Immunotherapy is a revolutionary class of cancer drugs that leverage the power of a patient’s own immune system to destroy their tumor. This anti-cancer immune response is initiated by a series of steps. First, when a cancer cell dies (apoptosis), it releases cancer cell-specific antigens that are captured by dendritic cells (DCs) for processing (Step 1).  Next, dendritic cells use major histocompatibility complex (MHC) molecules to present the cancer antigens on their cell surface (Step 2).  T cells (lymphocytes), then recognize the cancer antigens, which results in priming and activation of effector T cell response against them (Step 3). This allows the T cells to view the cancer cells as “foreign” instead of “self”.

Finally, the now activated cytotoxic T lymphocytes (CTLs) migrate to the tumor (Step 4) and infiltrate the tumor bed (Step 5). These CTLs specifically recognize and bind to cancer cells through the interaction between the T cell receptor (TCR) and its equivalent antigen presented by MHCI on the surface of the cancer cell (Step 6). This interaction of CTLs with tumor cells, initiates cell death of both cells (Step 7). Death of the cells releases additional tumor-associated antigens (back to Step 1) to increase the breadth and depth of the response in subsequent revolutions of the cycle.

Steps in Anti-Cancer Immune Response Cycle1

Several types of immunotherapy are in clinical development including vaccines and “adoptive immunotherapy”, which has been successful in treating hematologic malignancies.  However, one of the most promising types of immunotherapy, known as checkpoint inhibitors, are already available for treating a great number of solid tumor cancer types today.

Checkpoint inhibitors stimulate a patient’s immune system to recognize cancer cells as “non-self”, allowing the immune system to attack the cancer cells. These treatments work in one of two ways – by blocking proteins on the cancer cell surface with monoclonal antibodies, or by inhibiting receptor proteins on the surface of T cells with monoclonal antibodies. Both of these mechanism of action “uncloak” cancer cells that hide from attack by the immune system. Once the immune system can recognize a tumor, it can work to eliminate cancer cells in a similar fashion to the immune system’s response to viral or bacterial infections.

About 30% of patients treated with checkpoint inhibitors respond, and among those who do, the results can be completely transformational and durable. For example, in August 2015, former U.S. President Jimmy Carter announced that he had an aggressive form of melanoma skin cancer, with metastasis to both his liver and his brain. On December 6, 2015, after he was treated with Keytruda® (pembrolizumab) from Merck & Co., he said that all signs of his cancer were gone.[2] (Swetlitz, 2015).  Nearly one year after his initial treatment was completed, there was still no evidence of disease (

However, despite the promise of potential curative-like results from checkpoint inhibitor therapy, it usually takes patients longer to respond. The 70% of patients who do not ultimately benefit from these drugs, which can cost $150,000 USD or more, lose critical treatment time that could have been spent on effective therapy. There are also over 800 clinical trials underway for new immunotherapies, combination therapies and additional indications, underscoring an urgent need for biomarker tests that identify the patients most likely to benefit.

Currently, there are four checkpoint inhibitors – atezoluzimab, ipilumumab, nivolumab, and pembroluzimab – with approved indications for frontline or subsequent therapy in 5 solid tumor types including bladder cancer, head and neck cancer, kidney cancer, non-small cell lung cancer (NSCLC), and melanoma. Today, only pembrolizumab has an associated FDA-approved biomarker for first line treatment of NSCLC, i.e. PD-L1 immunohistochemistry (IHC), which is a sub-optimal technology for this application. First, IHC is subjective. Interpretation varies between pathologists because it is inherently qualitative, not quantitative. Therefore, IHC is not accurately reproducible. Second, IHC uses too much sample. Beyond several markers, the tissue requirements become unmanageable. Pharmaceutical pipelines will continue to add possibly hundreds of incremental markers over the coming years. Third, IHC does not scale. It does not provide economies of scale: costs are linear as incremental markers are added.

Most importantly, IHC is simply not accurate. The DAKO pharmDx 22C3 IHC assay identifies 25% of potential patients as responders, of which only ~42% (10% of total) of these patients respond. Conversely, there are many patients this assay identifies as non-responders that actually do respond to immunotherapy. This is unacceptable to payers, pharmaceutical companies, and patients. Yet, IHC is the current standard of care.

OmniSeq is taking a comprehensive approach to patient stratification with Immune AdvanceSM – a Multianalyte Assay with Algorithmic Analysis (MAAA) that uses next generation sequencing (NGS) to predict response to checkpoint inhibitors. NGS addresses the shortcomings of IHC. NGS provides quantitative counts of transcripts that do not vary in interpretation from sample to sample. NGS can study many markers simultaneously from a small amount of tissue.



[1] Reprinted from Immunity, Volume 39, Chen, Daniel S. et al., Oncology Meets Immunology: The Cancer-Immunity Cycle, 1-10, Copyright 2013, with permission from Elsevier.

[2] Swetlitz, I. (2015, December 18). ‘I want what Jimmy Carter had’: Patients clamor for the president’s cancer drug. Retrieved from Stat: