Locally advanced pancreatic adenocarcinoma (LAPC) is an aggressive and fatal disease. It is usually inoperable because of its proximity to vital blood vessels and organs. Recent attempts with targeted immunotherapies have had some success with anti-PD-1/anti-PD-L1 antibody drugs.
It has been shown that stereotactic body radiation therapy (SPRT) increases tumor response to anti-PD-1 therapy. Dr. Zheng and his team have demonstrated that combining an immune-boosting drug (Cy) with a pancreatic cancer vaccine (GVAX) also increased the immune response.
The goal of this study is to assess the effectiveness of combining five treatment modalities on fifty-four LAPC patients at Johns Hopkins. Biopsies, survival and Quality of Life will be compared to former patients who had received two of the treatments – chemotherapy and SPRT.
After receiving chemotherapy, the enrolled patients will be treated with Cy, GVAX, antiPD-1 therapy, and SBRT. It is hoped that this novel combination of therapies will reveal the key to unlocking LAPC’s resistance to desperately needed immunotherapies.
Locally advanced pancreatic adenocarcinoma (LAPC) is an aggressive and often rapidly fatal disease. Surgery is the only known possibly curative treatment for pancreatic cancer at this time, but patients with LAPC have tumors that are associated with important blood vessels and organs making them ineligible for surgery. Therefore, the mainstay of treatment is similar to that for Stage IV disease (cancer that has spread remotely) with chemotherapy and radiation, which works only for a limited time period. Immunotherapy (in particular with antibody drugs called anti-PD-1 or anti-PD-L1 therapy) has been recently approved for a number of other tumor types, and works by enhancing the immune system, by recruiting active T-cells to tumors, which then identify and attack the cancer cells. However, pancreatic tumors have proven generally unresponsive to immunotherapy, and we are still learning about how the tumor is able to block the immune system from recognizing tumors as foreign, and thus, safe from immune attack.
Dr. Zheng’s team is hoping to identify ways in which they can make pancreatic tumor cells more amenable to immune attack. They have been actively testing a pancreatic cancer vaccine (GVAX) that secretes GM-CSF, which stimulates the immune system when given along with immune boosting doses of a chemotherapy agent, cyclophosphamide (Cy). When this therapy was given to patients with pancreatic cancer before and after surgery, they found that tumors removed from patients treated with Cy/GVAX had increased numbers of immune cells and developed lymphnode like structures, suggesting a more active immune system infiltrating into the tumors. They also found that the vaccine causes an increase in signals, including PD-1, which allows the immune system to attack the tumors. Mice with pancreatic cancer treated with combination vaccine and anti-PD-1 antibody therapy, also show more immune reactivity in their tumors and have better responses to treatment.
Stereotactic body radiation therapy (SBRT) is a form of short-term, directed, higher dose radiation that is being tested in the treatment of patients with LAPC. There have been reports that radiation can enhance response to anti-PD-1 therapy. Breast cancer and melanoma cells exposed to SBRT and anti-PD-1 therapy have shown increases in markers that stimulate recognition by the immune system. Dr. Zheng and his team, therefore, expect that combining both Cy/GVAX and SBRT will make the LAPC tumors more responsive to anti-PD-1 therapy. In this study, they will enroll 54 patients with LAPC who have already received routine chemotherapy, and then treat them with Cy/GVAX, anti-PD-1 antibody therapy, and SBRT. They will compare these patients to the results of prior patients at Johns Hopkins Hospital with LAPC who had been treated with chemotherapy and SBRT alone, and they will also gather and compare biopsies before and after two doses of Cy/GVAX, anti-PD-1, and SBRT therapy. In this way, they will be able to determine how safe this novel treatment is, how effective it is at changing the immune system in the tumor, and how it impacts the health and survival of these patients with LAPC.