We have created this section of our web site to inform our members of the status of Grants the Foundation has completed as well as the Grants that ECEF has made for the current year to various Institutions and Grants it is considering during the coming year and beyond. The funds we receive from donations are earmarked to cover our commitment to these projects and support the Grants in Process.
ECEF has established a Research Subcommittee of the Medical Advisory Committee to give us guidance in determining what Research Projects ECEF will support in the future.
We have displayed these Grants in the following categories:
GRANTS IN PROCESS
The following research projects have been designated for grant consideration
Project 1. MEMORIAL SLOAN KETTERING CANCER CENTER
Immunomodulation and study of anti-tumor immune responses in esophageal cancer
2018 GOAL $50,000
2019 GOAL $50,000
Prasad S. Adusumilli, MD
Current investigations and treatment modalities for esophageal cancer are focused on chemoradiation therapy and surgery. Our laboratory focuses on investigating the immune responses in patients with solid tumors. Based on the data obtained from the study of the immune microenvironment in thousands of tumors in the chest (esophageal, lung cancers and mesothelioma), we have developed chimeric antigen receptor (CAR) T-cell therapy, a method of genetic engineering where we can redirect a patient’s own T cells to target cancer cells. We have successfully translated CAR T-cell therapy to two clinical trials. Furthermore, we have demonstrated that a combination of CAR T cells and checkpoint blockade agents—immunotherapy agents that can remove breaks on immune cells and enhance their efficacy—can promote a patient’s own, as well as induced, antitumor immune responses resulting in beneficial outcomes.
Previously, we have studied the tumor microenvironment in esophageal cancers with support from the Esophageal Cancer Education Foundation (ECEF). These results are published in the March 2012 edition of the Cancer Epidemiology, Biomarkers and Prevention. However, the influence of chemotherapy and radiation therapy on the esophageal cancer immune microenvironment is not well known. More importantly, tumor immune modulation following checkpoint blockade agent therapy is an unexplored territory. Investigating the tumoral immune environment following chemotherapy, radiation therapy, and immunotherapy will provide support for a rational combination of these therapies to improve patient outcomes.
One recent advance in the study of tumor immunology is the ability to conduct multiplex fluorescent imaging. This method allows for automated, quantitative cancer and immune cell imaging in a high-resolution fashion. The imaging is complemented with powerful software that employs pattern-recognition learning algorithms that support a tissue classifier tool. In our laboratory, we have optimized the methodology for esophageal cancer so that it can automatically identify areas of interest through visual characteristics, thereby reserving these sections for a more detailed analysis. The quantitative imaging system, staining protocols, and pattern-recognition software with learning algorithms that already have been optimized in our laboratory will be used to investigate patient tumor biopsies prior to and after chemoradiation therapy and immunotherapy. By serial quantification, localization, and colocalization of immune cells during various stages of therapy, we will be able to delineate the influence of therapy on patients’ tumor immune microenvironment.
These results will lay the foundation for successful implementation of immunotherapy for esophageal cancer patients and, more importantly, provide a rationale for combination with existing standard of care chemoradiation therapy.
PROJECT 2. MEMORIAL SLOAN KETTERING CANCER CENTER
BLOOD TEST TO DETECT ESOPHAGEAL CANCER
2012 -2015 $300,000 PAID
2017. $20,000 PAID
2018. GOAL $20,000
Project 1: A prospective clinical trial to evaluate mesothelin as a biomarker for the clinical management of esophageal adenocarcinoma
Project description: In our search for a tumor marker that imparts aggressiveness and can be used as a prognostic marker and as an antigen target in patients with esophageal cancer (EC), we observed that a protein named mesothelin is overexpressed in EC cells in 3 out of 4 patients. Most intriguingly, the protein expression is observed only when there is cancerous transformation in the Barrett’s esophagus (high grade dysplasia), and not expressed in low grade dysplasia or in acid reflux patients. This protein can be measured by a simple blood test. In fact, investigations revealed that more than two-thirds of EC patients had elevated blood levels of the cancer-specific protein. Acknowledging ECEF support, this study results were published in the American Association for Cancer Research, AACR journal, Cancer Epidemiology, Biomarkers and Prevention (http://www.ncbi.nlm.nih.gov/pubmed/22237988) in March 2012. Since then, other investigators have published confirming these results. Based on this convincing data that resulted from ECEF support, we were awarded National Cancer Institute, NCI R-21 award (1R21CA164585-01A1) to prospectively investigate the utility of the blood test as a biomarker in the management of esophageal adenocarcinoma. This prospective clinical trial is listed on clinical trials.gov (http://www.clinicaltrials.gov/ct2/show/NCT01393483?term=esophageal+cancer+mesothelin&rank=1).
