Method for HLA LOH Detection in Liquid Biopsies

Human leukocyte antigen (HLA) LOH (LOH) is a known resistance mechanism by which cancers evade T cell receptor-(TCR-)based immunotherapies. This class of therapies includes immune checkpoint inhibition (ICI, e.g., Pembrolizumab), engineered TCR (T cell receptor)-T cell adoptive transfer, tumor infiltrating lymphocytes (TIL), T-cell engagers, and other modalities. Dozens of therapies in this category were developed with many in clinical trials. The resistance mechanism noted here, HLA LOH, causes these therapies to fail. Therefore, it is beneficial to know before treating a patient whether their cancer’s genome has undergone HLA LOH. There is currently no HLA LOH detection method with widespread use in the market and, furthermore, no non-invasive HLA LOH detection test available. Approximately 17% of all cancer patients undergo HLA LOH (Montesion et al., Cancer Discovery, 2021) and would therefore be less likely to respond to TCR-based immunotherapies, making a test for HLA LOH crucial for attaining better patient outcomes.

The inventors at the National Cancer Institute (NCI) a developed a non-invasive test for HLA LOH detection in liquid biopsies from blood. As a companion diagnostic (CDx), this HLA LOH detection method allows for improved patient selection. It determines patients unlikely to benefit prior to immunotherapy and thus, can avoid the toxicity, costs, and prevent delay in effective therapy. 

This is an application of precision oncology. For HLA LOH detection, treatment decisions can be based in part on the HLA LOH status of the patient’s cancer, and a patient’s treatment course is tailored to give the patient rapid access to more effective therapy. Because the test is non-invasive, determining HLA LOH status does not require surgery. This dramatically increases patient comfort, improves their experience and decreases healthcare costs. An additional benefit is that the patient will not undergo unnecessary treatments that could cause toxicities. 

The Center for Immuno-Oncology at the NCI is primarily looking for collaborators to co-develop this technology with the inventor. As a companion diagnostic, it will be paired with immunotherapies, to select patients who are most likely to achieve treatment benefit. The inventors seek co-development partners who developed immunotherapies that function via TCR-based mechanisms. The goal is to conduct clinical trials for the diagnostic concomitantly with the drug. The end-result of the trial will be determination of how accurately the diagnostic predicts efficacy of the drug. A companion diagnostic can increase the market potential of therapeutics by allowing them to be used as a first-line treatment. The companion diagnostic can be co-developed and/or co-marketed with a drug at any stage of the drug’s regulatory approval process, from Phase I to FDA-approved. The next step for the diagnostic is a Phase I clinical trial, with possible IDE exemption. The companion diagnostic may also be a candidate for College of American Pathologists (CAP) accreditation and, more stringently, Clinical Laboratory Improvement Amendments (CLIA) designation while the clinical trials are being conducted.

Competitive Advantages:

• Mean overall survival (mOS) in TMB-(tumor mutational burden-)low, HLA-intact patients is twice as high as in patients with TMB-low and HLA LOH, which creates an opportunity to benefit patients by treating them with Pembrolizumab despite their TMB-low status (Montesion et al., Cancer Discovery, 2021); therefore HLA LOH as a biomarker may complement TMB-low for improved patient selection
• Non-invasive test not requiring surgical removal of solid tumor tissue
• Allows patient-tailored treatment utilizing a wide range of TCR-based immunotherapies
• Potential improvement in patient survival
• Potential time and money savings for patients, insurance companies, oncologists, and immunotherapy manufacturers by facilitating the selection of a precision treatment course for each patient

Commercial Applications:

• Companion diagnostic for TCR-based immunotherapies in experimental clinical trials
• Companion diagnostic for TCR-based immunotherapies FDA-approved clinical practice
• Research use in labs studying/developing new pre-clinical therapeutic candidates
• Research use in basic research labs studying immunotherapy resistance mechanisms, antigen processing and presentation and basic immunology