Research

Colon cancer and colorectal liver metastases (CRLM) are a significant and increasingly lethal disease. Though there is a strong scientific premise to harness the immune system to treat this cancer, there remains a fundamental gap in understanding of how immunotherapies can be utilized for the majority of these tumors, particularly microsatellite stable cancers. The central hypothesis is that the tumor microenvironment can be manipulated to enhance cytotoxic lymphocyte infiltration and activation, and that checkpoint blockade can be simultaneously utilized to incite a clinically relevant immune response. This one-two punch hypothesis has been formulated on the basis of preliminary data produced by our laboratory where increased T-cell trafficking to tumors, when combined with CTLA4 blockade, resulted in complete CRLM regressions.

The rationale current research is that once it is known how to enhance immunostimulatory signals in the microenvironment and simultaneously suppress inhibitory influences, a new strategy for the management of colon cancer is possible. Supported by a very strong scientific premise based on published papers and robust preliminary data, this hypothesis will be tested by pursuing three specific aims:

1) Determine mechanisms to enhance lymphocyte proliferation and anti-tumor specific immune responses in colon cancer by manipulating immunosuppressive signals. We expect to increase lymphocyte infiltration, proliferation and activation while simultaneously curbing immunosuppressive signals/cells in the microenvironment utilizing a validated pre-clinical model established in our lab

2) Examine mechanisms that supply immunostimulatory influences directly into the tumor, using a viral delivery system engineered in our lab

3) Combine checkpoint blockade with selective delivery of human LIGHT to treat surgically resected tumors and human CRLM in a preclinical autologous system. To achieve this aim patient tumors will be utilized in an autologous humanized mouse model and treated with CTLA4 blockade combined with oncolytic viral delivery mechanisms to increase LIGHT expression.

The proposed research is innovative, because the multi-combination therapy of LIGHT expression in CRLM with tumor specific oncolysis and checkpoint blockade will deliver an inventive approach that will be universally applicable from patient to patient. New horizons that will stem from this innovative strategy include a better understanding of anti-CTLA4 biology that may not only enhance response rates, but also vastly increase indications for its use in previously cold tumors, including microsatellite stable gastrointestinal cancer. The implications of our results may improve patient quality of life and provide survival advantages over the best current surgical and chemotherapeutic strategies for this disease.

Pancreatic cancer is projected to become the second leading cause of cancer related death by 2030. As new therapies are developed to treat malignant lesions of the pancreas, a big effort is also dedicated to the early detection of pancreatic lesions with the potential to progress to an invasive cancer. The only radiologically identifiable precursors that we know of are Intraductal Papillary Mucinous Neoplasms (IPMN) and Mucinous Cystic Neoplasms (MCN). These cystic tumors are nowadays diagnosed with increasing incidence thanks to the widespread use of high-resolution tomographic imaging (e.g. CT scan). However, the majority of these lesions will never progress to an invasive cancer and will never require surgical resection. Identifying which lesions require to be closely surveilled and resected is the main aim of this project.

Over the years we built one of the biggest cyst fluid repositories in the country, opening collaboration with national and international centers, including MGH and Harvard University, Indiana university, the University of Heidelberg in Germany and the Pancreas Institute of the University of Verona in Italy. On the ground of such a large human samples repository, our main goals are:

1)     To build an easy and effective test that is able to differentiate cystic lesion that have a high risk of progression

2)     To identify combination therapies that are able to slow or stop the progression of cystic tumors

Our preliminary results show that we can achieve a high sensitivity and specificity in identifying the correct diagnosis and stratify the risk of degeneration with a practical and accurate solution using a microfluidic platform. These results are relevant because they can reduce the number of unnecessary pancreatic resection that are currently performed worldwide for benign lesions, avoiding the high number of associated postoperative complications and deaths.