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Featured Technologies

TCR Cell Therapy Targeting MAGE-A1

  • Stage: IND enabling
  • Type: Cell Therapy, Therapeutic
  • Categories: Immuno Oncology, Target

52 technologies found

Additional Technologies

Acute Myeloid Leukemia Quallty of Life Questionnaire (AML-QOL)

A validated and reliable quality of life instrument that is specific to patients with acute myeloid leukemia.

  • Stage: QoL fully developed and validated
  • Type: Health IT
  • Categories: Assay / Method
Technology overview
Researchers at Fred Hutchinson Cancer center has developed a novel and validated quality of life instrument specifically designed for patients with acute myeloid leukemia (AML). Developed through an iterative process involving feedback from patients, medical providers, and psychometricians, the AML-QOL underwent rigorous testing and validation, including factor analysis and test-retest reliability studies with 202 patients. The final instrument includes 27 items organized into 5 domains, a Symptom Index, and a Summary Score. The AML-QOL has been shown to have high internal consistency, good test-retest reliability, and strong convergent and divergent validity when compared to a non-disease-specific instrument. Furthermore, the Summary Score demonstrates good sensitivity to change when anchored to patient perception of QOL change, providing a clinically meaningful difference of 8-10 points out of 100. The AML-QOL is a reliable and valid measure of quality of life for patients with AML and other aggressive myeloid neoplasms.

Barcoding for the Tracking and Quantification of DNA

System and methods for digital quantification and tracking of cells and DNA including, DTC, CTCs, and ctDNA.

  • Stage: Preclinical in vitro
  • Type: Research Tool, Therapeutic, Diagnostic
  • Categories: Assay / Method, Nucleic Acid
Technology overview
Dr. Bielas and colleagues have been working on developing methods to quantify DNA and reduce background noise to better track, sequence, and quantify DNA. Genetic constructs are created using repeats of unique genetic sequences separated by restriction enzymes. These constructs act as barcodes to tag and track cells and DNA including mitochondrial DNA (mtDNA), disseminated tumor cells (DTCs), circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and implanted cells of a species within the same species. Detection and analyses can be performed through ddPCR, dPCR, qPCR, NGS, other sequencing platforms. This tool can be applied pre-clinically or applied as a clinical tool to aid in diagnosis and/ or treatment of a subject.

Biomarkers Predicting Risk of Cytokine Release Syndrome and Neurotoxicity Following Adoptive T Cell Therapy

Risk stratification using serum-derived biomarkers to predict adverse patient responses following adoptive T cell therapies.

  • Stage: Preclinical human
  • Type: Diagnostic
  • Categories: Biomarker
Technology overview
Few assays are currently available that identify patients who are at risk of developing severe cytokine release syndrome (CRS) and neurotoxicity following adoptive T cell immunotherapy. CRS and neurotoxicity usually occur within the first 1-2 weeks after in vivo CAR-T cell activation and proliferation, complicating wide adoption of adoptive cell therapies given the specialized care. Although CRS and neurotoxicity can be reversed, severe cases can result in intensive care admission and in some cases, be fatal. Dr. Turtle and his colleagues have identified biomarker signatures in patient samples after adoptive T cell therapy associated with endothelial activation, initiation of intravascular coagulation and blood-brain barrier leak. The Turtle Lab has identified a biomarker panel to detect and identify these biomarkers in patient serum before lymphodepletion, chemotherapy, or adoptive cell therapy infusion. These biomarkers will help in risk assessment of patients receiving adoptive T cell therapy, and to inform dosing and other pre-emptive treatments in order to minimize and prevent severe and potentially life-threatening CRS and neurotoxicity.

CAR Design Improvements for the Recognition of Low-Density Antigens

Methods and tools to increase CAR-T cell recognition of tumor cells expressing low density antigens

  • Stage: Preclinical in vitro
  • Type: Cell Therapy
  • Categories: Immuno Oncology
Technology overview
Adoptive transfer of CAR-expressing T cells is an effective cancer therapy for a proportion of individuals with B cell malignancies and multiple myeloma, but efficacy is limited by relapses that stem from antigen downregulation or loss. In addition, CAR T cell therapy is also not as effective for solid tumors, where tumor-associated antigens are expressed heterogeneously and at lower levels than hematological malignancies. Thus, enhancing CAR T cell recognition of low-density tumor antigens may both improve initial anti-tumor efficacy and reduce the risk of relapse. Although CARs were designed to mimic T cell receptor (TCR) signaling, natural TCRs have 100-fold greater sensitivity for recognition of peptide major histocompatibility antigen complexes. Members of the Riddell lab reasoned that comparing TCR and CAR signaling events might guide rationale adaptations to CAR design that improve antigen sensitivity. They studied the similarities and differences between TCR and CAR recognition-induced signaling and identified key TCR signaling intermediates not activated by CAR stimulation. They show that the addition of key domains into existing CAR structures improves CAR-T cell recognition of tumor cells expressing low amounts of surface antigen.

Chimeric and Humanized Anti-CD45 Antibody for Therapeutic Applications

Humanized antibody offers reduced toxicity and anti-mouse antibody immunization

  • Stage: Preclinical in vivo
  • Type: Therapeutic
  • Categories: Hybridoma / Antibody, Immuno Oncology, Target
Technology overview
CD45 is a transmembrane cell surface glycoprotein expressed on almost all hematopoietic cells and absent on non-hematopoietic cells. CD45 is an abundantly expressed target in most hematologic malignancies, including 85-90% of cases of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Due to the stability of CD45 on the cell surface, it is an attractive candidate for antigen-specific immunotherapy and other targeted oncology approaches. This humanized anti-CD45 antibody has the potential to decrease infusion toxicities in some patients. Moreover, the humanized antibody limits anti-mouse antibody (HAMA) immunization leaving additional treatment options open for patients. Drs. Brenda Sandmaier and Roland Walter at Fred Hutch have developed chimeric and humanized forms of CD45 antibodies. Initial in vivo CD45+ cell targeting biodistribution studies show enrichment of radiolabeled antibody in immunodeficient mice xenotransplanted with human CD45+ leukemia cells.

Codon-Mutant Libraries of Protein-Coding Genes

  • Stage: Preclinical in vitro
  • Type: Therapeutic
  • Categories: Assay / Method
Technology overview
Random mutant libraries of genes are used in a wide variety of molecular biology and bioengineering applications. Current techniques (such as error-prone PCR and its variants) are well suited for introducing mutations at the nucleotide level. PCR with oligonucleotides containing degenerate bases at certain positions are well suited for creating randomized codons at a small number of positions, particularly if these positions are nearly contiguous in primary sequence. However, there are no standard techniques for randomizing codons uniformly throughout a gene at a low rate of mutagenesis. Dr. Bloom has devised an approach to create random codon mutations distributed uniformly across a gene. The Bloom Lab has successfully applied this technique to randomly mutate all codon positions (except the start and stop codons) in the 1.5 kb influenza nucleoprotein gene as proof of concept.

Colon Cancer Biomarkers

Validated 5-protein panel for early detection of colon cancer and adenoma.

