CAR T-Cell Therapy for Esophageal Cancer
Recruiting in Palo Alto (17 mi)
+6 other locations
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Memorial Sloan Kettering Cancer Center
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.
12345Is 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.
678910What 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.
25111213Eligibility 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 have been diagnosed with esophagogastric adenocarcinoma.
I am fully active or can carry out light work.
I am 18 years old or older.
I have received at least one treatment for my HER2 positive condition.
My cancer has worsened or I couldn't tolerate the treatment after at least one therapy.
My cancer has returned or spread to other parts of my body.
My tumor shows high MSLN levels.
My cancer is stage IV and has spread to the lining of my abdomen.
Exclusion Criteria
I am currently being treated for another cancer.
I have or had lung inflammation that needed steroid treatment.
I do not have HIV or active hepatitis B or C infections.
I am taking 10 mg or more of prednisone daily or similar medications.
I have previously received CAR T cell therapy or another type of cellular therapy.
I have untreated brain metastases.
I have serious heart conditions or infections that are not under control.
I have had blood cancer treatment within the last 5 years.
I have had treatment targeting mesothelin before.
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Participants with Mesothelin-Positive Esophagogastric Adenocarcinoma with Peritoneal CarcinomatosisExperimental Treatment1 Intervention
Participants will be diagnoses with Mesothelin-Positive Esophagogastric Adenocarcinoma with Peritoneal Carcinomatosis
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Memorial Sloan Kettering Westchester (Limited Protocol Activities)Harrison, NY
Memorial Sloan Kettering Monmouth (Limited protocol activities)Middletown, NJ
Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)Basking Ridge, NJ
Memorial Sloan Kettering Bergen (Limited Protocol Activities)Montvale, NJ
More Trial Locations
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Who is running the clinical trial?
Memorial Sloan Kettering Cancer CenterLead Sponsor
References
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]Standard first-line therapy for advanced or metastatic esophageal carcinoma is chemotherapy, but the prognosis remains poor. Camrelizumab (an anti-programmed death receptor 1 [PD-1] antibody) showed antitumor activity in previously treated advanced or metastatic esophageal squamous cell carcinoma.
Multi-institutional Evaluation of Curative Intent Chemoradiotherapy for Patients With Clinical T1N0 Esophageal Adenocarcinoma. [2022]To evaluate the safety and efficacy of definitive chemoradiotherapy (CRT) for patients with clinical T1N0M0 esophageal adenocarcinoma.
Characteristics and response to next-generation sequencing-guided therapy in locally advanced or metastatic esophageal cancer. [2023]Esophageal cancer (EC) is a main cause of cancer-related deaths. However, genomic alterations and the clinical value of next-generation sequencing (NGS) in advanced or metastatic EC for precision therapy remain largely unclear. Herein, we performed comprehensive analyses on a cohort of 47 individuals with advanced or metastatic EC who underwent NGS between May 2017 and February 2020. Eventually, 227 mutated genes were identified in the cohort. TP53, NQO1, DPYD, GSTM1, XRCC1 and ERCC1 were the most mutated genes and associated with immune cell infiltration, autophagy and hypoxia. Patients who received NGS-guided treatments exhibited better objective remission rate (ORR) (72.22%), disease control rate (DCR) (88.89%), overall survival (OS) (P = .0019) and progression-free survival (PFS) (P = .0077) than those not receiving NGS-guided therapies. The multivariate analyses further demonstrated that the NGS-guided therapy was an independently prognostic factor (OS: hazard radio [HR] 0.31, 95% coincidence interval [CI] 0.1-0.97, P = .04). In conclusion, we depicted a comprehensive mutational landscape of 47 patients with locally advanced or metastatic EC and illustrated the utility of NGS testing to guide clinical management in improving ORR, DCR, OS and PFS.
Change in PD-L1 and CD8 Expression after Chemoradiotherapy for Esophageal Squamous Cell Carcinoma. [2022]Esophageal cancer has a dismal prognosis with a five-year survival rate below 20%. Recently, immunotherapy has become a new standard of care for this cancer; therefore, we aimed to examine the programmed death ligand 1 (PD-L1) expression in esophageal squamous cell carcinoma (ESCC) tissues before and after concurrent chemoradiation therapy (CCRT). In total, 64 patients with pre-CCRT ESCC specimens were examined for PD-L1 expression, with twenty-three of them having a partial response (N = 23) or stable disease (N = 1) after CCRT while post-CCRT tissue specimens were collected. All of them were tested for PD-L1 and 15 of them also had CD8 expression in the paired ESCC samples. The prevalence of PD-L1 positivity was 54.7% and we found a trend of decreased PD-L1 expression and increased CD8 positive signal after CCRT. High pre-CCRT PD-L1 H-score in tumors was related to poor prognosis (adjusted hazard ratio = 2.81; p = 0.02), although CD8 signal was not associated with overall survival either in pre- or post-CCRT treatment. In conclusion, we found that PD-L1 expression tended to decrease in CCRT responders and our result supports PD-L1 expression in tumor as a predictor of ESCC prognosis.