2015-2017 progress: To date, with the excellent help of MSKCC Research Study Assistants, more than 300 patients are accrued to the study with active follow-up after their completion of chemoradiation therapy and / or surgical resection. More importantly, we are treating patients in our phase I ‘mesothelin-targeted CAR (chimeric antigen receptor) T-cell clinical trials’, wherein lung, breast cancer and mesothelioma patients were treated with their own immune cells genetically engineered to target and kill mesothelin-expressing cancer. We hope to translate this clinical trial to EC patients. The data obtained from tissue and serum mesothelin supported by ECEF will be crucial to submit to FDA and obtain approval to extend the trial to EC patients.
An article has been published about this research project and it is attached for your review
Project 3. MEMORIAL SLOAN KETTERING CANCER CENTER
IMMUNE MICROENVIRONMENT IN ESOPHAGEAL CANCER
2016 $100,000 PAID
2017 $20,000 PAID
2018 $20,000 GOAL
Project 2: Immune microenvironment in esophageal cancer
Our laboratory principle focus is investigating tumor immunology and immunotherapy. The tumor immune microenvironment in EC is not well studied. To advance immunotherapy, it is essential to understand the basic immune microenvironment of this cancer. With this in mind, we would like to develop a well-annotated clinicopathological database along with well characterized tissue from a cohort of EC patients. Our team has performed this task for lung cancer (>2000 patients) and published more than 20 publications to date including in the Journal of Clinical Oncology and Journal of The National Cancer Institute. To date, we are updating the clinical database and identifying the patients where proper tissue is available. We have made significant progress on a new technology – multispectral immune imaging to quantify and characterize immune cells phenotypes on a tumor slide. We have already investigated EC patient tumors immune microenvironment.
We plan to analyze EC tumor immune microenvironment in an ongoing multicenter study of checkpoint blockade. This analysis and the knowledge acquired will be the key to subsequent correlative studies of EC checkpoint blockade immunotherapy with Dr Ku and EC CAR T-cell therapy. Furthermore, we will compare and contrast the tumoral and stromal microenvironment in patient tumors.
An article has been published for this project and it is attached for your review. We have also attached a clinical trial for this research project.
Project 4. Memorial Sloan Kettering Cancer Center
May 2017 $12,500 PAID
August 2017 $12,500 PAID
November 2017 $12,500 PAID
February 2018 $12,500 PAID
In a move away from our normal research project support, we are getting involved with a young investigator to become an effective and efficient Thoracic Surgeons involved in research.
We will be supporting Dr. Arianna Barbetta for one year career development grant at a cost of $50,000. She will be working on research projects titled “Esophago” – Gastric Junction Cancer: “a rapidly growing malignancy lacking standardized Treatment”
The first project is :Assessment of Neutrophil to Lymphocyte Ratio as a Predictor of Response to Chemoradiotherapy in Patients with Esophageal Squamous Cell Carcinoma
We investigated in patients with squamous cell carcinoma treated with pre-operative or definitive chemoradiotherapy the changes of the neutrophil/lymphocyte ratio in the blood. We believe that this blood parameter changes after the chemoradiation therapy and could be useful to predict patients who have a better treatment response.
This project is almost ended, it was accepted as oral presentation at the STSA meeting that will take place in San Antonio this coming November. see below for a summary of Dr. Barbettas presentation.
Southern Thoracic Surgical Association (STSA) 64th annual meeting presentation
During the STSA annual national meeting held in San Antonio, TX on November 8-11, Dr Arianna Barbetta presented the study “Neutrophil to Lymphocyte Ratio as Predictor of Treatment Response in Esophageal Squamous Cell Cancer”. This study was supported by ECEF and mentored by Dr Daniela Molena, Director of esophageal surgery at Memorial Sloan Kettering Cancer Center. The original manuscript about this project was submitted to the “Annals of Thoracic Surgery” and it is currently under revision.
