CAR T-Cell Therapy for Esophageal Cancer

Recruiting in Palo Alto (17 mi)

+6 other locations

Overseen by Geoffrey Y. Ku

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Pregnancy, HIV, Active hepatitis, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

Participants will have a sample of their white blood cells, called T cells, collected using a procedure called leukapheresis. The collected T cells will be sent to a laboratory at Memorial Sloan Kettering to be changed (modified) to become MSLN-targeted CAR T cells, the CAR T-cell therapy that participants will receive during the study. Participant study therapy will take about 3-4 weeks.

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.

What data supports the effectiveness of the treatment M28z1XXPD1DNR CAR for esophageal cancer?

Research shows that CAR-T cell therapy, which is a type of treatment that uses modified immune cells to target cancer, has been effective in reducing tumors in esophageal cancer models. Specifically, CAR-T cells targeting a protein called CD276 have shown promising results in killing cancer cells and shrinking tumors in studies with mice. ^{1 2 3 4 5}

Is CAR T-Cell Therapy for Esophageal Cancer safe?

The safety of CAR T-Cell Therapy for esophageal cancer specifically isn't detailed, but similar treatments like PD-1 inhibitors have shown manageable safety profiles in esophageal cancer. In studies, serious side effects occurred in some patients, but no treatment-related deaths were reported, and overall safety was considered acceptable. ^{6 7 8 9 10}

What makes the M28z1XXPD1DNR CAR treatment unique for esophageal cancer?

The M28z1XXPD1DNR CAR treatment is unique because it uses CAR-T cells, a type of cell-based immunotherapy, to target specific proteins on esophageal cancer cells, potentially improving the effectiveness of treatment for solid tumors like esophageal cancer, which traditionally have limited therapeutic options. ^{2 5 11 12 13}

Research Team

Geoffrey Y. Ku

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

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.

I am 18 years old or older.

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

Trial Timeline

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

Treatment Details

Interventions

• M28z1XXPD1DNR CAR (CAR T-cell Therapy)

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.

Participant Groups

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+

Lisa M. DeAngelis

Memorial Sloan Kettering Cancer Center

Chief Medical Officer since 2021

MD from Columbia University

Selwyn M. Vickers

Memorial Sloan Kettering Cancer Center

Chief Executive Officer since 2022

MD from Johns Hopkins University

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2022]

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

Multi-institutional Evaluation of Curative Intent Chemoradiotherapy for Patients With Clinical T1N0 Esophageal Adenocarcinoma. [2022]

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

Characteristics and response to next-generation sequencing-guided therapy in locally advanced or metastatic esophageal cancer. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Change in PD-L1 and CD8 Expression after Chemoradiotherapy for Esophageal Squamous Cell Carcinoma. [2022]

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

Targeting CD276 by CAR-T cells induces regression of esophagus squamous cell carcinoma in xenograft mouse models. [2021]

6. Netherlands 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. [2023]

7. United States 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. [2021]

8. England pubmed.ncbi.nlm.nih.gov

PD-1 inhibitors versus chemotherapy as second-line treatment for advanced esophageal squamous cell carcinoma: a meta-analysis. [2022]

9. Switzerland 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. [2023]

10. United States 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. [2022]

11. New Zealand pubmed.ncbi.nlm.nih.gov

JAK-STAT Domain Enhanced MUC1-CAR-T Cells Induced Esophageal Cancer Elimination. [2022]

12. Greece pubmed.ncbi.nlm.nih.gov

A method for establishing a patient-derived xenograft model to explore new therapeutic strategies for esophageal squamous cell carcinoma. [2022]

13. China pubmed.ncbi.nlm.nih.gov

EphA2 chimeric antigen receptor-modified T cells for the immunotherapy of esophageal squamous cell carcinoma. [2022]