  • Stage: Development of multiplex assay for high throughput testing
  • Type: Diagnostic
  • Categories: Biomarker, Protein / Peptide
Technology overview
Dr. Lampe’s laboratory has identified and validated a five protein panel for early detection of adenoma and colon cancer: BAG4, IL6ST, VWF, EGFR and glycosylated CD44. This biomarker panel has been confirmed in two independent studies of patient plasma samples in a custom high-dimensional antibody microarray containing 3,200 different antibodies: (i) pre-diagnostic plasma samples from 79 individuals diagnosed with colon cancer less than 3 years following sample collection and 79 cancer-free controls and (ii) 120 plasma samples from people diagnosed with adenoma or cancer, and 60 controls. This biomarker panel has the potential to revolutionize the diagnosis of colon cancer. The panel has a specificity of 90% and sensitivities of 83-89% (adenoma) and 86-95% (cancer).

Cross protective antibodies against common endemic respiratory viruses

  • Stage: Preclinical in vitro, Preclinical in vivo
  • Type: Therapeutic
  • Categories: HSC Therapy, Hybridoma / Antibody
Technology overview
Respiratory viruses are a major cause of death worldwide, with an estimated 2.7 million attributable deaths in 2015. Apart from RSV, there are currently no preventative or therapeutic products to protect vulnerable populations such as transplant patients and elderly adults against common respiratory viral infections (e.g., HMPV, HPIV1, or HPIV3). The administration of neutralizing monoclonal antibodies (mAbs) provides an effective alternative to vaccination. An effective strategy to reduce the overall burden of the broad array of viruses that cause lower respiratory tract infections (LTRIs) in at-risk adults and immunocompromised patients must rely on targeting multiple viruses simultaneously, rather than a single virus. To efficiently achieve broader protection against these viruses, Fred Hutchinson Cancer Center researchers have identified and developed cross-neutralizing mAbs that could target more than one virus at a time. The mAb 3x1 cross-neutralizes both HPIV3 and HPIV1, while MxR effectively cross-neutralizes both HMPV and RSV. Together, 3x1 and MxR comprise an antibody cocktail with the ability to achieve simultaneous protection against multiple viruses. Novel modifications of the Fc region that enhance half-life, respiratory bioavailability, and potency of these antibodies are being developed and validated (Tech ID: 22-213).

cTRPs: Circular Tandem Repeat Proteins

A novel protein scaffold and functional display platform for use in human therapeutic cell systems.

  • Stage: Preclinical in vitro
  • Type: Therapeutic, Cell Therapy
  • Categories: Protein / Peptide
Technology overview
Drs. Stoddard and Bradley have combined their expertise in protein engineering and structural modeling to engineer a novel platform technology of artificial circular protein display scaffolds. Configured unlike any proteins found in nature, and made from smaller components, these unique self-assembling scaffolds can be generated in various dimensions and sizes; and to display various functional units (a.k.a. functionalized cTRPs). Functionalized cTRPs can facilitate (i) precise pre-organization of biologically active proteins in defined symmetric arrangements; (ii) enhanced activity on cell surfaces via increased avidity; and (iii) enhanced expression, stability and solubility. The first functionalized cTRPs will be cytokine TRPs, MHC TRPs, and stimulatory stem cell TRPs. The resulting functional cTRPs will offer reagents for stimulation, expansion, differentiation, and isolation of human therapeutic cells to facilitate cell culture and expansion under tightly-controlled conditions for the desired final biological properties.

Digital Deletion Detection and QuantiSize

This method allows for measurement of rare deletions, while concurrently gathering information about size and homogeneity of the unknown template.

  • Stage: Preclinical in vitro
  • Type: Diagnostic, Research Tool
  • Categories: Assay / Method, Nucleic Acid
Technology overview
Dr. Bielas has developed a sensitive, quantitative method to detect rare mutations in genomic and mitochondrial DNA. The main strategy is a three-step process starting with targeted enrichment for deletions, followed by amplification, and then analysis for quantification or characterization. This method shows improvements in specificity, sensitivity, and accuracy over other available methods. In addition, the lab observed a linear correlation between the fluorescence amplitude produced in droplet digital PCR (ddPCR) and the length of the amplified DNA molecule, which they named QuantiSize. QuantiSize is based off of the ddPCR absolute quantification system and adds in the ability to determine the size of a target DNA. This allows for accurate preparation of NGS libraries, while avoiding limitations of other quantification systems.

EBV Neutralizing Antibody and Vulnerability Site for Vaccine Design

A human monoclonal antibody that neutralizes EBV infections in both B cells and epithelial cells, and new approaches to developing an EBV vaccine.

  • Stage: Preclinical in vivo
  • Type: Therapeutic, Vaccine
  • Categories: Hybridoma / Antibody
Technology overview
Dr. McGuire and colleagues have isolated a human monoclonal antibody that binds the gH/gL protein on Epstein-Barr virus (EBV). This antibody, called AMM01, can neutralize infections in B cells and epithelial cells, the two types of cells infected by EBV. Existing antibodies only neutralize infection in one of the cell types (B cell or epithelial cell); however, AMM01 neutralizes infections in both cell types and is a human-derived antibody. A crucial epitope of EBV vulnerability, formed by both gH and gL at the Domain-I/Domain-II interface, was identified and paves the way for the design of next-generation subunit vaccines.

Engineering B cells to secrete select antibodies and gene products for the treatment of diseases

  • Stage: Preclinical in vitro Preclinical in vivo
  • Type: Cell Therapy
  • Categories: Nucleic Acid, Protein / Peptide
Technology overview
Several medical disorders are caused by an insufficiency of a gene product or a defective gene product. For example, lysosomal storage diseases are inherited metabolic disorders characterized by lack of sufficient enzymatic activity of lysosomal enzymes leading to abnormal accumulation of specific macromolecules that can lead to organ dysfunction or even organ failure. Enzyme replacement therapy (ERT) can be used as a symptomatic treatment. While beneficial, ERT is cumbersome as it requires patients to have bi-weekly IV infusion of the enzyme for the lifetime of the patient, affecting their quality of life. Thus, better treatment options are needed. To address this, Fred Hutchinson Cancer Center researchers have developed methods to engineer B cells to express a selected antibody and a gene product (secreted and non-secreted). The expression of the gene product is tunable and can be upregulated or downregulated to achieve safe, optimal and prolonged expression of the therapeutic product in-vivo.

FOLR1-directed CAR T Cell Therapy

CAR T cells to treat osteosarcoma, ovarian cancer, and high-risk pediatric leukemia

  • Stage: IND enabling work completed
  • Type: Cell Therapy
  • Categories: Immuno Oncology, Target, Vectors
Technology overview
The folate receptors FOLR1 and FOLR2 are overexpressed in multiple cancers. The overexpression of FOLR1 is often associated with increased cancer progression and poor patient prognosis in osteosarcoma, ovarian cancer, pediatric AML, etc. A cryptic CBF/GLIS fusion found only in infants drives a rare but highly aggressive type of acute myeloid leukemia (AML). Dr. Soheil Meshinchi’s group at Fred Hutch Cancer Center found that FOLR1, which encodes for folate receptor alpha, is highly and uniquely expressed in CBF/GLIS AML but is entirely absent in normal hematopoietic cells. Additionally, FOLR1 surface expression is shown to be causally linked to CBF/GLIS-induced malignant transformation, thus making it an attractive antigen for targeted therapies against CBF/GLIS AML cells. Dr. Meshinchi’s group has now developed FOLR1-directed CAR T cells for treating CBF/GLIS AML. In vivo experiments show that FOLR1-directed CAR T effectively eradicates CBF/GLIS AML cells without compromising normal HSPCs, providing a promising approach for the treatment of high-risk CBF/GLIS AML.

