherapy and the anti-PD-1 antibody camrelizumab showed a manageable safety profile, with serious treatment-related adverse events occurring in 40% of patients but no treatment-related deaths.

The treatment demonstrated promising efficacy, with a 65% objective response rate after 40 Gy of radiation and 12-month and 24-month overall survival rates of 85.0% and 69.6%, respectively, indicating potential for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of camrelizumab to docetaxel, cisplatin, and radiation therapy in patients with locally advanced esophageal squamous cell carcinoma: a phase 1b study. Zhang, W., Yan, C., Zhang, T., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12439142/

Intraperitoneal CAR T-cell therapy for peritoneal ... Intraperitoneal administration of M28z1XXPD1DNR CAR T cells achieved better antitumor efficacy than intravenous administration, even at a ...

2. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT06623396?draw=2&rank=1

A Study of Mesothelin-Targeted CAR T-Cell Therapy in ... Radiographic demonstration of improvement upon completion of CNS-directed therapy and no evidence of interim progression between completion of CNS-directed ...

3. jitc.bmj.com jitc.bmj.com/content/13/9/e012292.full.pdf

Intraperitoneal CAR T- cell therapy for peritoneal ... 16 17 When cocultured with M281XXPD1DNR CAR T cells, gastroesophageal adenocarcinoma cells with variable expression of MSLN and PD- L1 (figure 2B) demonstrated ...

4. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/537435

A Study of Mesothelin-Targeted CAR T-Cell Therapy in ... Maximum Tolerated Dose of M28z1XXPD1DNR CAR ... T-Cell Therapy in Patients With Mesothelin-Positive Esophagogastric Adenocarcinoma With Peritoneal Carcinomatosis ...

5. withpower.com withpower.com/trial/car-t-cell-therapy-for-esophageal-cancer-9f816

CAR T-Cell Therapy for Esophageal Cancer This Phase 1 medical study run by Memorial Sloan Kettering Cancer Center is evaluating whether M28z1XXPD1DNR CAR will have tolerable side effects & efficacy ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06623396

A Study of Mesothelin-Targeted CAR T-Cell Therapy in ... A type of clinical study in which participants are identified as belonging to study groups and are assessed for biomedical or health outcomes. Participants may ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.TPS513

A phase I trial of intraperitoneal (IP) mesothelin (MSLN) This is a single-arm phase I study assessing the safety, maximum tolerated dose (MTD) and preliminary efficacy of IP administered M28zXXPD1DNR CAR T cells.