Massachusetts General Hospital Archives | Alliance for Cancer Gene Therapy

ACGT – Edward Netter Memorial Investigator Award in Cell and Gene Therapy for Pancreatic Cancer Research

Pancreatic cancer is a devastating disease with a dismal prognosis. Our lab develops treatments for difficult-to-treat cancers, such as pancreatic cancer. The main treatment we focus on is CAR (chimeric antigen receptor) T cell therapy. CAR T cells are made by taking a patient’s immune cells, reprogramming them to target the patient’s cancer, and putting them back into the patient. The reprogramming informs the T cells how to distinguish tumor cells from normal cells through markers specifically expressed by the tumor cells.

This therapy has worked well for blood cancers but has been less effective against solid tumors, like pancreatic cancer. Solid tumors are more difficult to treat with CAR T cells because they are less accessible by immune cells, which are usually injected into the blood, and they don’t survive as well once they get into the tumor. The tumor cells can also decrease the expression of the tumor-specific marker, causing them to go unrecognized by the CAR T cells and, therefore, evade killing.

To overcome these challenges, we have used a high-throughput screening approach to identify additional changes we can induce in CAR T cells to make them more effective in solid tumors. We created a mixture of CAR T cells, all targeting the same marker but with one additional, unique change per cell. This mixture was then injected into mice with pancreatic tumors, and after 4 weeks, the CAR T cells making it into the tumor and surviving during that time were identified, representing CAR T cells with changes that enhanced their presence in the tumor over time. Although these changes improved tumor killing, the tumors eventually returned, demonstrating room for further improvement.

In this proposal, we will make CAR T cells with combinations of two of the changes we identified to improve function, to see if combining them will make them more effective and control tumor growth for longer. We will also repeat our screening approach using tumor cells with different levels of the tumor-specific marker to identify changes to the CAR T cells that make them more effective when there are lower maker levels. Overall, this work will provide valuable information on how to adjust CAR T cell therapy for pancreatic tumors to ultimately make them an effective treatment for pancreatic cancer.

Malignant glioblastomas have virtually defied all therapeutic modalities to date. Successful therapies will need novel strategies targeting the underlying pathogenesis which may ultimately offer an innovative approach for glioblastoma patients.

This proposal aims at using neural stem cells to deliver therapeutic drugs that can stop tumor cells to proliferate and simultaneously kill them while leaving the normal brain cells intact. This will be combined with novel in vivo imaging methods that will allow us to monitor the location and size of tumors and track the migration of neural stem cell delivery vehicles in experimental animal models.

There are four basic components of the proposed therapeutic system.

First, the “shell” of a virus, will be used to efficiently carry therapeutic and imaging genes into cells.
Second, neural stem cells will be employed as delivery vehicles as they have been found to home to tumor cells in the brain and can change themselves into normal cells of the nervous system.
Third, engineered apoptotic and anti-proliferative proteins that are released at the tumor destination by the delivery cells will be employed which will stop tumor cells to divide and selectively kill them while leaving the normal brain cells intact.
Fourth, fluorescent and bioluminescent markers will be incorporated into tumor cells and delivery cells such that we can monitor their fate in the brains in real time.

Although these studies are experimental, we can envision a therapeutic modality in which the main tumor mass in the brains of patients will be removed at the time of surgery and therapeutic neural stem cells will be introduced near the remaining tumor cells thus eliminating the risk of recurrence. This will have a major impact in developing more efficient means of eradicating gliomas and saving the lives of many brain cancer patients.

This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America.