Genomics at the core of cancer immunotherapy efficacy
We owe much of the progress in cancer immunotherapy to the understanding of basic science. Decades of research have helped establish hallmarks of cancer, which include a complex battle between oncogenes and tumor suppressor genes driven by accumulating somatic mutations in the tumor .
It is now understood that the immune system also plays a key role in regulating tumor growth. At the molecular level, somatic mutations in a cancer cell result in the display of neoantigens through the HLA complex. These surface neoantigens are recognized as non-self (or “foreign”) antigens by T-cells of the adaptive immune system, which can trigger an immune attack against the tumor. However, we’ve also learned that cancer cells evade immune response through regulation of immune checkpoints, a mechanism that prevents the completion of T-cell effector functions . These novel concepts have revolutionized the design of cancer therapies and have — for the first time — leveraged knowledge from two scientific disciplines, genomics and immunology.
Genomics for personalized cancer vaccines
Novel designs of personalized cancer vaccines rely on data from comprehensive genomic characterization of a patient’s tumor. The notion that each patient has a unique profile of tumor-specific somatic mutations, and consequently displays a unique neoantigen set on the surface of cancer cells, has paved the way for the development of personalized therapies. With the advancement of high-throughput next generation sequencing (NGS), it is now possible to sequence tumor DNA and RNA with unprecedented accuracy for putative neoantigen identification. This genomic and transcriptomic dataset feeds into a neoantigen prediction algorithm that scores and ranks tumor antigens based on immunogenicity potential. A number of biotechnology companies have recently emerged to develop this successful therapeutic approach. Each has an exclusive design to boost neoantigen-specific T-cell responses and improve clinical efficacy for patients with advanced disease .
There is much excitement around the first approved clinical trial for a neoantigen-based vaccine with results anticipated in 2017. The trial will investigate NEO-PV-01, a synthetic peptide vaccine developed by Neon Therapeutics (Cambridge, MA), in combination with nivolumab (Bristol-Myers Squibb), in a cohort of patients with melanoma, non-small cell lung cancer, and bladder cancer. This tremendous progress in individualized cancer vaccines is built on information derived from tumor genomic profiling and the understanding of immune response to cancer. Additional clinical trials are underway with hopes of reviving vaccination as a promising therapeutic approach against cancer with the advantage of producing a sustained memory response.
Genomics for immune checkpoint agents
The recent scientific breakthrough in cancer immunotherapy arose from the understanding of cancer immune evasion mechanisms. Cancer cells have the ability to inhibit anti-tumor T-cell functions through a lock-and-key interaction, implicating immune checkpoints such as PD-1 and its ligand PD-L1. Blocking the interaction of the PD-1 receptor on T-cells and its corresponding ligand, PD-L1, on cancer cells with monoclonal antibodies releases the tumor-induced inhibition of T-cells; facilitating an immune attack on perpetrating cancer cells.
Studies have shown that clinical response to PD-1 blockade is mostly observed in patients who exhibit high levels of tumor PD-L1 . Indeed, a major clinical trial investigating nivolumab treatment in patients with lung cancer independent of their PD-L1 status showed that patient outcomes are not improved when administered nivolumab versus traditional chemotherapy. As a result, PD-L1 expression status has become a biomarker of response to anti-PD-1 agents and can be used to identify patients who will benefit most from this type of immunotherapy. In addition, it was recently reported through DNA sequencing of tumors in patients treated with immune checkpoint inhibitors, that a higher tumor mutational burden correlates with increased durable clinical benefit and progression-free survival . The number of non-synonymous tumor-specific somatic mutations was also associated with increased T-cell infiltration into tumors. Presumably, if immunogenic, the resulting neoantigens presented on the surface of tumor cells constitute the basic trigger of T-cell mobilization and recruitment into the tumor site. Therefore, it becomes apparent that characterizing tumor-specific neoantigen load with DNA and RNA sequencing could serve as an accurate and more reliable predictor of response to immune checkpoint agents.
Genomics for immune modulators on the horizon
Currently FDA-approved anti-PD-1 agents, pembrolizumab (Merck) and nivolumab, have provided hope to many new patients with advanced solid tumors. One of many success stories is that of former president Jimmy Carter who was successfully treated with pembrolizumab therapy for metastatic brain lesions arising from melanoma. In addition to PD-1, there is a multitude of immune checkpoint modulators that can influence T-cell functions. A number of blocking antibodies against immune checkpoint inhibitors (e.g. LAG3, TIM3) to release the brake on T-cells, and agonists (e.g. OX40, GITR) to boost stimulation of T-cells, are underway. Will they hold the same potential as PD-1 blockade? And which predictive biomarkers would be most beneficial for patients? Precision genomic and transcriptomic analysis of tumor biopsies provide the foundation to identifying the correct monotherapy or combination of immune checkpoint agents to be administered to specific patients by assessing immune modulators’ ligand status on tumor cells.
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