EMT Targeting Vaccination, Concurrent with Chemoimmunotherapy, in Advanced NSCLC
Abstract
Immunotherapy drugs called immune checkpoint inhibitors (ICI) have changed treatment for non-small cell lung cancer (NSCLC). In the past, the only option for patients with metastatic disease was chemotherapy. Today, patients receive immuno-chemotherapy; a combination of ICI and conventional drugs. Immuno-chemotherapy has resulted in a remarkable increase in disease-free and overall survival compared to chemotherapy alone. The majority of patients, however, develop progressive disease within 2 years and most will die of lung cancer. Our challenge is to make immunotherapy work for all patients with lung cancer. Once T-cells are appropriately activated, the cells will home to any site of disease, migrate from the blood stream into the tissue, and kill the cancer cells until none remain. Furthermore, if “memory” is generated, tumor specific T-cells will remain in a resting state able to re-expand if the cancer returns. ICI therapy is most effective in patients who have started their own immune response before treatment. Studies have found that patients with higher levels of CD8+ T-cells in their tumors (TIL) prior to treatment respond the best to ICI. Unfortunately, most patients with NSCLC have minimum levels of TIL. Our objective in the randomized Phase II clinical trial we are proposing is to evaluate whether a multiple antigen vaccine, STEMVAC, given with GM-CSF as an adjuvant and used to immunize NSCLC patients who are not responding to immuno-chemotherapy, will increase the level of CD8 T-cells in the tumor. STEMVAC might “jump start” the immune system and lead to more clinical responses. STEMVAC targets five proteins involved in the metastatic process in NSCLC. These proteins, when upregulated, are responsible for the cancer spreading throughout the lung and into other organs. These proteins also cause the cancer to become resistant to chemotherapy and radiation. When these proteins become upregulated, the cancer goes through a process called epithelial to mesenchymal transition (EMT). One of the major hurdles in targeting these proteins with vaccination is that the proteins are non-mutated, meaning they are very similar to “self,” and the body does not make a destructive immune response. The STEMVAC vaccine is made in such a way that the portions of the proteins that are included in the vaccine do stimulate highly inflammatory immunity. This is because we have edited the proteins in the vaccine to remove the regulatory fragments that prevent an inflammatory response. In mouse models, immunization with STEMVAC significantly inhibits tumor growth, markedly increases CD8 T-cells in the tumor, and results in the elimination of cells that have undergone EMT. We think that, if the same effects occur in patients with NSCLC, they will respond better to ICI, and their immune systems, stimulated by STEMVAC, may eliminate the cancer cells that cause metastases. The clinical trial will address two areas of emphasis: (1) identify innovative strategies for the treatment of lung cancer and (2) identify innovative strategies for the prevention of recurrence of or metastases from lung cancer. We aim to give STEMVAC to patients with metastatic NSCLC who have gone through immuno-chemotherapy and still have measurable disease. While the patients are on a maintenance therapy with a drug called pemetrexed and an ICI called pembrolizumab, we will vaccinate patients with STEMVAC and an immune stimulator called GM-CSF or the GM-CSF immune stimulator alone. GM-CSF has been shown to have anti-tumor effects, so it is important to have two arms to the study to determine which effects are due to STEMVAC and which are due to GM-CSF. Our study is designed to evaluate whether the vaccine increases CD8+ T-cells in the tumor, is safe to use in combination with maintenance therapy, and will result in further clinical responses. We will also test whether vaccine induced T-cells home to the tumor and eliminate cells that have
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110272
Entities
People
- Rafael Santana-davila
Organizations
- United States Army
- University of Washington