Gene Expression Biomarkers to Track Facioscapulohumeral Dystrophy Disease Progression

DUX4-dependent gene expression is a major molecular signature of Facioscapulohumeral Dystrophy (FSHD).

  • Stage: Pre-clinical in vitro, Clinical validation
  • Type: Diagnostic
  • Categories: Biomarker, Nucleic Acid
Technology overview
Facioscapulohumeral dystrophy (FSHD) is a human muscular dystrophy that initially affects the muscles of the face and upper extremities, but can progress to affect most skeletal muscles. Despite genetic evidence suggesting that DUX4 mRNA expression is necessary for FSHD, due to its low abundance in muscle biopsies, its critical role in disease pathogenesis has been questioned. Researchers in the Tapscott lab have studied biopsies from FSHD affected, and normal patients and have identified a panel of DUX4-dependent biomarkers that associate with clinical severity. These biomarkers could be used to monitor patients and also to assess the efficaciousness of new therapeutic entities that are currently in the clinic for FSHD.

Gene-level Metagenomic Analysis to enable Human Microbiome Therapeutic and Diagnostic Development

An end-to-end bioinformatic microbiome analysis tool using co-abundant gene groups to probe high-dimensional shotgun metagenomic data sets

  • Stage: Code fully developed and validated
  • Type: Research Tool
  • Categories: IT / Software
Technology overview
Observational studies on the gut microbiome have firmly established that the human gut microbiome affects health, disease, and response to treatments. However, the current analysis methods available for whole-genome shotgun (WGS) microbiome data does not effectively identify the underlying causal mechanisms, which are the critical next step to translate microbiome science into novel therapies. Moreover, existing gene-level metagenomics methods have been limited by the high dimensionality of the data generated. To address the limitations of current approaches, Dr. Samuel Minot has developed geneshot – a novel bioinformatics tool for identifying testable hypotheses based on gene-level metagenomic analysis of whole genome sequencing microbiome data. The high dimensionality issue of microbial protein-coding genes is solved by identifying the groups of genes with correlated levels of relative abundance across specimens (co-abundant gene groups). By applying geneshot to two independent cohorts, Dr. Minot was able to identify taxa and strain-specific genomic islands consistently associated with response to immune checkpoint inhibitor -based cancer treatment. Furthermore, geneshot identified specific possible mechanisms of action (type II secretion, TonB-dependent transport, and phage) that are potential novel strategies for intervention.

Immune Modulation of DUX4 in Cancer

DUX4 as predictive biomarker and therapeutic target to enhance the effectiveness of immunotherapies

  • Stage: Preclinical in vitro
  • Type: Diagnostic
  • Categories: Biomarker, Immuno Oncology, Target
Technology overview
Although immune checkpoint blockade therapies represent important treatments for cancer, most patients are non-responders or may relapse. The efficacy of these treatments relies on cytotoxic T-cell recognition of antigens presented by MHC Class I on tumor cells and can be reduced by suppression of antigen presentation or blunt tumor-immune interactions. Fred Hutch researchers have discovered that DUX4, a double homeobox transcription factor expressed normally only early in development, is a novel regulator of antigen presentation and immune modulation. They found that DUX4 is re-expressed in solid tumors, is associated with anti-tumor activity, and promotes resistance to immune checkpoint blockade. Therefore, DUX4 is useful not only as a biomarker for identifying patients that may respond to immunotherapies, but also as a target to increase the effectiveness of immunotherapies.

Immunosuppressive Regulatory T cells to Attenuate Autoimmune Disorders, Inflammatory Disorders, and Graft-versus-Host-Diseases

Methods to identify, produce, and elicit immune tolerance using TR1 cells

  • Stage: Preclinical in vivo
  • Type: Therapeutic
  • Categories: Immuno Oncology
Technology overview
Identification of the bona fide transcriptional and cellular control of Type-1 regulatory T (TR1) allows for the therapeutic utilization of these cells in diseases where excessive and aberrant immunity results in immune pathology. Dr. Geoff Hill’s group has developed a method to screen and identify TR1 cells that produce abundant IL-10 and Eomes. These FoxP3- immunosuppressive TR1 cells can be used for dampening undesired and excessive immune response that causes autoimmune diseases and tissue inflammation. Additionally, these TR1 cells can also be used to elicit immune tolerance to novel alloantigen in patients receiving bone marrow transplant (BMT), hematopoietic stem cell transplantation (HSCT), organ transplant, etc. Consistent with the findings in the mouse model, high Eomes and low T-bet expressing CD4+ T cells can identify a population enriched for TR1 cells and can discriminate healthy donors from BMT recipients. Furthermore, this method could be used to diagnose the presence of immune tolerance in a subject.

Immunotherapy for Kidney Cancer

Cellular immunotherapy targeting 5T4 to treat kidney cancer.

  • Stage: Preclinical in vitro
  • Type: Cell Therapy, Therapeutic
  • Categories: Immuno Oncology, Protein / Peptide, Target
Technology overview
Researchers at Fred Hutch are focused on developing novel kidney cancer immunotherapies. One of the main targets of this research is 5T4, a well- characterized kidney cancer marker that is found on the surface of almost all kidney cancer cells and rarely in a healthy cell. Work has been completed to validate 5T4 as a potential target. The team is now developing genetically engineered T cells that recognize and attack 5T4-bearing cancer cells using an optimized T-cell receptor (TCR). Their final goal is to provide a TCR-based immunotherapy for infusions of autologous T cells to treat kidney cancer. A recent clinical trial for a 5T4-based vaccine has shown no safety concerns from 5T4 being targeted by the immune system. The team’s TCR immunotherapy approach offers an improvement to the vaccine approach. A vaccine will only work in a minority of patients that already possess T cells that recognize the specific markers in the vaccine, whereas the TCR immunotherapy approach provides all treated patients with an arsenal of properly-targeted T cells.

Immunotherapy for the Treatment of Obesity

A method for using immunotherapy to identify, target and eliminate fat cells.

  • Stage: Preclinical in vitro, Preclinical in vivo
  • Type: Cell Therapy, Therapeutic, Gene Therapy
  • Categories: HSC Therapy
Technology overview
Currently, there are no treatments for obesity that directly target and eliminate fat cells (adipocytes). Dr. Stanley Riddell, in collaboration with colleagues at the NIH, have demonstrated that an anti-ROR1 CAR T is able to specifically recognize mature adipocytes and exert cytolytic activity. Interestingly, the only normal tissue that expresses the ROR1 protein on the surface of the cell is preadipocytes, progenitor fat cells, which make them an ideal therapeutic target for immunotherapy. Experiments in non-human primates also demonstrated the favorable safety profile of administering anti-ROR1 CAR T cells in vivo.

Kit for Detecting and Classifying Sexually Transmitted Infections based on the Genitourinary Microbiome

  • Stage: Preclinical in vivo
  • Type: Diagnostic
  • Categories: Biomarker, Microbiome, Nucleic Acid
Technology overview
A growing need exists to increase the detection and surveillance of STIs, especially among adolescents and adults of reproductive age. STIs can cause genital neoplasia (HPV), infertility (Chlamydia) and fetal and neonatal damage (Chlamydia, Neisseria gonorrhoeae syphilis). With the availability of reliable tests, asymptomatic infections can be detected early, and effective and appropriate treatment can be initiated to stop the spread of STIs. Drs. Srinivasan and Fredricks have developed kits and methods for detecting novel bacterial biomarkers associated with nongonococcal urethritis (NGU) in men, and for detecting vaginal bacteria and the risk of human immunodeficiency virus (HIV) acquisition in women based on a patient’s genitourinary microbiome (bacteria in the genital tract). Some agents of male urethritis can also cause pelvic inflammatory disease in women, leading to infertility in some.

