The Mechanistic Basis of Radiation-Induced Immunomodulation in Early Non-Small Cell Lung Cancer
Abstract
Background: The successful use of immune checkpoint inhibitors (ICIs) in the treatment of locally advanced and metastatic lung cancer has spiked interest in using these agents in treating patients with earlier stages of the disease. There are currently several ongoing randomized phase 3 trials testing the efficacy of ICIs in patients with stages 1B-3A either in the adjuvant setting (after surgery) or in the neoadjuvant setting (prior to surgery). In the interim, several phase 2 trials of using neoadjuvant ICIs have been reported with encouraging results. The largest of these trials enrolled 180 patients with stages 1B-3A. A major pathological response (MPR), defined as 10% or less residual cancer cells after treatment, was reported in 19% of patients. Though encouraging, there is a clear need to further improve these response rate. Improvements in response rates may be accomplished by combining two ICIs or using ICIs in combination with chemotherapy. These strategies are also being tested in ongoing randomized trials. In this regard, there is good laboratory evidence that low dose focal radiation (SBRT) can enhance the immune response when delivered in combination with ICIs. The mechanisms by which radiation enhances ant-tumor immunity are not fully understood. We recently completed a randomized phase II neoadjuvant trial (NCT02904954) of 60 patients with early-stage lung cancer (1B-3A) who were randomly allocated to two doses of preoperative ICI (anti-PD-L1) alone or the same treatment preceded by three consecutive daily doses of low-dose SBRT. We observed an MPR rate of 50 % in the SBRT/ICI arm and of 6.8% in the ICI alone arm. Our theory is that this significant anti-tumor effect of the combined therapy is mediated by the efficacy of low-dose SBRT in enhancing the expression of tumor antigens and/or enhancing recognition of tumor antigens by the immune system. We also propose that low-dose radiation will tilt the balance within the tumor mass toward a more robust anti-tumor environment. To test our theories, we have collected throughout the trial tumor samples from each patient before and after treatment. We also collected blood before and after treatment. In this project, the tumor samples will be genetically tested to determine the frequency of cancer antigens present in each tumor before and after treatment. This will allow us to determine the change in cancer antigen expression as a result of the anti-PDL-1 alone versus after the combination of SBRT and anti-PDL-1. The highly expressed antigens will then be tested for recognition by the immune cells (T cells) in the blood before and after treatment to determine the increased ability of the immune system to recognize cancer antigens and attack them effectively killing the cancer cell. Finally, we will use genetic testing and tissue staining to determine the composition and activation of the various immune cells contained in the tumor mass before and after treatment. This will allow us to determine whether radiation (for example) eliminates some of the cells that promote tumor growth or impede immune cancer cell killing such as myeloid suppressive cells or regulatory T cells. The results of this proposal will vastly advance our knowledge of how the immune system works to eradicate cancer cells after ICIs alone or by the addition of fairly low doses of radiation. We will also understand why some people do not respond, thus allowing us to develop strategies to overcome resistance based on information derived directly from human material. The results will also give us deep insight into the landscape of cancer antigens in early-stage lung cancer and whether there are overlapping antigens between patients that may be useful in developing future lung cancer vaccines.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110309
Entities
People
- Nasser K. Altorki
Organizations
- United States Army
- Weill Cornell Medicine