The aim of the project was to evaluate the role of inflammatory markers that can be measured in blood samples to predict treatment response in patients with esophageal squamous cell carcinoma undergoing chemoradiation with or without surgery. The marker evaluated in this study was the ratio between neutrophils and lymphocytes with particular attention to the change of the ratio before and after chemoradiation. The study addresses the current inability to select patients who would benefit from surgery after chemotherapy and radiation. Current trends show in fact that less and less patients are referred to surgery, in part because squamous cell cancer of the esophagus has a good response when treated with chemoradiotherapy and about 50% patients have no residual tumor at surgery. Unfortunately, clinical tools such as CT-scan, PET and EGD with biopsy, are not accurate to identify patients with residual disease who would benefit from esophagectomy and we have recently shown that the chance of recurrence is higher for patients treated without surgery.
Thus, the aim of this study was to investigate additional clinical factor that can help predict patients’ response to treatment and could be use in the future to tailor personalized treatments.
Relationship among cancer, immune system and inflammation has been widely studied. We analyzed the variation of two types of inflammatory cells measured in the blood, neutrophils and lymphocytes. In particular we investigated their ratio, before and after chemoradiotherapy to understand whether their change reflect patient’s response to the received treatment.
Our results showed that patients who had a lower post-treatment neutrophil-to-lymphocyte ratio than the ratio assessed pre-treatment, had a better treatment response, conversely patients who exhibited a post chemoradiotherapy increase of this ratio were more likely to have residual disease detected at time of surgery.
Moreover increase of this marker was also associated with a higher risk of disease recurrence after treatment completion.
Our results will open frontiers for new research: we aim to investigate if the changes seen in the blood reflect what happens in the tumor within in the esophagus. This next step could validate the use of neutrophil-to-lymphocyte ratio in clinical practice as a tool for the physicians to direct each patient towards the best treatment option.
This meeting was an important experience for Dr Barbetta as it gave her the opportunity to present her data to many experts of esophageal cancer coming from all around United States, from whom she received great feedback and compliments for her accomplishments. The role of ECEF was very important and this project would not have been completed without its support.
The second project is ongoing: Neoadjuvant Chemotherapy versus Neoadjuvant Chemoradiotherapy for Treatment of EGJ ( esophago-gastric junction) Adenocarcinoma.
In this work we are evaluating in EGJ adenocarcinoma patients treated at MSKCC with either of the two aforementioned approaches, the outcomes such as overall,disease free survival and post-operative complication rates. Since there is no standard approach for this tumor, our aim is to better understand which pre-surgical treatment can give some survival advantages to our patients.
The third project is brand new: Risk of recurrence in patients with pathological complete response.
A certain percentage of patients with esophageal cancer who undergo neoadjuvant chemoradiotherapy before surgery, have no residual tumor in the pathological specimen, neither in the esophagus nor in the lymph nodes. Even with this great results, some of them still recur. Our aim is to assess risk factors, patients and tumor characteristics that can help to identify patients with higher risk of recurrence.
Grants: Memorial Sloan Kettering Cancer Center
2004 $75,000 PAID
ECEF was established in 2003 with the main purpose at the time to raise the $75,000 that Memorial Sloan-Kettering Cancer Center deemed the cost to be to use its resources to establish a computer disk that people could use as a reference source if they were diagnosed with esophageal cancer. This CD ROM was completed in 2004 and it has been given to each esophageal cancer patient that has been so diagnosed at MSKCC. In addition this CD ROM is available on our web site as something you can request and ECEF will send that out to patients and caregivers who join ECEF at no cost to the person requesting it. It is ECEF’S intent not update this CD ROM since it is an expensive way of getting the message out about this disease. Instead we are awaiting MSKCC decision to place the contents of this CD updated on their web site. When this is done then ECEF will link to that file and have it available to ECEF members.
Grants:MEMORIAL SLOAN KETTERING CANCER CENTER
2012 $1,800 PAID
ECEF decided to give Memorial Sloan Kettering Cancer Center a $1,800 grant to cover the purchase of 100 books called 100 Questions & Anmswers About Esopjhageal Cancer to be distributed to patients who have been newly diagnosed with this disease.
