SEATTLE — April 10, 2018 — Fred Hutchinson Cancer Research Center’s latest findings will be featured in about 50 presentations at the annual meeting of the American Association for Cancer Research, “Driving Innovative Cancer Science to Patient Care,” to be held April 14-18 in Chicago. Here are several highlights:
Next-generation T-cell therapies
This year’s AACR annual meeting puts a spotlight on Hutch researchers working on next-gen approaches to transgenic T-cell receptor, or TCR, immunotherapy, in which patients’ T cells are genetically engineered to produce a naturally occurring, cancer-targeting receptor called a TCR.
Using a new technology called single-cell RNA sequencing, or scRNA-seq, Fred Hutch researchers are determining how different cell types interact in the complex environment of a tumor.
- Single-cell RNA sequencing reveals AML immunoediting under pressure from engineered T-cell therapy. The immunotherapy field has a growing awareness that patients’ cancers can sometimes evolve resistance to genetically engineered T-cell therapies. Dr. Kelly Paulson will discuss how scRNA-seq revealed how a clinical trial participant’s advanced leukemia came back after he experienced an outgrowth of a tiny number of certain pre-existing cancer cells. The test showed that cancer cells could use an alternative cellular machinery to present a version of the target that couldn’t be recognized by the TCR that had been engineered into his T cells.
- Novel approaches to high-affinity TCR isolation for clinical translation enabled by single-cell RNA sequencing. One challenge in TCR-based cellular immunotherapy is selecting the single best TCR — out of a pool of thousands of different natural TCRs that all recognize the same target — to genetically engineer into patients’ cells. In a poster presentation, Dr. Megan McAfee will describe the use of scRNA-seq to identify extremely rare TCR variants that bind unusually strongly to their cancer targets — variants too rare to be identified using the standard techniques.
- Engineering adoptive T-cell therapy to co-opt Fas ligand-mediated death signaling in solid tumors. Due to their formidable immune-suppressing defenses, solid tumors — such as ovarian cancer, a notorious killer — pose the next challenge for cellular immunotherapies. Researchers in the lab of Dr. Phil Greenberg at Fred Hutch have been engineering workarounds around one common tumor-defense mechanism: triggering “shut-down” signals on T cells. Their strategy is to trick tumors into activating T cells instead by reprogramming the cells to hide an activation signal under a shutdown switch. In a poster presentation, Dr. Kristin Anderson will show how using this trick significantly increases the effectiveness of a preclinical T-cell therapy for ovarian cancer.
Big data for cancer research
Studies using scRNA-seq, described above, generate orders of magnitude more data than less-precise methods. This is made possible by advances in next-gen sequencing, data storage, and big-data analytical methods. Dr. Ulrike Peters studies risk factors for colorectal cancer, or CRC, making use of epidemiologic clinical and genome-wide genetic data from tens of thousands of people in multinational consortium studies, including the Genetics and Epidemiology of Colorectal Cancer Consortium (based at Fred Hutch) and the Colon Cancer Family Registry. The sheer size of the data sets gives these researchers the power to study the disease’s genetic risk factors and interaction with environmental and lifestyle risk factors at deeper levels than would otherwise be possible.
- Functionally informed genome-wide interaction analysis of nonsteroidal anti-inflammatory drugs on colorectal cancer risk. Dr. Xiaoling Wang will describe a study that used functional information to discover a novel gene that may interact with aspirin use to confer colorectal cancer risk. These findings provide preliminary support for new biological insights that could help explain the chemopreventive mechanisms of aspirin on CRC and may identify subgroups in the population for which aspirin can be particularly beneficial to prevent the disease.
- Genome-wide association study by colorectal carcinoma subtype. More than 50 genetic variants have been associated with colorectal cancer risk through genome-wide association studies yet these variants represent only a fraction of the total estimated heritability. Tabitha Harrison will present a study using microsatellite instability, an established CRC classifier with etiological and therapeutic relevance, to define CRC subtypes for genome-wide association study analyses. Results suggest that accounting for molecular heterogeneity is important for discovery and characterization of genetic variants associated with CRC risk.
- Interactions between genetic predictors of gene expression and dietary factors associated with risk of colorectal cancer. Gene-environment, or GxE, interaction studies may help identify novel genetic loci and biological interactions that give insight to the pathogenesis of CRC. Previous genome-wide GxE studies with dietary factors have identified interactions between loci and consumption of processed meat and alcohol. However, limited statistical power remains a primary concern. Set-based SNP (single nucleotide polymorphisms) testing has the potential to increase statistical power to detect GxE interactions by aggregating functionally relevant SNPs. Paneen Petersen will describe data incorporating functional information from a transcriptome prediction tool into a novel set-based approach for testing GxE interactions. The findings highlight the efficacy of integrating functional information and set-based testing for novel discovery of genes interacting with known dietary risk factors of CRC.
Racial disparities in prostate cancer
Prostate cancer screening and the contribution of genetics/biology to racial disparity outcomes. Compared to American men of European descent, African-American men have a 60 percent higher incidence of prostate cancer and a mortality rate that is two to three times greater, but there is no consensus on the age at which African-American men should be screened. Dr. Ruth Etzioni will talk about how modifying screening and treatment guidelines could eliminate the mortality gap.
Exploring cancer survivorship and the growing demands on health care delivery. Advances in cancer treatment allow more and more patients to live with and through their disease. But cancer survivorship presents new hurdles of its own. Identifying and managing late effects of cancer and the complexities of comorbid conditions is imperative. Dr. Gary Lyman, oncologist, health economist, and co-director of the Hutchinson Institute for Cancer Outcomes Research, will explore the changing clinical landscape and discuss measures that care providers may employ as they grapple with these challenges.
Personalization of cancer treatments with a CLIA-certified high-complexity and high-throughput drug sensitivity test. SEngine Precision Medicine, a spinoff of Fred Hutch, offers a precision-medicine approach to cancer treatment through its assay called PARIS, named for the Greek hero who defeated Achilles by finding his one weak spot. The test is used to determine which drugs will work and which won’t before patients are treated. The researchers will present an overview of the approach that led to Clinical Laboratory Improvement Amendments certification and will highlight insights gained by comparative analysis across a multitude of cancer samples. The researchers will also present a case study from a metastatic breast cancer patient showing the potential power of the test.
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At Fred Hutchinson Cancer Research Center, home to three Nobel laureates, interdisciplinary teams of world-renowned scientists seek new and innovative ways to prevent, diagnose and treat cancer, HIV/AIDS and other life-threatening diseases. Fred Hutch’s pioneering work in bone marrow transplantation led to the development of immunotherapy, which harnesses the power of the immune system to treat cancer. An independent, nonprofit research institute based in Seattle, Fred Hutch houses the nation’s first National Cancer Institute-funded cancer prevention research program, as well as the clinical coordinating center of the Women’s Health Initiative and the international headquarters of the HIV Vaccine Trials Network.