MAIT Cell Immunomodulation for Targeted Treatment of Inflammatory Diseases

  • Stage: Preclinical in vitro
  • Type: Cell Therapy
  • Categories: Assay / Method
Technology overview
Mucosal-associated invariant T (MAIT) cells are non-conventional T cells that localize within inflamed tissue. Upon activation, MAIT cells act as effector cells with both cytotoxic and pro-inflammatory properties. The Prlic Lab determined MAIT cells have a unique transcriptional signature based on whether located within the blood or inflamed tissue. Conventional T cells activate through a TCR signal, however, MAIT cells require both TCR and inflammatory signals to elicit sustained effector function. They also established that an inflammatory signal could elicit CTLA-4 expression ex vivo, and that use of both TCR and inflammatory signals had a synergistic effect. Given MAIT cells detect bacteria-derived metabolites and not peptides, MAIT cells can be specifically targeted to alter CTLA-4 expression for immunomodulatory purposes.

Mesothelin-directed CAR T Cells for the Treatment of Acute Myeloid Leukemia

CAR T cells targeting mesothelin to treat Leukemia

  • Stage: Preclinical in vivo work completed
  • Type: Cell Therapy
  • Categories: Biomarker, Target, Vectors
Technology overview
Despite maximally intensive therapy, approximately 40% of patients with acute myeloid leukemia (AML) will relapse. An effective targeted therapy is still needed to save the lives of AML patients. Through computational interrogation of the transcriptome data, Dr. Soheil Meshinchi’s group discovered and validated mesothelin (MSLN) to be highly expressed on the cell surface of AML blasts and leukemic stem cells in a subset of AML patients. Specifically, MSLN is expressed in 36% of pediatric and adult AML patients and is virtually absent in normal marrow. Dr. Meshinchi’s group has developed MSLN-directed CAR T cells and preclinical in vivo experiments further establish that MSLN CAR T cells are highly effective in eliminating MSLN-positive AML cells in cell line and patient-derived xenograft models. Importantly, MSLN CAR T cells can target and eradicate MSNL-positive cells without impacting the viability of normal hematopoietic stem cells. These finding demonstrate that MSLN-directed CAR (T or NK cell) immunotherapy could be potential therapeutic candidates for MSLN-positive AML.

Methods to avoid Graft-versus-Host Disease after allogenic transplant

Methods to prevent or reduce GI tract inflammation by modulating the gut microbiome and immune system

  • Stage: Preclinical in vivo
  • Type: Therapeutic
  • Categories: Immuno Oncology
Technology overview
Allogeneic hematopoietic stem cell transplantation (HSCT) intends to cure high-risk hematological malignancies, immunodeficiencies, metabolic disease, or a life-threatening bone marrow failure syndrome. Despite substantial advances, graft-versus-host disease (GvHD) is a major contributor to morbidity and mortality after allogenic HSCT. The intestinal epithelial cells (IECs) in the gastrointestinal (GI) tract plays a critical role in driving the pathogenesis of acute GvHD, which occurs within the first few months following transplantation. Dr. Geoff Hill’s group has developed methods of reducing the risk of GvHD by (i) modulating the subject’s microbiome via administration of antibiotics, probiotics, or fecal transplant, and/or (ii) by reducing the activity of an inflammatory cytokine by administering cytokine inhibitor(s), and/or (iii) by reducing the expression of MHC II on intestinal epithelial cells in the subject by administering innate defense regulators and host defense peptides. These methods are developed based on the finding that IECs presented alloantigen to CD4+ T cells, which is crucial in initiating GvHD. Additional In vivo mouse experiments demonstrate that inhibition of microbiota-driven IL-12 pretransplant was sufficient to attenuate MHC class II expression by IECs and prevent acute GvHD lethality. In order to reduce the risk of GVHD in a transplant recipient, a composition addressing the above approaches can be administered to the subject before transplantation and preferably prior to conditioning therapy.

Methods to expand and manipulate hematopoietic stem and progenitor cells

Culture strategies for cost effective, ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs) with enhanced in vivo repopulating ability.

  • Stage: Preclinical in vitro
  • Type: Cell Therapy
  • Categories: HSC Therapy
Technology overview
HSPCs can be used to treat over 70 types of diseases including a variety of hematological disorders through transplantation and genetic therapies. Insufficient numbers of HSPCs introduced during transplantations prolong engraftment which can limit the use of single-unit patient samples. Ex vivo expansion increases the dose of HSPCs and promotes rapid and sustained engraftment, which is critical to patient recovery and survival. Fred Hutch researchers have discovered several methodologies of generating higher numbers of HSPCs in a cost-effective manner by delaying differentiation and enhancing proliferation of HPSCs ex vivo. In one methodology, researchers activated the Notch pathway using Deltaext-IgG and inhibited the aryl hydrocarbon receptor using SR1 in cultured HSPCs. Furthermore, the team cultured HSPCs with a Notch agonist and a leukocyte immunoglobulin-like receptor B2 agonist. Both techniques significantly enhanced the generation of repopulating HSPCs compared to either reagent alone. These innovations allow for improved clinical access to HSPCs and HSPC derived products.

Methods to Target Hematopoietic Stem Cells for Ablation or Expansion

Luteinizing hormone receptor (LHR) binding agents and luteinizing hormone (LH) agonists to target and expand HSCs.

  • Stage: Preclinical in vitro and in vivo
  • Type: Cell Therapy, Research Tool, Therapeutic
  • Categories: Assay / Method, HSC Therapy
Technology overview
Hematopoietic stem cell transplant (HCT) has been curative for many cancer malignancies and monogenetic diseases. However, current clinical limitations include small number of true HSCs in the transplant graft and the need for genotoxic myeloablative conditioning regimens. Teams at Fred Hutch and Memorial Sloan Kettering have discovered a novel role of LH in HSC biology and have demonstrated expansion of primitive HSC populations in the presence of LH. Furthermore, the teams are developing novel therapeutic agents to target the LHR receptor to specifically ablate HSCs as a non-myeloablative conditioning regimen prior to HCT.

Monoclonal NKG2D Antibodies for the Treatment of Autoimmune and Inflammatory Disorders

  • Stage: Preclinical in vitro
  • Type: Therapeutic
  • Categories: Hybridoma / Antibody
Technology overview
A precise balance of effector T cell activity is required to maintain effective immune surveillance without initiating an autoimmune reaction. NKG2D is an activating receptor that interacts with MHC Class I MICA and MICB glycoproteins. Drs. Spies and Groh made the surprising discovery that rheumatoid arthritis and other immunoproliferative disorders are often associated with abnormal expression of NKG2D receptor in immune cells (particularly CD4+CD28- T cells). These cells are cytotoxic, secret large amounts of IFN-gamma and proliferate upon stimulation. The Spies Lab has developed two unique anti-human NKG2D monoclonal antibodies to specifically target the NKG2D receptor. Therapeutic immunomodulation can then be achieved through targeted cellular inhibition by contacting the cell with a cytotoxic agent (e.g., radioisotope, toxin, or drug).

Multimerized HIV gp120s for Vaccine Development

An engineered HIV Env glycoprotein that improves antibody-recognition potential for HIV vaccine development.

