The Immune system as medicine
NGS
The immune system as medicine

Nathalie Labarrière, a biologist and immunologist by training, peers into a microscope. Beside her sit several plastic trays, each about the size of a paperback book, their surfaces dotted with small wells filled with pale pink fluid. They are stacked high in an incubator, an insulated cabinet the size of an oven, that provides the ideal environment for these cells to multiply. In this case, it is filled with T-cells, a specific type of lymphocyte that actively participates in the body’s immune response. These cells are the core of Labarrière's research in immunotherapy.

The immune system can be modulated in patients to target cancer cells. Nathalie Labarrière describes her work using QIAseq to target colon cancer and melanoma tumors in new immuno-oncology therapies.

Her focus area – immuno-oncology (I-O) – has recently become one of the hottest in oncology, and is considered a revolution in cancer therapy. Behind I-O lies the straightforward principle of manipulating the body’s immune system’s T-cells, enabling them to recognize tumor cells which they can then kill off.

The idea of attacking tumors by activating the patient’s immune system dates back more than 20 years. The pioneers of this research, James Allison of the University of Texas and Tasuko Honjo of Kyoto University, were awarded the Nobel prize in medicine in 2018 by the Swedish Academy of Sciences, highlighting immuno-oncology as one of the most promising advancements in cancer therapy in this day and age. 

ACT therapy
Adoptive cell therapy (ACT) is another form of immunotherapy, where doctors collect T-cells from a patient’s blood or tumor tissue, and genetically alter the cells before returning them back into the body. The un-altered white blood cells collected are programmed to target damaged cells, but they sometimes fail to recognize cancer cells. In CAR T-cell therapy, a form of ACT, the extracted T-cells are manipulated in the laboratory where the CAR, a chimeric antigen receptor, is added to their surface. This enables the altered T-cells, now called CAR T-cells, to recognize a specific antigen found on cancer cells to better target and destroy them.

In Nathalie Labarrière’s words, “I-O” can be defined as “using the immune system as medicine.” She started her research at the National Health and Research Institute in Nantes with a number of clinical trials when she first became interested in tumor immunology in 1995. Back then, her work mostly focused on melanoma, a type of cancer affecting the pigment-containing cells (melanocytes) in the skin. Well recognized by the human immune system, these cells were the perfect model for studying “I-O”.

T-cells and anti‑PD‑1 antibodies

“My research targets ways to monitor the immune responses of cancer patients treated with anti PD-1 (anti-programmed cell death protein-1) antibodies, as well as the best selection of T-cells for adoptive cell transfer,” Labarrière explains. She and her team analyze the many different proteins on the surface of T-cells, using QIAGEN's QIAseq Immune Repertoire RNA Library Kits, to help them to find specific markers that can be used to identify patients who are most likely to benefit from immunotherapy. This approach allows them to decide if a patient will be among those who will best respond to a particular immunotherapy treatment, as well as patients who may be in the greatest danger of a relapse.

Blocking the Deactivation
The immune system has multiple checkpoints in place to avoid mistakenly killing healthy cells. The PD-1 (Programmed cell death protein 1) checkpoint on T cells is just one example of such a precaution. A cancer cell uses these checkpoints to its advantage and can mask itself by producing PD-L1 (programmed death ligand) to block the activity of a T-cell. In “anti-PD-1” immunotherapy, immune checkpoint inhibitors, such anti-PD-1 and anti-PD-L1, block the interaction between the receptors PD-1 and PD-L1, which ensures that the T cell remains active and the cancer cell is recognized as a threat.

Unique molecular indices (UMI) are a great help in this research, says Labarrière. UMIs are molecular barcodes that are ligated to the ends of nucleic acid fragments prior to sequencing. Tagging DNA and RNA with UMIs before any amplification takes place allows reads to be assigned to individual molecules, allowing for a computational correction of amplification bias and sequencing errors. “With UMI we can detect low-frequency variants, for instance, to identify T-cell receptor (TCR) repertoire variations in melanoma patients responding to immunotherapy with anti-PD-1, and to characterize immune cell subsets associated with therapeutic response.”