Grants: MOUNT SINAI MEDICAL CENTER
FLUORESCENT STAIN FOR ENDOSCOPIC EXAMINATION
2012 – 2013 $60,000 PAID
Esophageal adenocarcinoma (EAC) is one of the most rapidly rising cancers in the United States today and carries a poor five-year survival rate (<15%) due to late diagnosis. EAC arises in a condition known as Barrett’s esophagus and progresses to cancer through an intermediate stage known as dysplasia. While this would seem to allow ample opportunity for early detection and intervention, the current standard of endoscopic surveillance of Barrett’s esophagus is inadequate and has been shown to miss up to 57% of early cancers.
Advanced endoscopic imaging technologies, such as confocal microendoscopy, have arisen as a way of improving endoscopic surveillance. Confocal microendoscopy relies on the use of fluorescent contrast agents to provide tissue contrast and 1100x magnified images of the esophageal lining. This technology gives endoscopist’s the remarkable ability to see and remove cancer at an early, treatable stage. The technology has revolutionized the way gastroenterologists screen the esophagus, allowing cancer (and precancer) to be detected when it is < 1-2 mm in size and easily removeable. Current confocal endoscopes rely on non-specific contrast agents such as IV fluorescein. Unfortunately, current agents do not target the molecular ‘footprint’ of esophageal cancer.
In our project, we proposed to develop and test novel, molecule-specific contrast agents to specific markers of cancer for use with confocal microendoscopes. We believe that such contrast agents can be used to highlight areas of pre-cancer or cancer (“molecular beacon”) during real-time endoscopic surveillance thus enhancing early detection efforts and facilitating minimally invasive therapy. In our current project, we have evaluated multiple patients with varying grades of disease. We have noted differences in both the intensity and pattern of fluorescent imaging with progression to cancer. We are now trying to develop a larger repository of images and better understand the patterns that develop as Barrett’s progresses to cancer.
Grants: Memorial Sloan Kettering Cancer Center
WIRELESS PULSE OXIMETRY TO PREVENT SURGICAL Leaks
2013 – 2014 $80,000 PAID
Project description: The most effective approach todate to treat EC is to resect the esophagus and restore the continuity by anastomosing (joining) the stomach to the resected esophagus. Dehiscence or leakage from anastomotic sites following esophageal surgery occurs in one of six patients, and is associated with significant morbidity and mortality. Currently, following stomach mobilization, surgeons assess tissue viability and blood supply by simple visual inspection. Increasingly, esophageal operations are performed by minimally invasive techniques, which add complexity to the problem of assessing stomach oxygenation prior to the anastomosis.
We have motivated a group of senior bioengineering students at the City College of Bioengineering, New York to develop a handheld device that measures tissue oxygenation during surgery by use of a simple Wireless Pulse Oximeter (WiPOX). This device is validated in animal studies (http://www.ncbi.nlm.nih.gov/pubmed/20972585) and is tested in a pilot trial at the MSKCC. The thoracic surgeons at MSKCC utilized this device in a prospective clinical trial (http://clinicaltrials.gov/ct2/show/NCT01551433?term=wipox&rank=1) to measure tissue oxygenation in real-time ensuring the viability of surgical anastomoses, thereby reducing the morbidity and mortality of esophageal cancer operations. With the help of the preliminary data obtained by ECEF support, we were scored high in a NIH application and were awarded partial support for the study.
2014-2015 progress: This prospective clinical trial is successfully completed in accruing patients and testing the device. The study will remain open till the last follow-up information is obtained from all the patients. We have now completed data collection, follow-up and the primary and secondary events. The data is intriguing that – a) among patients who participated in the study (WiPOX used), the leak rate is three-fold lower than our historical leak rate, b) among patients that participated in the study (WiPOX used), the leak rate is two-fold lower than in patients who did not participate in the study during the same study period, and c) the leak rate is back to historical control after the study is completed (no device being used). We are submitting these results to American Association of Thoracic Surgery, AATS annual meeting as late breaking clinical trial abstract and are in the process of writing the manuscript.
To Date ECEF has given $706,800 to the various research projects mentioned above.