  • Stage: Phase I clinical trial ongoing:NCT05471076
  • Type: Therapeutic
  • Categories: Protein / Peptide
Technology overview
Dr. Leo Stamatatos and Dr. Roland Strong have developed a unique and promising approach to developing an effective HIV vaccine by engineering an HIV Env glycoprotein using specific gp120 modifications and multimerization strategies. This multimerized gp120 expands the germline (gl) VRC01-class antibody- recognition potential of the Env, as desired in vaccine development for HIV. HIV-1 broadly neutralizing antibodies (bNAbs) are antibodies capable of neutralizing HIV but efforts to elicit stimulation of such antibodies using recombinant Env (rEnv) have been unsuccessful. One of the reasons for the lack of success is thought to be the inability of the Env proteins used as immunogens to engage B cell receptors (BCRs) that encode the germline of VRC01-class antibodies.

Neutalizing Monoclonal Antibodies Against SARS-CoV-2 for COVID-19 Screening and Treatment

Development of neutralizing monoclonal antibodies (mAbs) that bind to the spike glycoprotein on SARS-CoV-2.

  • Stage: Preclinical in vivo
  • Type: Therapeutic
  • Categories: Protein / Peptide
Technology overview
The WHO declared COVID-19 a global pandemic as of March, 2020. The infection is caused by SARS-CoV-2, a beta coronavirus with 79.5% genome sequence identify to SARS-CoV. As of June, 2020. more than 400,000 people have died globally from COVID-19, and there remains no vaccine or approved therapeutic. The surface spike protein of SARS-CoV-2 binds ACE2 receptors on the surface of human cells. Once bound, the virus is able to enter the cell and translate RNA to produce more viruses. The SARS-CoV-2 envelope glycoprotein is a surface-exposed class-I fusion protein that has an ectodomain comprised of a receptor binding domain (RBD) subunit and a membrane-fusion subunit. Researchers at the Fred Hutch have developed neutralizing monoclonal antibodies capable of binding specific regions of the SARS-CoV-2 ectodomain. Drs. Stamatatos, McGuire, and Pancera have isolated 45+ monoclonal antibodies from serum samples derived from SARS-CoV-2 seropositive patients.

NKG2D Biologic to Reduce Immune Cell Activation

A multimeric decoy to block activation of NKG2D and treat autoimmune and inflammatory diseases, and for use in vaccine development.

  • Stage: Preclinical in vivo, Preclinical in vitro
  • Type: Therapeutic, Vaccine
  • Categories: Protein / Peptide
Technology overview
Dr. Roland Strong and Dr. Martin Prlic have developed a multimeric NKG2D decoy that will bind all NKG2D ligands and block the NKG2D pathway. NKG2D is a receptor expressed by immune cells which activates the immune cell upon ligand binding. While stimulation of NKG2D can be beneficial in some circumstances, its activation is associated with several autoimmune and inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and graft versus host disease (GVHD). NKG2D stimulation can also dampen the effectiveness of vaccine administrations. Blocking NKG2D stimulation can reduce immune cell activation as a treatment for autoimmune diseases, and for increasing vaccine efficacy.

NKG2D-Targeted Therapy for Ovarian Cancer

Therapeutic for ovarian cancer that targets NKG2D ligands and prevents binding and stimulating the NKG2D receptor.

  • Stage: Preclinical in vivo, Preclinical in vitro
  • Type: Therapeutic
  • Categories: Protein / Peptide, Target
Technology overview
Normally expressed by immune cells, subsets of human cancer cells co-opt expression of the NKG2D receptor to exploit the presence of its ligands on cancer cells for oncogenic/tumorigenic stimulation. One such cancer subtype is ovarian cancer (OC). Dr. Thomas Spies has demonstrated the ability to interfere with cancer growth by interfering with NKG2D ligand binding, while Dr. Roland Strong and Dr. Martin Prlic have developed a NKG2D heptamer that targets and binds all known human NKG2D ligands and prevents them from binding and stimulating the NKG2D receptor. The NKG2D heptamer significantly reduces NKG2D+ cancer cells in vitro and in vivo. OC is currently treated with toxic chemotherapy drugs (e.g., carboplatin and paclitaxel), which lose efficacy due to drug resistance.

NOD2 Mediated Thymic Regeneration Boosts Compromised Immune Function

  • Stage: Preclinical in vivo
  • Type: Therapeutic
  • Categories: Target
Technology overview
As the primary site for T cell development, thymic regeneration is critical for the renewal and development of immune competence following stress (e.g., conditioning required for hematopoietic stem cell transplant or cytotoxic cancer treatments). IL-22 and BMP4 secretion through innate lymphoid (ILCs)- and endothelial (ECs)- cellular activity have been established as important for thymic regeneration. However, the pathways that trigger these mechanisms are poorly understood. Dr. Dudakov established how NOD2 governs these pathways and that mice deficient in NOD2 show increased intrathymic levels of IL-22, IL-23, and BMP4. By targeting NOD2 expression, thymus regeneration could be induced in patients whose thymus has been damaged by age, infection, and cancer therapies (e.g., chemotherapy and irradiation).

Novel biologics targeting Siglec-8 to treat eosinophil-driven diseases

Fully human mAbs, bispecific antibodies, and NK CARs that target Siglec-8.

  • Stage: Preclinical in vitro experiments completed
  • Type: Therapeutic
  • Categories: Hybridoma / Antibody, Immuno Oncology, Target
Technology overview
Siglec-8 is a transmembrane protein expressed on mature eosinophils, mast cells, and (to a lesser degree) basophils. Excessive eosinophil and mast cell activity have been implicated in the pathology of multiple diseases, including atopic dermatitis, chronic rhinosinusitis, chronic urticaria, and eosinophilic esophagitis. Dr. Roland Walter’s group in the Clinical Research Division at Fred Hutch has developed multiple fully human Siglec-8 mAbs, bispecific molecules that can engage T cells and Siglec-8, and NK CARs that target Siglec-8. These biologics could be used as targeted therapies for patients with eosinophil or mast cell driven disease.

Novel Bispecific to Alter the Immunosuppressive Tumor Microenvironment

Compositions and methods of treatment of a novel bispecific reagent that targets Notch ligand to tumor sites.

  • Stage: Preclinical in vivo
  • Type: Therapeutic
  • Categories: Hybridoma / Antibody, Immuno Oncology
Technology overview
The tumor microenvironment (TME) consists of the complex ecosystem where cancerous cells reside and interact with their non-malignant neighbors, including immunosuppressive myeloid cells that hinder immune control of tumors. In particular, immunosuppressive macrophages lead to the resistance of tumors to immunotherapy, a valuable treatment against many different types of cancers. Although numerous approaches are under development to eliminate, or modify specific pathways within immunosuppressive myeloid cells, methods that alter the TME from an immunosuppressive to anti-tumor state could present additional therapeutic benefits. Notch signaling has been shown to polarize macrophages towards a pro-inflammatory (anti-tumor) state and away from an immunosuppressive state. However, development of a Notch activation approach to elicit this anti-tumor effect has not been considered, likely due to the lack of selective in vivo targeting. Hutch researchers have developed a bispecific protein which targets a high affinity Notch ligand to tumor cells, activating Notch receptors expressed on surrounding immunosuppressive macrophages, thereby shifting the TME from a pro-tumor to anti-tumor state; alterations which we believe will increase the penetrance and efficacies of various immunotherapies.