She uses UMIs from the QIAseq Immune Repertoire RNA Library Kit and the QIAseq UPX3' Targeted RNA Panel to eliminate PCR bias and to improve accuracy in variant detection and estimation of the allelic fraction and allele frequency, saying that she gets a “more accurate quantification of the transcript count and reduced technical noise” this way.

Accuracy is important as the immune system for every patient is unique and needs to be genetically defined. There are more than 10,000 different types of T-cells found in blood, all of which have different functions. Of these 10,000-plus T-cells, one must be identified that will react to a tumor’s specific genetic profile—comparable to finding a needle in the proverbial haystack.

“My research targets ways to monitor the immune responses of cancer patients treated with anti PD-1 antibodies, as well as the best selection of T-cells for adoptive cell transfer.”
Nathalie Labarrière, French Institute of Health and Medical Research, University of Nantes

A partner to pioneers

QIAGEN has been an important partner to pioneers in “I-O” research from the very beginning. Today, scientists work with QIAGEN’s next-generation sequencing (NGS) technologies to identify new biomarkers and antigens, as well as QIAGEN’s huge databases to develop new drugs for application in hospitals.

In 2018, QIAGEN launched its first applications specifically developed for use in immuno-oncology to help researchers gain better and faster insights. The new QIAseq Tumor Mutational Burden Panels target variants in 486 genes, with over 98% correlation to exome. The new panel generates data with higher sensitivity and has lower requirements for DNA input. It also employs robust analysis and interpretation modules – IVA and QCI, driving somatic cancer clinical-decision support.

Nathalie Labarrière describes QIAGEN’s role in her studies as “a real scientific collaboration, in which technology offers us great opportunity. But we also benefit from QIAGEN’s know-how, for example, with its Ingenuity Scientific Advisory Board.” And she adds: “It’s really rare that a private company is interested in real scientific collaboration because it is an efficient approach to advancements in research.”

Nathalie Labarrière
works at the University of Nantes, where she received her Ph.D., and is part of a research group on immuno-oncology founded by the National Health and Medical Research Institute (INSERM) in Nantes, France. The laboratory is housed in a steel- and glass-clad building nestled on the banks of the Loire. The INSERM is the only French public research organization entirely dedicated to human health. Their scientific and technology institute employs more than 5000 researchers, engineers and technicians from all over the world and runs 13 regional offices, 9 Thematic Institutes and 281 research groups.

Positive effect, but not for all

In her most recent study, collaboration with QIAGEN helped answer why immunotherapy has a positive effect on some, but not all, patients. “Anti-PD-1 therapy, for instance, helps fewer than half of cancer patients,” Labarrière says. However, the comprehensive analysis of PD-1 regulation and signaling could have a considerable impact on the optimization of other immunotherapies, such as T-cell-based immunotherapies. Being able to find early and robust predictive markers of clinical response not only improves patient management but can reduce costs.

“Knowing that my team’s hard work could be part of a sea of change in oncology to save more lives is the biggest motivation.”
Nathalie Labarrière, French Institute of Health and Medical Research, University of Nantes

Nathalie Labarrière is convinced that the research community is experiencing “the beginning of a revolution.” She foresees many changes ahead that will result in improved patient outcomes: “Knowing that my team’s hard work could be part of a sea of change in oncology that can save more lives is the biggest motivation.”

Promising results with high-precision treatments
In 2010, patients with incurable chronic lymphocytic leukemia were successfully treated for the first time. In two of these three patients, the tumor completely regressed within four weeks. The first patient received therapy in 2012 and is still cancer-free today. In 2017, the first therapies with CAR T-cells, Kymriah and Yescarta, were approved for use in the U.S., one of which subsequently also received EU approval.

QIAGEN, with Bristol-Myers Squibb, is exploring the use of NGS technology to create gene expression profiles (GEPs) as predictive or prognostic tools for novel I-O therapies. A potential outcome could be the first-ever NGS-based companion or complementary diagnostic to provide key insights for personalized decision-making in I-O. Fouad Namouni, M.D., Head of Oncology Development at Bristol-Myers Squibb has stated that “working with QIAGEN will help develop better diagnostic tools to target the most appropriate immunotherapies across a number of different tumor types.”

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