Technology Transfer

Patent: PCT/US2020/050487
Inventors: Dr. Kristina Young and Dr. Andrew Gunderson

Researchers at Providence’s Earle A. Chiles Research Institute focus on harnessing the power of the immune system to cure cancer, including use of immune checkpoint blockade (ICB). ICB is revolutionizing cancer care; however, not all patients respond to this treatment. Given the time, expense, and potential side effects of ICB treatment, there is a dire need for assays that can rapidly identify patients who are likely to respond to this therapy. Our researchers discovered, in colorectal cancer patients treated with ICB plus radiotherapy and standard of care, varying levels of CXCR3+ T cells in the peripheral blood correlated with response to treatment. A decrease in CXCR3+ T cells in blood soon after the start of treatment correlates with a response to the treatment, whereas an increase correlates with no response. Our researchers are developing a CXCR3+ assay to predict treatment response quickly that can aid physicians in clinical decision-making.

• Aid physicians in clinical decision-making by rapidly stratifying patients into likely responders and non-responders to therapy
• Blood-based assay, easy to administer in any clinic
• Single biomarker with easy read-out using standard flow-cytometry instruments
• Potentially applicable to many other tumor types

Assay optimization.

TGFβ suppresses CD8(+) T cell expression of CXCR3 and tumor trafficking. Nat Commun. 2020 Apr 9;11(1):1749

Patent No: PCT/US2020/052551
Inventors: Dr. Hong-Ming Hu, Dr. Jaina Patel and Catherine Dinh

Treatment of solid tumors by therapeutic antibodies is limited by the inefficient passive diffusion and poor retention of these antibodies within tumor beds. Our researchers invented a new platform to improve the tumor retention of therapeutic antibodies or other agents by engineering chimeric fusion proteins of cell matrix proteins and antibody binding domains. The engineered chimeric protein (called Z-nectin) is composed of a cell binding fibronectin fragment and the Z-domain of Protein A. Protein A is a cell surface protein which is found on the cell walls of Staphylococcus aureus bacterial strains. It functions as an immunoglobulin-binding protein, able to bind with the Fc-region of IgG (immunoglobulin G). Our results show Z-nectin is able to dramatically improve antitumor efficacy. Using cell matrix proteins to prolong the in situ action of antibodies and other agents has the potential to improve response rates to therapeutic antibodies in cancer. Z-nectin can be used with other biologics to improve their retention in targeted sites.

• This invention solves the problem of low retention and transient activities of therapeutic antibodies or other agents within the tumor microenvironment
• Platform technology, easily modifiable to carry any antibody or therapeutic molecule
• Dramatic efficacy in proof-of-concept animal studies

We have proof-of-concept in animal models of lung cancer and pancreatic cancer, where we successfully show use of Z-nectin dramatically improves T-cell response when combined with GITR or OX40 agonists. We are currently developing the technology for use in first-in-human trials.

Patent: PCT/US2018/045570
Inventors: Dr. Walaa F. Abdelmoaty, Dr. Lee L. Swanstrom, Dr. Christy M. Dunst

Short bowel syndrome (SBS) is a complex malabsorptive disease that results from physical loss of large parts of the small intestine or loss of intestinal function. Patients with SBS have insufficient absorptive capacity to provide an adequate alimentary supply. SBS may also be defined as the need for prolonged parenteral nutrition (PN) secondary to intestinal failure after bowel resection. Intestinal failure (IF) refers to a malabsorptive state in which the residual intestinal function is inadequate to support growth, nutrition and hydration. SBS is a common cause of IF in pediatrics. Necrotizing enterocolitis (NEC) is the most common cause of neonatal SBS and accounts for at least 30% of most reported series, whereas volvulus and trauma are the leading causes in the non-neonatal population. In older children and adults, the long-segment resections for Crohn’s disease, ischemic vascular disease, radiation enteritis, malignancy, trauma, and adhesive obstructions are common causes. One-year and 4-year survival rate are 90% and 60%, respectively. In newborn infants, the 4-year survival rate on parenteral nutrition is approximately 70%, and in newborn infants with less than 10% of expected intestinal length, the 5-year survival is only 20%. Much of the mortality is thought to be due to complications of the total parenteral nutrition which puts a heavy burden on the body, leading to chronic liver disease.

Magnetic Intestinal Lengthening Device (MILD) is an intraluminal or extraluminal, small intestine lengthening device proposed as a treatment for short bowel syndrome. It allows full small intestine function during the lengthening process as it is open on both ends, and its walls are porous (or just thin parts with wide spaces in between) to allow full intestinal function. It accommodates the increased diameter of the small intestine as needed because of its design that allows diameter expansion. More than one device can be used in series to achieve faster results as it doesn’t need the creation of blind-ended segments, as other ideas suggest for lengthening of small intestine. The device can be made of a biodegradable material so it doesn’t need a second procedure for retrieval. The device initiates the longitudinal mechanical force needed for lengthening and is controlled remotely by an innovative magnetic system.

• Increased survival rates for a condition with a high mortality rate
• Decreased morbidity, mortality and hospitalization rates
• Ability to move away from total parenteral nutrition
• Lower cost of care

A prototype has been developed and tested in pigs to lengthen intestines. The prototype is currently undergoing optimization prior to human testing.

Patent: 10,925,945
Inventors: Dr. Keith Bahjat, Dr. Yoshinobu Koguchi, Dr. Alejandro F. Alice

The use of attenuated bacteria as cancer therapeutic tools is gaining increasing attention, largely due to the development of bacterial strains that potentiate anti-tumor efficacy, with reduced potential to cause toxicities to the host. One problem with the existing technology is the host immune response detects microbial products, such as pyrophosphates, e.g. (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), produced via the methylerythritol phosphate (MEP) pathway. This pyrophosphate is a potent stimulator of human Vγ9Vδ2 (or simply γδ) T-cells, which cause rapid clearance of the bacterial vaccine and greatly limits the treatment response. Thus, activation of the host immune response, without rapid clearance of the bacterial vaccine, is of great interest. Researchers at Providence engineered a listeria strain deficient in the MEP pathway that does not produce HMBPP, and can be used to deliver tumor-specific antigens. In the absence of HMBPP, the host displays a reduced activation and expansion of γδ T cells, resulting in an increase in the magnitude and duration of inflammation and antigen presentation. The engineered listeria also harbor several mutations to avoid liver toxicity in the recipient.

• Potent activation of the immune system for cancer immunotherapy
• MEP-deficient bacteria are not rapidly cleared, which causes a greater increase in the magnitude and duration of inflammation and antigen presentation
• Prolonged antigen presentation leads to an improved anti-tumor response
• Considerably less challenging to develop and bring to clinic than alternatives such as Adoptive Cell Transfer
• Not HLA-class restricted
• Applicable to a variety of cancers
• Amenable to combination therapies
• Engineered bacteria harbor additional mutations to prevent liver toxicity

Patent issued February 2021.