Next-Generation Sequencing to Support Immuno-Oncology Therapy: The Emerging Role of Tumor Mutation Burden

Published: Friday, Aug 03, 2018
The introduction of immunotherapy has changed the treatment paradigm in cancer. Agents directed at immune checkpoint blockade obviate processes that inhibit antitumor activity of the native immune system, thereby restoring capacity to the cancer-immunity cycle.1 As cancer cells proliferate and accumulate genetic alterations, they express varying degrees of neoantigens, differentiation antigens, or cancer/testis antigens that become bound to major histocompatibility class I (MHCI) molecules on the surfaces of cancer cells. Under normal physiologic conditions, neoantigens produced by oncogenesis are captured by dendritic cells and are then presented to T cells via MHC class I and and class II (MHCII) molecules. In the presence of immunogenic signals, naïve T cells generate an anticancer response as opposed to a tolerant response to the antigen (ie, priming and activation of effector T cells). Activated effector T cells then migrate to the tumor site, infiltrate the tumor bed, interact with the antigen bound to the MHCI molecule, and ultimately recognize the original antigen as foreign, thus initiating immune activity that results in cell death.1

Cancer cells may escape this process by accumulating genetic variability from continual tumor cell division.2,3 Although immunologically vulnerable cells are destroyed as a result, those that evade immune responses proliferate, eventually escaping the carefully regulated cancer-immunity cycle. Conceptually, immune checkpoint therapy infers blockade of immune escape pathways, thereby enhancing the ability of the immune system to eliminate cancerous cells.4 In particular, 2 immune checkpoint molecules—cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1)—have emerged as promising targets of immunotherapy. To date, the US Food and Drug Administration (FDA) has approved 2 anti–PD-1 monoclonal antibodies (PD-1 blockade): nivolumab (Opdivo; Bristol-Myers Squibb) and pembrolizumab (Keytruda; Merck); 3 monoclonal antibodies targeting the ligated form of PD-1 (PD-L1): atezolizumab (Tecentriq; Genentech Oncology), avelumab (Bavencio; EMD Serono), and durvalumab (Imfinzi; AstraZeneca); and the CTLA-4 monoclonal antibody ipilimumab (Yervoy; Bristol-Myers Squibb) for the treatment of various cancers.

In clinical trials, immunotherapy has demonstrated impressive results among responders, including significant increases in progression-free survival (PFS) and overall survival (OS), in a variety of cancer types.5 However, the reported objective response rate (ORR) after immune checkpoint therapy is highly variable according to cancer type, with rates of about 20% in gastric cancer, 12% to 25% in head and neck cancer, 20% in hepatocellular carcinoma, 15% in ovarian cancer, 15% in small cell lung cancer (SCLC), 20% in triple-negative breast cancer, 25% in urothelial cancer, 60% in mismatch repair–deficient colorectal cancer, and 65% to 85% in Hodgkin lymphoma.5 The modest response rates associated with immunotherapy suggest a need for identification of predictive biomarkers for patient stratification and selection. Correctly identifying patients likely to respond to therapy portends improved treatment outcomes as well as reduced potential for overtreatment in potentially unsuccessful candidates. Predictive biomarkers may also limit unnecessary exposure, thereby reducing potential immune toxicities, and avoid hyperprogression, which may occur in a small fraction of patients on immunotherapy.6

Several potential biomarkers have been proposed. Currently, a variety of immunohistochemistry (IHC)-based companion diagnostic tests are recommended for use in identifying PD-L1 expression as an indicator of likely therapeutic benefit. However, lack of response among some patients considered to have high PD-L1 expression status, as well as positive responses among patients with no PD-L1 expression, would appear to undermine the value of PD-L1 as an exclusionary biomarker.6

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TitleExpiration DateCME Credits
Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
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