Novel Cancer/Testis Antigen: T Cell Epitopes of Short H2A Histone Variants

Short H2A histone variant epitopes commonly expressed in Diffuse Large B Cell Lymphoma to be used as immunotherapy targets

  • Stage: Preclinical in vitro
  • Type: Therapeutic
  • Categories: Target
Technology overview
By analyzing data from patients with a variety of cancers, Dr. Jay Sarthy’s group at Fred Hutch Cancer Center have identified short H2A histone variants as endogenous oncohistones and novel cancer testis antigens. The identified variants in short H2A (sH2A) histone have the ability to bind to common HLA alleles, thus acting as excellent targets for immunotherapy. By comparing sH2A variants with canonical sequences, the inventors have identified sH2A variants that are frequently associated with cancers, and are prominent in diffuse large B cell lymphoma (DLBCL). Development of transgenic T-cell receptors specific for these epitopes can be utilized for CAR T cell therapy to control tumor growth. Potential for T cell immunotherapies utilizing these novel epitopes can be used not only in treating Non-Hodgkin’s Lymphoma but could be utilized as treatment for multiple other cancers.

Novel Method Targeting the Tumor Microenvironment as Therapeutic Treatments for Metastatic Cancers

  • Stage: Preclinical in vivo
  • Type: Therapeutic
  • Categories: Biomarker, Target
Technology overview
Solid tumors and tumor cell clusters form intercellular cavities called Microlumen. These microlumen are enclosed pockets between two or more cancer cells that are bound by cell-cell junctions and separated from surrounding extracellular spaces. Cancer cells use the unique architecture of these Microlumen to restrict protein diffusion and aggregate growth factors. These mitogen reservoirs support tumor growth, promote metastasis, and elevate therapeutic resistance making cancer more difficult to treat. To overcome these obstacles, researchers at Fred Hutch have devised a method to identify and disrupt tumor cells’ Microlumen. Through targeted RNA interference (RNAi), pharmacological inhibition, and immunotherapy, Dr. Cheung and his research team can disrupt microlumen integrity and deprive tumor cells of growth sustaining signals. Microlumenal targeting creates a whole new approach in amplifying therapeutic efficacy (e.g., adoptive cell therapy) and improving prognosis for a wide spectrum of cancers.

Novel Treatment for Neuropathies and Neurodegeneration

Use of IL-17c as a novel neurotrophic factor can be applied to treat neurodegenerative disorders.

  • Stage: Preclinical in vitro
  • Type: Therapeutic
  • Categories: Protein / Peptide
Technology overview
Dr. Corey and his colleagues have discovered that Interleukin-17c, previously only known as a cytokine, is secreted by keratinocytes during HSV infection and acts as a neurotrophic factor for neural cells. They demonstrated for the first time, that IL-17c can promote neural cell survival, neural growth, and axon guidance. Use of IL-17c as a novel neurotrophic factor can be applied to treat neurodegenerative disorders, for example, neuropathies in the peripheral nervous system that cause weakness, paralysis, numbness or pain. Treatment using IL-17c can be applied to a vast array of patients experiencing neuropathies including those caused by diabetes, autoimmune disorders, tumors, heredity, infections, chemotherapy, medications, toxins, and trauma.

Portable and Disposable, Single-Use Snap Freezing Device to Preserve Biospecimen Integrity

  • Stage: Preclinical in vitro
  • Type: Research Tool
  • Categories: Biomarker, Immuno Oncology, Metabolomics, Protein / Peptide
Technology overview
Collection and processing of high-quality tissue biopsy samples are critical steps for accurate diagnosis, monitoring, and treatment. The current gold standard of snap-freezing tissue specimens in liquid nitrogen has multiple limitations, including access to liquid nitrogen, trained personnel, and/or the infrastructure to support this method. As a result, biospecimens are subjected to prolonged warm ischemia, leading to changes in the activation states of biological pathways and compromising biospecimen integrity. These potentially altered biological pathways can be direct targets of anti-tumor agents and may be important clinical biomarkers. Moreover, variation in freezing protocols affects freezing rates that can also alter the specimen’s integrity. Dr. Paulovich has designed a simple, economical, and single-use biospecimen snap-freeze device that has demonstrated favorable performance characteristics compared to the traditional liquid nitrogen method.

Pre-clinical and Clinical Development of Serotherapy for Cytomegalovirus (CMV) Reactivation after Transplantation

Methods and tools to treat CMV reactivation in immunosuppressed patients using serotherapy

  • Stage: Preclinical in vivo
  • Type: Therapeutic
  • Categories: Immuno Oncology
Technology overview
Cytomegalovirus (CMV) is a common virus that infects 50-80% of the population by age 40. Although symptoms are generally mild in patients with healthy immune systems, infection or reactivation of CMV is associated with significantly lower survival after transplantation. Despite monitoring and preemptive antiviral therapy, 50-70% of CMV seropositive transplant patients experience CMV reactivation and 5-10% develop life-threatening end-organ CMV disease. CMV infection and reactivation is currently treated with antiviral drugs or using adoptive T cell immunotherapy to mitigate the impact of infection and reduce disease. However, antiviral therapies are limited by toxicity and the emergence of drug resistant CMV strains. Using a novel mouse model of CMV reactivation, Hutch researchers found that anti-CMV antibodies produced by the humoral immune response are sufficient to inhibit or prevent CMV reactivation prior to the generation of antigen-specific T cell responses. Specifically, CMV serotherapy confers high level protection and is effective even during GVHD if strain specific antibodies are used.

Pretargeted radioimmunotherapy for the treatment of Multiple Myeloma & B cell malignancies

Anti-CD38 and anti-BCMA bispecific antibodies deliver targeted radioimmunotherapy and avoid systemic toxicity.

  • Stage: Preclinical in vivo
  • Type: Therapeutic
  • Categories: Hybridoma / Antibody, Immuno Oncology, Target
Technology overview
Pretargeted radioimmunotherapy (PRIT) differs from conventional RIT in that a nonradioactive bispecific targeting antibody is first administered allowing for localization in tumor sites. Then a low molecular weight radioactive moiety (such as Y90) is added facilitating rapid tumor penetration, capture, and retention of Y90 by the pretargeted antibody. The rapid clearance of unbound radioactive molecules greatly decreases radiation absorption by healthy tissues. Multiple myeloma (MM) is an excellent candidate for PRIT due to the high degree of target expression (CD38 or BCMA) compared to normal myeloid and lymphoid cells. The Green Lab has constructed bispecific antibodies which target either CD38 or BCMA and have demonstrated their superiority over prior PRIT approaches. In preclinical studies, the CD38 PRIT clinical candidate cured over 75% of mice vs. 5% cured in the control group and showed similarly promising results in non-Hodgkin lymphoma.

Pretargeted Radioimmunotherapy for the Treatment of of Acute Myeloid Leukemia

  • Stage: Preclinical in vivo
  • Type: Therapeutic
  • Categories: Hybridoma / Antibody, Protein / Peptide
Technology overview
Pretargeted radioimmunotherapy (PRIT) is a two-step approach that delivers radioactivity separate from the initial targeting step. CD45 is a great target for PRIT as it is expressed on nearly all hematopoietic cells and negligibly expressed on non-hematopoietic tissues. Therapeutic efficacy was shown in AML previously when targeting CD45 using a streptavidin-biotin PRIT system, however, some expressed concerns, like endogenous biotin. Therefore, Dr. Orozco and colleagues developed a bispecific antibody targeting CD45 and 90Y-DOTA-biotin that showed survival benefits in two leukemia models. Initial proof-of-concept studies in the syngeneic murine leukemia model showed that mice treated with the murine 90Y-DOTA-biotin construct had a median survival of 43 days compared to 30 days for the control mice. Then in mice bearing human AML cells (HEL), 60% of the mice treated with the human CD45-90Y-DOTA-biotin construct survived 170 days post injection. Untreated controls and non-targeted negative control HEL-bearing mice required euthanasia due to tumor size at day 26 and 32, respectively.

