Six Fred Hutchinson Cancer Research Center teams have been selected as this years recipients of grants from the Evergreen Fund, which supports early research projects thought to have enough commercial potential to attract future business partners.

Since 2017, the donor-supported Evergreen Fund has awarded over $4 million to projects proposed by scientists seeking a well-timed financial boost to translate their ideas into lifesaving advances for patients.

Despite the disruption of COVID-19, the Evergreen Fund once again offers our researchers the opportunity to complete the critical experiments that venture capital and pharma partners expect to see when evaluating a partnership opportunity, said Hilary Hehman, the Hutchs associate vice president of Strategic Partnerships & Alliances.

The Hutch program also provides researchers feedback on their research, funded or not, from a group of seasoned investors who evaluated their proposals.

This year, the Evergreen Fund distributed three pilot grants of $50,000 each that are designed to give big and bold ideas with commercial application an infusion of funds to demonstrate the projects potential within a six-month period. Another trio of projects were awarded $200,000 each to accelerate their research over a two-year period. The goal of these larger, so-called Beyond Pilot grants is to help researchers whose ideas are further along. These scientists have shown promising data and a commercial path forward, but their projects need more development to attract external financial support.

Drs. Kristin Anderson and Lucas Sullivan received a Beyond Pilot grant for their project to boost the viability of T cells engineered to destroy pancreatic tumors, malignancies stubbornly resistant to therapies. Andersons T cells, designed with receptors that zero in on specific molecular markers on the pancreatic tumor cell surface, have shown promise in preclinical studies.

Yet these living drugs cannot survive for long in the toxic microenvironment of pancreatic tumors. The team is experimenting with new approach they call metabolic reprogramming, which involves a second bit of T-cell engineering. It equips the T cells with an enzyme that allows them to make their own supply of aspartate, a critical amino acid they are starved of inside these tumors.

Both tumor and healthy cells alike need aspartate, but within these toxic tumors, T cells are outcompeted by cancer cells for the raw material both need to make it. By engineering an aspartate-making enzyme into their T cells, the researchers hope to give them the extra oomph needed to survive. If they stay alive, these T cells may have a fighting chance against a cancer known to researchers as the beast of all beasts.

Drs.Irv Bernsteinand Suzanne Furuyama are studying whether they can reverse the ability of solid tumors to evade immunotherapy. Their focus is on the tumor microenvironment, where a tug-of-war is underway for control of the bodys immune response. Key to winning is to turn on an intercellular signaling system called Notch, which shifts the balance of immune cells from a tumor-protective to an anti-tumor state.

But simply flipping the Notch switch on can set inflammation loose against healthy cells as well. Bernsteins team has engineered a switch-flipper that recognizes both tumor cells and Notch to ramp up the inflammatory response of immune cells only in the right places. Their project will involve studies in mice to determine if the Notch-induced, anti-tumor immune cell state enhances solid tumor susceptibility to immunotherapies.

Drs. Justin Taylor and Jim Boonyaratanakornkit are developing a laboratory-designed antibody, a type of immune protein, capable of blocking four different respiratory viruses. Each of these common viruses poses a significant threat to the lives of cancer patients recovering from blood stem cell transplants. The four targeted viruses respiratory syncytial virus, human metapneumovirus, and two common strains of human parainfluenzavirus are among the deadliest for these patients and afflict vulnerable children and the elderly as well. Previously, the Taylor Lab has been able to isolate antibodies capable of protecting against at least two such viruses at the same time. The aim of this project is to engineer and test in animal models an antibody that can neutralize all four targeted viruses, leading to a new type of drug capable of saving thousands of lives each year.

Drs. Jarrod Dudakov and Sinad Kinsella study age-related decline of the thymus, the gland responsible for generating the diverse selection of T-cell receptors needed for a successful response to vaccines or pathogens. In their search for ways to stimulate regeneration of the thymus, they have identified two proteins, known as FOXN1 and DLL4, that are critical to regenerating thymus cells. The goal of their pilot project is to create a screening test for molecules that drive production of either of those proteins. Such protein-inducing molecules might serve as the basis for new clinical approaches that boost T- cell reconstitution. They could help restore immune function in transplant recipients as well as in patients whose thymus glands have been decimated by age, infection or chemotherapies.

Dr. Stephen Tapscott has joined with Dr. Robert Bradley, holder of the McIlwain Family Endowed Chair in Data Science, on a pilot project to explore the therapeutic potential of their discoveries of one way tumors may evade destruction by our immune system. Their focus is on a protein called DUX4, which may be used by a developing embryo and fetus to shield its cells from a mothers immune system. Shut down during childhood, the DUX4 gene is reawakened by some tumor cells, which use the ensuing shower of DUX4 proteins as an invisibility cloak against assault by cancer-attacking T cells. The researchers will develop an inventory of tumor cells that ramp up production of DUX4, explore what mutations enable this reawakening and establish strategies to disrupt it.

Drs. Ming Yu and William Grady are developing a highly sensitive test for early detection of both a deadly form of esophageal cancer and a precursor condition of abnormal cell growth known as high grade dysplasia, or HGD. Their testing panel, which picks up three distinctive genetic markers in patient specimens, has been shown to detect either HGD or the cancer esophageal adenocarcinoma in samples from biopsies or endoscopies. However, those procedures are invasive and expensive.

The pilot project aims to validate their test panel for use in a low-cost device that probes the esophagus with a pill-sized balloon rather than an endoscope. A less-expensive early detection test is expected to reduce mortality from esophageal adenocarcinoma, which is diagnosed in nearly 20,000 Americans each year.

Note:Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future

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Fred Hutch Evergreen Fund awards six grants to promising projects - Fred Hutch News Service