Improving Immunotherapy With Novel T-Cell Engagers

Technology Overview

Dr. James M. Olson

Immunotherapy with bispecific antibody-based proteins that target both immune cells and cancer markers is effective against leukemias. Bispecific immunotherapy for brain and solid tumors, however, lags behind blood cancers because of delivery challenges and protective features in the tumor microenvironment. Pediatric oncologist James M. Olson, MD, PhD, is a physician-scientist and biotech cofounder whose research advances solid tumor treatment with antibody-based bispecific T-cell engagers (TCEs) and binders.

The Olson Lab, collaborating with protein engineer Jason Price, PhD, has diverse collections of fully human, highly specific binders of the T-cell activator CD3. The binders are nonpolyreactive, meaning they do not bind unrelated antigens. In vivo evidence demonstrates the ability of these CD3 engagers to boost recruitment and activation of T cells while reducing risk of cytokine release syndrome (i.e., cytokine storm).

Binding protein applications

With protein engineer Zachary Crook, PhD, Dr. Olson applied cutting-edge protein design to create a library of half a billion unique cysteine-dense peptides (CDPs), a class of stable, specific, low-immunogenicity miniproteins. One set of CDPs binds the immune suppressor PD-L1, some with picomolar affinity. Targeting PD-L1 turns a cancer-promoting feature into a vulnerability by neutralizing immune-evading, tumor-tolerating effects of cancers, particularly in solid tumors.

This approach also bypasses the challenge that pediatric cancers often are “immunologically cold,” with few mutations that provide unique tumor markers. Drs. Olson and Crook co-mentor a postdoctoral scholar in the Invent at Seattle Children’s Scholars Program who is working on next-generation TCEs that co-target multiple antigens on tumor cells to increase cancer specificity and reduce treatment toxicity.

By combining PD-L1 CDPs with CD3 binders, the Olson Lab can generate bispecific TCEs that eliminate tumors and extend survival in animal models. These therapies are allometrically safe at doses scaled to size for nonhuman primates. Data room access for information on CD3 engagers and PD-L1-CD3 bispecific binders is available on request. Additionally, CD3-PD-L1 TCEs could improve treatment of pediatric brain tumors with poor prognosis and aggressive adult cancers including lung, breast and colon cancers that metastasize to the brain.

Dr. Olson, with an Invent at Seattle Children’s postdoctoral scholar, leads a local immunotherapy program in collaboration with the Washington State University College of Veterinary Medicine, and the team has launched clinical trials of locally injected TCEs in canine patients. The team is collaborating with neurosurgeons, sarcoma and head and neck surgeons, and interventional radiologists at University of Washington Medicine to plan human clinical trials of slow-release, locally injected TCEs.

Additionally, the Olson Lab is collaborating with pediatric hematologist-oncologist Elizabeth R. Lawlor, MD, PhD, to add domains that bind the glycoprotein tenascin-C to bispecific TCEs. These domains deliver therapeutics to tumor microenvironments that express tenascin-C in the extracellular matrix. Tenascin-C TCEs have applications in metastatic tumors including breast cancer, prostate cancer, pancreatic cancer, glioblastoma, osteosarcoma, Ewing sarcoma and melanoma.

The modular protein engineering principles that the Olson Lab uses to create bispecific and multispecific engagers have other applications such as directing anti-inflammatory therapeutics, including to the brain. Dr. Olson has extensive experience working with industry partners and cofounding biotech companies. He is interested in partnerships to advance the development, preclinical and clinical testing, and delivery of advanced bispecific and multispecific therapeutic binding proteins.  

Stage of Development

• Preclinical in vitro
• Preclinical ex vivo
• Preclinical in vivo
• Clinical trials
• Early-stage manufacturing (for PD-L1-CD3 bispecific TCEs)

Partnering Opportunities

• Collaborative research and development
• Sponsored research agreement
• Consultation agreement
• Licensing agreements
• Clinical trial consulting

Publications

1. Simon S, Bugos G, Prins R … Olson JM, et al. Design of sensitive monospecific and bispecific synthetic chimeric T cell receptors for cancer therapy. Nat Cancer. 2025;6(4):647-665.
2. Jamet S, Zhang H, Ditzler S … Olson JM, et al. Affinity-tuned T-cell engager for dual targeting of B-myeloid mixed-phenotype acute leukemia (B-MPAL). Blood. 2024;144 (Supplement 1):90.
3. Nealy ES, Reed SJ, Adelmund SM … Olson JM. Versatile tissue-injectable hydrogels capable of the extended hydrolytic release of bioactive protein therapeutics. Bioeng Transl Med. 2024;9(5):e10668.
4. Wrenn ED, Price JP, Ruff RO … Olson JM, et al. Abstract C050: Leveraging ECM deposition by CAF-like Ewing sarcoma tumor cells to target micrometastases with matrix-binding VHHs.
   Cancer Res. 2024;84(22_Supplement):C050.
5. Crook Z, Girard EJ, Sevilla GP … Olson JM. Ex silico engineering of cystine-dense peptides yielding a potent bispecific T cell engager. Sci Transl Med. 2022;14(645):eabn0402.

Learn More

• James M. Olson, MD, PhD
• Olson Lab
• Olson Lab Therapeutics for Chronic Inflammatory Diseases
• Olson Lab Degradation of Pathogenic Proteins
• Olson Lab Drugs for Schizophrenia
• Brain Tumor Research Lab

Last updated March 2026