Targeting CD276 by CAR-T cells induces regression of esophagus squamous cell carcinoma in xenograft mouse models. [2021]Esophageal cancer, including esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), has a poor prognosis and limited therapeutic options. Chimeric antigen receptor (CAR)-T cells represent a potential ESCC treatment. In this study, we examined CD276 expression in healthy and esophageal tumor tissues and explored the tumoricidal potential of CD276-targeting CAR-T cells in ESCC. CD276 was strongly and homogenously expressed in ESCC and EAC tumor lesions but mildly in healthy tissues, representing a good target for CAR-T cell therapy. We generated CD276-directed CAR-T cells with a humanized antigen-recognizing domain and CD28 or 4-1BB co-stimulation. CD276-specific CAR-T cells efficiently killed ESCC tumor cells in an antigen-dependent manner both in vitro and in vivo. In patient-derived xenograft models, CAR-T cells induced tumor regression and extended mouse survival. In addition, CAR-T cells generated from patient T cells demonstrated potent cytotoxicity against autologous tumor cells. Our study indicates that CD276 is an attractive target for ESCC therapy, and CD276-targeting CAR-T cells are worth testing in ESCC clinical trials.
Profile of treatment-related adverse events of PD-1 blockade-based therapies in advanced esophageal cancer: A systematic review and meta-analysis. [2023]PD-1 blockade-based therapies are the most promising treatment for advanced esophageal cancer (EC). It is crucial to investigate the corresponding toxicity profiles of treatment-related adverse events (TRAEs). We conducted a systematic review and meta-analysis to explore toxicity profiles across different PD-1 blockade-based treatments in EC. A total of 5595 patients from 10 clinical trials were included. The overall rates of TRAEs were 88 % (95 % CI 72.0-95.0), 98.0 % (97.0-99.0), and 79.5 % (74.6-83.7) for all grade TRAEs, 24.0 % (15.0-36.0), 64.0 % (56.0-71.0), and 34.2 % (29.1-39.7) for grade 3 or higher TRAEs in PD-1 blockade alone, PD-1 blockade plus chemotherapy, and dual blockade group, respectively. Compared to chemotherapy, RRs for patients receiving PD-1 blockade-based treatments for all grade TRAEs were 0.96 (93.0-100.0) and 0.75 (60.0-94.0) for grade 3 or higher TRAEs. We exhibited comprehensive statistics on the toxicity of the PD-1 blockade-based regimens, providing useful references for clinicians.
Addition of camrelizumab to docetaxel, cisplatin, and radiation therapy in patients with locally advanced esophageal squamous cell carcinoma: a phase 1b study. [2021]Patients with locally advanced esophageal squamous cell carcinoma (ESCC) show poor survival after concurrent chemoradiotherapy. This study investigated the safety and feasibility of combining concurrent chemoradiotherapy with the anti-PD-1 antibody camrelizumab as first-line treatment for these patients. In this phase 1b study (ClinicalTrials.gov NCT03671265), patients received concurrent chemotherapy (cisplatin [25 mg/m2] plus docetaxel [25 mg/m2] for 4 weeks) and radiotherapy (2.0 Gy/fraction, total 60 Gy) with camrelizumab (200 mg every 2 weeks for 32 weeks). Primary endpoints were safety and tolerability, and health-related quality of life. Secondary endpoints were radiological and pathological response rates, overall survival (OS), and progression-free survival (PFS). Candidate biomarkers in tumor and peripheral blood were monitored at baseline and after 40 Gy radiation. Twenty patients were enrolled. The most common treatment-related grade 3 adverse events included radiation esophagitis (20%) and esophageal fistula (10%). Serious treatment-related adverse events occurred in eight (40%) patients. No treatment-related deaths were reported. Health-related quality of life did not deteriorate. Thirteen (65%) patients had an objective response after 40 Gy radiation. At a median follow-up of 23.7 months (95% CI 21.9-24.5), OS and PFS time ranged from 8.2-28.5 and 4.0-28.5 months, respectively. The 12-month and 24-month OS rate was 85.0% and 69.6%; PFS rate was 80.0% and 65.0%. Tumor PD-L1 expression and CD11c+ dendritic cells and peripheral-blood IL-27, IL-15, Eotaxin-3, and IL-22 were associated with OS. First-line concurrent chemoradiotherapy plus camrelizumab had a manageable safety profile and promising antitumour efficacy for ESCC, and deserves further study.