Production of Malaria Vaccine Antigens by Increased Stability and Expression of Malarial Circumsporozoite Proteins

  • Stage: Preclinical in vivo
  • Type: Vaccine
  • Categories: Protein / Peptide, Vectors
Technology overview
Malaria is a life-threatening disease that resulted in 405,000 estimated deaths in 2018. Children under 5 years are most vulnerable, and account for 67% of all deaths worldwide. However, malaria is both preventable and curable. Nevertheless, resistance to antimalarial drugs and insecticides is a recurring problem that has severely impacted control and elimination of this disease. RTS,S/AS01 is a promising candidate vaccine, which completed Phase III trial, that has significantly reduced the incidence of malaria caused by the most deadly parasite, Plasmodium falciparum. It consists of a truncated form of a protein of this parasite, Plasmodium falciparum Circumsporozoite protein (PfCSP). Recent discoveries have shown that potent protective antibodies bind to epitopes of PfCSP not included in RTS,S. However, despite its significant advantages, expression of full length PfCSP, which includes these epitopes, in mammalian system consistently produce low yields. Dr. Pancera describes methods that increase the stabi lity and yield of the mutated form of PfCSP by 100-300%, containing all PfCSP domains. Some were truncated in the repeat domains to lower its immunodominance.

QuitBot, an innovative chat app to assist smoking cessation

A smoking cessation app that implements a novel virtual coach to answer users’ questions.

  • Stage: Pilot clincial trial completed; Phase III trial ongoing
  • Type: Health IT
  • Categories: IT / Software
Technology overview
Smoking remains a major public health challenge that leads to disease, premature death, and loss of productivity. Approximately 30% to 70% of smokers are interested in quitting, but in the US, less than 10% are successful at smoking cessation. Dr. Jonathan Bricker of the Public Health Sciences Division at Fred Hutch has developed an innovative smartphone app called QuitBot to help users stop smoking. QuitBot is unique for its use of natural language processing technology implemented in the form of a virtual coach. This virtual coach is trained with clinical knowledge of common questions asked by individuals attempting to stop smoking and can respond on demand to users. Following a pilot clinical trial with promising results, a Phase III randomized clinical trial is currently underway with over 220 individuals enrolled.

Selection and Use of Hematopoietic Stem Cells for Cell Transplantation and Gene Therapy Approaches

Defined population predicts and quantitatively correlates with in vivo engraftment and multilineage potential.

  • Stage: Preclinical in vivo
  • Type: Cell Therapy, Gene Therapy
  • Categories: HSC Therapy
Technology overview
Hematopoietic stem cells (HSC) are the preferred target population for ex vivo gene therapy with applications ranging from rare monogenetic diseases to HIV. Currently, HSCs are isolated by the marker CD34. However, use of this population has severe limitations. Fred Hutch researchers have identified a unique combination of genetic markers that defines a small subset within the CD34-expressing population, which represents HSCs with self-renewing capacity, multilineage potential, long-term engraftment capability and is conserved between human and nonhuman primate. This method to isolate, expand, and manipulate HSCs has dramatic potential to reduce the cost of goods for manufacturing of gene and cell based therapeutics and provides a quantitative measure of graft potency.

Siderocalin Fusions Improve Protein Production in Clinically Relevant Difficult-to-Express-Proteins

  • Stage: Preclinical in vitro
  • Type: Therapeutic
  • Categories: Protein / Peptide
Technology overview
Difficult-to-express-proteins (DTEPs), like those folded through interwoven disulfides, are highly desirable due to their extreme biochemical properties and unique clinical applications. Although chemical synthesis has previously been employed to facilitate DTEP production, the process is expensive, time consuming, and protein dependent. Eukaryotic protein expression platforms struggle to produce crucial clinically relevant DTEPs due largely to errors in protein folding. Drs. Strong and Correnti have developed a novel high-throughput, large-scale biological production method that agnostically fuses siderocalin to a multitude of protein types. Siderocalin fusion facilitates enhanced protein folding, facilitating rapid protein expression and has been validated in over 600 protein types including Fab fragments.

Targeting Runx3 for the Treatment of Pancreatic Cancer

Novel therapeutic target to prevent metastasis of pancreatic cancer.

  • Stage: Target identification
  • Type: Therapeutic
  • Categories: Target
Technology overview
Dr. Hingorani and colleagues have discovered that RUNX3 controls the balance between local growth and metastasis in pancreatic ductal adenocarcinoma. By varying RUNX3 expression levels in vitro they found that RUNX3 functions to promote metastatic programs, and by silencing RUNX3 they observed decreased metastasis. In vivo experiments demonstrated that RUNX3 depletion significantly impairs the ability of tumor cells to seed and support secondary liver metastases. Importantly, Kaplan Meier survival curves revealed that human patients bearing tumors expressing high levels of RUNX3 had a significantly shorter (~50%) survival time than patients with low RUNX3 expressing tumors. This work identifies RUNX3 as a critical target for preventing pancreatic cancer metastasis.

TCR Cell Therapy Targeting MAGE-A1

High-affinity MAGE-A1-specific TCR for the treatment of multiple myeloma and solid tumors

  • Stage: IND enabling
  • Type: Cell Therapy, Therapeutic
  • Categories: Immuno Oncology, Target
Technology overview
The MAGE family are CTAs expressed in many tumor types and MAGE-A1 has been shown to directly drive tumorigenesis. Specifically, MAGE-A1 is expressed in about 50% of multiple myeloma, up to 60% in triple negative breast cancer, 30% in non-small cell lung cancer and up to 50% in ovarian cancer cells. Using a high throughput platform to identify high affinity native antigen-specific TCRs, investigators at Fred Hutch led by Dr. Chapuis have identified and generated engineered version of rare high affinity anti-MAGE-A1 TCRs specific that avoids some of the significant toxicity and off-target specificity seen using transgenic mice or amino acid substitutions in the HLA/peptide complex. Preclinical validation of these MAGE-A1 TCRs displayed strong cytotoxicity towards MAGE-A1+ cell lines and furthermore are active in both CD4 and CD8 T cells, demonstrating their high affinity nature. IND enabling work and vector (LVV) manufacturing has been completed.

TCR mimic CAR T cells targeting PRAME/HLA-A2

Chimeric antigen receptor (CAR) that bind Preferentially Expressed Antigen in Melanoma (PRAME) ALYVDSLFFL (ALY) / HLA-A*0201 (HLA-A2) to treat PRAME-expressing cancers.

