Spatial Multiomic Evaluation of Clinical Responders with Advanced Triple-Negative Breast Cancer from KEYNOTE-890 to Validate a Published CXCR3 Gene Signature
Abstract
In the past decade, how cancer is treated has begun to change. If the patient has a type of breast cancer that is called triple-negative (TNBC), it is negative for most drug targets. The result is that patients with TNBC have limited treatment options. Immunotherapy is a new class of treatments that boost the patient s immune system s ability to fight their cancer. While the immune system is effective at fighting off viruses and bacteria, tumors are part of the patient s body. Most tumors find ways to take advantage of the fact that the immune system is not supposed to attack its own body. A new type of drug targeting a molecule called Programmed Cell Death Ligand 1 (PD-L1) was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of TNBC. PD-L1 is like an off limits sign to the immune system; this new drug blocks PD-L1 on the tumor so the immune system can get back to work. For some patients, this works well, and their tumors are killed. For other patients, it does not work at all. We still do not understand why or how to predict for whom it will work. This proposal will address the overarching challenge to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival for patients with locally advanced, inoperable or metastatic TNBC. One strategy that doctors can use to increase the likelihood of a good outcome from any treatment is by combining multiple therapies. In this way, the drugs can work together to get the immune system to recognize the tumor as foreign and attack it. In our recently closed clinical trial, called OMS-I141/KEYNOTE-890, we tested a therapy injected directly into the tumor to activate the immune system right at the source of the problem. We have previously tested this therapy on its own to confirm that it is safe. Now, we have combined it with a drug that also blocks PD-L1. The goal is to stimulate immune cells capacity to mount an attack on the tumor and block the tumor s ability to resist. The trial treated two different groups of patients. The first group had advanced TNBC that had resisted many previous types of therapy. The second group had advanced TNBC but had not been treated before. This difference is significant because some types of cancer treatments have side effects that disable some features of the immune system. Our OMS-I141/KEYNOTE-890 clinical trial was designed to study a mechanism to boost the immune system using an engineered component of the immune system, called IL-12, injected into the tumor. This intratumoral method is localized, which means that is has limited systemic toxicity. Patients were enrolled in this trial from 2018 until October 2022. Tumor biopsies and blood samples were taken before the treatment began and throughout the trial. The company that sponsored this trial has shifted its focus away from breast cancer and the planned analysis of the collected samples has been halted. We propose to complete the planned studies and add even more detail to them. The main goal of this proposal is to analyze these samples to understand why some patients responded better than others. We have previously published a gene signature, or specific group of genes, we think could be used to identify responsive tumors and avoid giving therapies to patients whose tumors will be resistant to immunotherapy. If these studies confirm that this gene signature can predict response, then we will be able to more confidently advise doctors and patients to use this as a tool to help them decide on their best treatment option. If not, we will have even more data to refine and improve it. The first aim of these studies will be to look at tumor biopsies and see what types of immune cells are present in the environment around the tumor and how they are interacting. We can see what the immune cells looked like before and after the treatment, like taking a snapshot of the tumo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311004
Entities
People
- Erika J Crosby
Organizations
- Duke University
- United States Army