PD-1 inhibitors versus chemotherapy as second-line treatment for advanced esophageal squamous cell carcinoma: a meta-analysis. [2022]Aim to establish the inhibitors of programmed cell death protein 1 (PD-1) as second-line therapy for advanced esophageal squamous cell carcinoma (ESCC).
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]To systematically evaluate the safety and adverse event profiles of immune checkpoint inhibitors (ICIs) in patients with esophageal cancer (EPC) or gastroesophageal junction cancer (GEJC).
PD-1 inhibitors in esophageal cancer: a systematic review of the oncological outcomes associated with PD-1 blockade and the evolving therapeutic paradigm. [2022]Patients with esophageal or gastroesophageal junction (GEJ) cancer who fail to respond to chemoradiotherapy have a poor clinical prognosis. Recent clinical trials have investigated the use of immune checkpoint inhibitors in these patients. The use of programmed cell death protein 1 (PD-1) inhibitors has emerged as exciting therapeutic options in the curative and palliative setting of other solid tumors. We assessed the efficacy and safety of PD-1 inhibitors in esophageal and GEJ cancers. This systematic review was performed in accordance with the PRISMA guidelines. A comprehensive electronic literature search from the EMBASE, Pubmed, Scopus, MEDLINE, and Google Scholar databases was conducted up to 25 July 2021. This review identified 11 eligible studies reporting outcomes of 3451 patients treated with PD-1 blockade compared with 2286 patients treated with either a placebo or the standard regimen of chemotherapy. Clinically significant improvements in median overall survival have been demonstrated in advanced and metastatic esophageal and GEJ cancer while maintaining acceptable safety profiles. Promising survival data have also recently emerged from PD-1 blockade in the adjuvant setting. PD-1 blockade in esophageal and GEJ cancer has delivered impressive survival benefit while remaining well tolerated. Its use in the adjuvant setting will further advance treatment options, and more advancements in this area of therapy are highly anticipated. However, further characterization of the PD-1/programmed death ligand-1 pathway and elucidation of biomarkers to predict response are required to optimize patient selection.
JAK-STAT Domain Enhanced MUC1-CAR-T Cells Induced Esophageal Cancer Elimination. [2022]Chimeric antigen receptor (CAR)-T cells have shown to play a vital role in anti-tumor functions in hematological malignancies, but have poor efficacy in solid tumors. To improve the activation and proliferation of CAR-T cell in solid tumors, we constructed an enhanced CAR-T cells to increase the survival of esophageal cancer.
A method for establishing a patient-derived xenograft model to explore new therapeutic strategies for esophageal squamous cell carcinoma. [2022]Esophageal squamous cell carcinoma (ESCC) is the predominant histological type of esophageal carcinoma in China. The overall 5-year survival rate of ESCC patients is in the low range of 15-25%. One important reason for the poor prognosis is that the underlying molecular mechanisms are unclear. Furthermore, the development of effective therapeutic strategies to improve patient outcome is needed. Animal models can be beneficial to analyze the molecular mechanisms as well as specific clinical therapeutic strategies for esophageal cancer. In recent years, patient-derived xenografts (PDXs) have been widely used in numerous types of cancers to investigate the basic mechanisms and to conduct preclinical research. Accumulating evidence indicates that the PDX model is an important tool for basic and clinical research. Herein, we successfully established 14 ESCC PDXs. These PDX models preserved the patient pathological characteristics and effectively reflected the patient biological heterogeneity. Cancers exhibit diverse growth rates and tumor texture, even more, they have different signaling pathways. The PDX model is a superior strategy for understanding the underlying molecular mechanisms of ESCC and for screening new therapeutic strategies for ESCC patients.
EphA2 chimeric antigen receptor-modified T cells for the immunotherapy of esophageal squamous cell carcinoma. [2022]Label="BACKGROUND" NlmCategory="BACKGROUND">It is urgent to explore an effective potential therapeutic strategy for ESCC. In recent years, cell-based cancer immunotherapy has become a potentially close for carcinoma therapy. Chimeric antigen receptor (CAR) T cell technology is a kind of adoptive cell therapy technique which has been developed rapidly. We sought to obtain EphA2.CAR-T cell and revealed the ability of EphA2.CAR-T cells to kill esophageal squamous cell carcinoma (ESCC) cells in vitro.