  • Stage: Preclinical in vivo
  • Type: Therapeutic
  • Categories: Immuno Oncology
Technology overview
PRAME is aberrantly expressed in childhood and adult AML and is absent in normal hematopoietic cells, providing an ideal target for adoptive T cell therapy. Dr. Soheil Meshinchi at the Fred Hutch has developed CAR T cells targeting the PRAME antigen in AML (referred to as PRAME mTCR CAR T cells). This CAR includes a binding domain derived from the Pr20, and a TCR mimic antibody that recognize PRAME AYL epitope in complex with HLA-A2. These mTCR CAR T cells showed strong in vitro efficacy against HLA-A2 restricted AML cell lines expressing the PRAME antigen and primary AML patient samples. In vivo cell-derived xenograft models treated with PRAME mTCR CAR T cells demonstrated potent leukemia clearance and improved survival compared to unmodified T cell controls. Additionally, co-administering interferon gamma increased PRAME expression by cancer cells, which enhanced the cytolytic activity of PRAME mTCR CAR T cells. These results support the evaluation of PRAME mTCR CAR T cells in clinical trials for refractory/relapsed AML and in a variety of solid tumors

Therapeutic targets to treat Androgen Receptor Deficient and Low Prostate Cancers

Methods to treat Androgen Receptor Deficient and Low Prostate Cancers by targeting 4EBP1

  • Stage: Preclinical in vivo
  • Type: Therapeutic
  • Categories: Target
Technology overview
Prostate cancer is the second most common male cancer, affecting cells of the prostate glands. About 90% of these early stage prostate cancers are dependent on androgens for growth, so inhibitors of the androgen receptor (AR) are often used as a treatment. However, prolonged use of androgen deprivation therapy (ADP) transforms many hormone sensitive prostate cancers into lethal castration-resistant prostate cancer (CRPC), which is not entirely dependent on the presence of androgens to grow. While improved targeting of androgen receptors is now possible, which can slow progression of CRPC, the disease remains uniformly lethal. Therefore, a need exists for new therapeutics targeted for lethal AR-deficient prostate cancers. Using a several types of human and mouse model samples, Hutch researchers discovered a “molecular brake” known as 4EBP1 which is inactivated in AR-resistant tumors and propagates a growth promoting cell-signaling pathway. By introducing 4EBP1 mimics, they discovered that these compounds killed AR-low, but not AR high, cells as well as significantly reduced the growth and survival of AR-low prostate cancers in mice. Therefore, they have identified a druggable link between the AR and protein synthesis that could be targeted in AR-low advanced prostate cancers.

Therapeutic targets to treat Facioscapulohumeral Dystrophy (FSHD)

Methods to treat Facioscapulohumeral Dystrophy (FSHD) by modulating chromatin repression

  • Stage: Preclinical in vitro
  • Type: Therapeutic
  • Categories: Target
Technology overview
Facioscapulohumeral muscular dystrophy (FSHD) is a disease with no currently approved treatments characterized by progressive muscle weakness and atrophy. FSHD is caused by ectopic expression of Double Homeobox 4 (DUX4), a gene normally only expressed early in development. In somatic tissue, DUX4 expression is epigenetically silenced through the presence of repeated sections of DNA called D4Z4 arrays. Mutations in the number of D4Z4 arrays or in chromatin repressors of D4Z4 underlie the molecular etiology of FSHD. Fred Hutchinson researchers have demonstrated in both skeletal muscle and induced pluripotent stem cells that the Nucleosome Remodeling Deacetylase (NuRD) and chromatin assembly factor-1 (CAF-1) complexes are necessary components which repress DUX4 expression by binding to D4Z4 arrays. In addition, they show that DUX4 presence mediates Methyl-CpG-binding domain protein 3-like (MBD3L) factors, which reduce D4Z4-mediated DUX4 repression. Taken together, these findings identify specific complexes which modulate DUX4 expression and reveal novel therapeutic targets to treat FSHD.

Therapeutics and Diagnostics for Cancer Targeting a Novel TrkB Splice Variant

Methods to treat or diagnose a variety of cancers using agents targeting a novel TrkB splice variant

  • Stage: Preclinical in vivo
  • Type: Therapeutic
  • Categories: Hybridoma / Antibody
Technology overview
Cancer-driving mutations are found across a wide range of tumor types yet are often only present in a subset of tumor cells, making early detection and subsequent treatment difficult. Many cancer types are driven by the signaling pathways downstream of tyrosine kinase receptors such as Akt, Ras, and Stat. Previously developed therapeutics targeting specific kinases have been highly profitable, yet resistance often occurs due to alternative methods of activating tumor dependent downstream pathways. Inhibitors of the Tropomyosin Kinase Receptors (TRK) family encoded by NTRK genes, are currently used for treating tumors with Trk gene fusions but have limitations due to tumor resistance. Hutch investigators have discovered a novel splice variant of the tyrosine receptor kinase B (TrkB) protein, TrkB.T1, that is highly expressed across nearly all human cancers when compared to normal. Using a highly specific novel antibody they developed against this isoform, their in vitro and in-vivo data demonstrate that this TrkB isoform has a causal role in the development of many types of cancers, and that its forced expression drives multiple tumor types in mice. Therefore, TrkB.T1 provides a useful validated target for cancer therapeutics, as well as represents a biomarker for the detection and observation of a variety of cancers.

Treatment of brain tumors with combinatorial NAMPT inhibitors and NAD precursors

Methods to treat glioblastomas and other brain cancers with combinations of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors and nicotinamide adenine dinucleotide (NAD) salvage pathway precursors.

  • Stage: Preclinical in vitro
  • Type: Therapeutic
  • Categories: Small Molecule
Technology overview
Treating brain tumors remain a challenging target due to challenges associated with crossing the blood brain barrier, accessibility, rapid spread, and tumor complexity. For all brain tumors, including benign tumors, the five-year survival rate is 33 percent. This survival rate drops to 5 percent for glioblastoma multiforme, the most malignant brain tumor type. One promising avenue to target cancerous cells is to alter components of their metabolism, as cancerous cells seem to require higher levels of nicotinamide adenine dinucleotide (NAD), a cofactor central to metabolism, than noncancerous cells. Nicotinamide phosphoribosyltransferase (NAMPT) plays a key role in the biosynthesis of NAD and can be upregulated in a variety of tumor types. Unfortunately, these trials have had limited success due to dose-limiting toxicities and low efficacy, potentially due to alternative cellular pathways for NAD synthesis. Hutch researchers have discovered alternative pathways not present in some cancer cells, which allow non-cancerous cells to produce NAD. By treating with a combination of these salvage pathway precursors and NAMPT inhibitors, researchers can selectively eliminate cancer cells and increase the therapeutic index of NAD synthesis inhibitors in specific subtypes of cancer, which include a variety of glioblastomas.

Two-Step Immunization Strategy to Elicit HIV Neutralizing Antibodies

Two-step immunization process guiding the maturation of VRC01-like antibodies by accommodating a conserved position of Env, which is known to restrict CD4-binding sites.

  • Stage: Preclinical in vivo
  • Type: Vaccine
  • Categories: Protein / Peptide
Technology overview
VRC01-class antibodies are considered potent and broad neutralizing antibodies (bnAbs) for HIV-1 and are important in eliciting protective immune responses in HIV vaccines. Although VRC01-class antibodies mature along different pathways, the complementarity determining region (CDR) domains similarly recognize CD4-binding sites of Env, thus providing their bnAb activity. Efforts to guide antibody maturation elicited by germline-targeting still lack the ability to efficiently bypass the major challenge N276 steric obstruction. Drs. Stamatatos and McGuire have developed a two-step immunization scheme consisting of an immunization with a VRC01 germline-targeting immunogen core, followed by a boost immunization with a heterologous Core expressing N276-associated glycans. As a result, they have discovered how to produce VRC01-like antibodies that overcome steric block and that neutralize the autologous, tier 2 426c virus.
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