Combating Resistance to Immune Checkpoint Inhibition: Identifying New Targets Using In Vivo Forward Genetics Screening
Abstract
Background: Our immune systems protect us from bacterial, viral, and parasitic infections. These invaders are viewed as foreign by our immune systems and are targeted for destruction. In contrast, our immune systems can have difficulty destroying cancer cells. In many cases, the immune system is ready and able to destroy the cancer cells, analogous to a car with its motor running, in gear, with the accelerator all the way to the floor. But the cancer cells produce deceptive, protective signals, called “checkpoints” that restrain the immune response, analogous to the brakes of that revved-up car also being fully engaged. With the brakes/checkpoints engaged, the car (or immune system) can go nowhere. Imagine what would happen if the brakes of the car were simply disengaged; it would go racing towards its goal. Immune checkpoint inhibitors, also known as immune checkpoint blockade, do exactly this, removing the brakes restraining the immune system to allow for cancer cell destruction. Importantly, much like with bacterial/viral/parasitic infections, once the immune system is engaged, it can provide long-term protection against additional cancer cells, resulting in durable responses for patients. The first successes of checkpoint blockade were in patients with metastatic melanoma, a particularly devastating disease. The use of checkpoint inhibitors has yielded unprecedented survival outcomes for these patients, doubling survival times and inducing long-term, durable responses in some patients. For this reason, immunotherapy is being been hailed as a “paradigm shift,” a “game-changer,” and a “revolution.” It has been highlighted as the “breakthrough of the year” in Science (2013), “advance of the year” by ACSO (American Society of Clinical Oncology; 2016), and has decorated the cover of top-ranking science journals (Nature, Science, Cell, Nature Medicine, Cancer Cell), news outlets (Time, Newsweek, New York Times, Fortune, US News and World Report) and even television shows (PBS, CNN, BBC, and CBS Sunday Morning, among others). In patients with breast cancer (BC), data from clinical trials are just beginning to emerge. Early studies describe response rates ranging from 8%-30% in heavily pretreated patients, some having seen >/= 5 prior lines of therapy. Again, when a patient responds, the responses are durable. This is quite distinct from conventional chemotherapy, where a patient’s promising initial response can lead to a recurrence. To see durable responses in patients with metastatic, chemotherapy-refractory BC (including aggressive, triple-negative BC; TNBC), provides an unprecedented opportunity to change disease treatment. As such, an incredible number of clinical trials combining checkpoint blockade with radiation treatment, chemotherapies, and targeted therapies are currently ongoing. However, the most important question to be answered regarding the use of immune checkpoint blockade is: Why do some patients respond while others do not? Objective: The objective of our proposal is to identify mechanisms of resistance to checkpoint inhibitors in metastatic TNBC. To achieve our objective, we propose a large-scale screen of the entire human genome using an innovative screening methodology (named VBIM), which was developed in our laboratories. The VBIM strategy has repeatedly proven its value, with important discoveries to its credit, including the discovery of numerous genes that make tumor cells resistant to standard chemotherapies (docetaxol, tamoxifen) and targeted therapies (erlotinib, quinacrine). Here, we will screen two TNBC models for resistance to two checkpoint inhibitors (known as anti-PD-L1 and ant-CTLA4). Both of these inhibitors are being used in clinical trials for patients with TNBC, either alone or in combination with radiation therapy (both of which will be tested here). Impact: Our proposal addresses the following Overarching Challenges: (1) identifying what drives BC growth
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810552
Entities
People
- Mark Jackson
Organizations
- Case Western Reserve University
- United States Army