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Mobilizing T Cells to Fight Pancreatic Cancer with Vaccines

Mar 2, 2015 1:00:15 PM / by Daisy Goodrich

Clinical trial results for pancreatic cancer vaccines GVAX and CRS-207 demonstrate an improved outcome for patients, resulting from cancer-fighting T cells.

Among deaths due to cancer in the USA, pancreatic cancer is the fourth most common cause. A diagnosis of pancreatic ductal adenocarcinoma (PDA) probably means a life expectancy of a few months. Outcomes from several other types of pancreatic cancers are not as dire, but PDA unfortunately accounts for ~85% of all pancreatic cancers.

T cells Cross-lines point to a pancreatic adenocarcinoma in a CT scan from a cancer patient. T cells have shown to have a positive effect for patients. Image credit: http://commons.wikimedia.org/wiki/File:MBq_cystic-carcinoma-pancreas.jpg

Here, we look at a phase 2 clinical trial that enlisted 90 patients who had metastatic PDA.  This study evaluated dual-vaccine therapy, GVAX and CRS-207, in comparison to single-vaccine therapy, GVAX. The drug, cyclophosphamide (Cy), was given prior to GVAX in both arms of the study.[1]

Cy is a drug that inhibits a subset of T cells, Tregs, that suppress induction and proliferation of effector T cells in the immune system. In a healthy person, Tregs maintain balance and keep the immune system from overreacting. In cancer patients, Cy therapy is beneficial because it eradicates Tregs, thereby removing checkpoints holding back effector T cells and consequently enhancing the immune response.

The GVAX vaccine consists of PDA cells (from a cell line grown in cell culture) that have been irradiated but still maintain their signature cancer cell proteins. Upon vaccination, dendritic cells in the body pick up PDA proteins and present them to T cells. PDA protein-responsive T cells are stimulated by their interaction with PDA protein-presenting dendritic cells and undergo clonal expansion. This event arms the immune system with proliferating T cells that target and destroy the cancer.

The CRS-207 vaccine consists of live bacteria that have been genetically engineered to be non-disease-causing and to express a specific protein, mesothelin. Mesothelin is overexpressed in PDA, and mesothelin-specific T cells are associated with improved outcomes in PDA patients. Therefore, a mesothelin-specific vaccine could potentially further improve outcomes for PDA patients.

In a prior study, patients who received Cy/GVAX experienced better induction of mesothelin-specific effector T cells than patients who received GVAX alone. Median overall survival (duration from start of study to when 50% of patients were living) was 4.3 and 2.3 months, respectively. In the current study, patients who received at least 3 vaccine doses had median overall survival of 9.7 and 4.6 months, for Cy/GVAX/CRS-207 and Cy/GVAX, respectively. Furthermore, patients who received CRS-207 had higher levels of mesothelin-specific effector T cells.

To further define the benefits of CRS-207, a phase 2b clinical trial (ECLIPSE study) is now in progress. Cancer immunotherapy is an exciting avenue, which includes not just vaccines as discussed here but previously discussed CAR T cells, cytokine therapy, and immune checkpoint inhibitors. At HemaCare, we provide T cells for research and enjoy presenting developments that mean more birthdays for cancer patients.

Reference

  1. Le DT, et al. Safety and Survival with GVAX Pancreas Prime and Listeria Monocytogenes-Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer. J Clin Oncol. 2015 Jan 12.

Topics: Cancer, T Cells, Vaccine Research, Basic Research

Daisy Goodrich

Written by Daisy Goodrich

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