Expression of a Primary Immune Marker above a validated cutoff can be used to select which patients are more likely to respond to Checkpoint Inhibitors (CPIs) such as anti-PD-1 therapies.  While some of these biomarkers are complementary diagnostics, i.e. they may inform or improve the benefit/risk ratio without restricting drug access, some diagnostic assays are essential for the safe and effective use of therapeutics, and thus physicians can only prescribe these drugs after testing with an FDA approved companion diagnostic.

For example, physicians can only administer single agent Pembrolizumab to “first line” metastatic non-small cell lung cancer (NSCLC) patients with PD-L1 IHC tumor proportion scores (TPS) at or above 50% as measured by the Dako 22C3 anti-body.  Unfortunately, even if a patient tests positive for a Primary Immune Marker, there is no guarantee that a patient will respond to the corresponding therapy, as there are many variables that contribute to the effectiveness of a therapy.  Thus, only 30% of NSCLC patients with TPS > 50% in Merck’s KEYNOTE-010 had an objective response to Pembrolizumab.

The use of multiple Primary Immune Markers as part of a comprehensive immune profile can benefit physicians and patients by testing across the full range of biomarkers described in the literature, many of which probe different dimensions of the cancer immune response cycle.  For example, MSI and mutational burden assays are designed to determine how like the patient’s tumor is to be identified as non-self by their immune system.  By contrast, quantitating tumor infiltrating lymphocytes (TILs) such as CD3/CD8+ cells and measuring PD-L1 copy number and/or protein expression by FISH and IHC, respectively, can inform how prepared the tumor micro-environment is to attack the patient’s cancer once the PD-1/PD-L1 pathway is blocked.  Often patients may express high levels of one or two of these markers, but not the others.  Thus, comprehensive immune profiling identifies more sources of “higher” responders, while also identifying likely gaps in mounting a response when assays have conflicting results.

By performing an RNA-Seq expression analysis of 43 T-Cell Receptor Signaling (TCRS) genes and 11 TIL genes, the Immune Report Card provides a comprehensive examination of Secondary Immune Markers to describe the underlying immune phenotype of a patient.   Secondary Immune Markers may be able to identify gaps or alternative tumor defenses to the cancer immune response cycle.  Thus, patients whose cancers progress despite positive indications from their primary immune markers may be selected to enroll into combination immune therapy clinical trials based on the biology of their tumor micro-environment.

For example, some tumors are known to “escape” immune response by over-expressing Indoleamine 2, 3-dioxygenase (IDO).  Patients expressing high levels of IDO may rationally be expected to benefit from a clinical trial that combines an anti-PD-1 agent with an anti-IDO therapy.