Technology-Driven Innovations for Engineered Cell Therapies

Technology Overview

Physician-scientist Andras Heczey, MD, leads a technology-driven, disease-agnostic research program to make immunotherapies safe, effective and patient-friendly. Using advanced synthetic immunology and genetic engineering methods, Dr. Heczey develops new strategies to direct a patient’s own immune system to respond rapidly and appropriately to diseases, including cancers.

A major focus of the Heczey Lab is armoring immunotherapy cells against factors in the tumor microenvironment that limit immune cell expansion and survival. These factors — which include cell surface checkpoint molecules, low oxygen or pH, or a lack of sufficient metabolites — suppress disease-fighting immune cells, including chimeric antigen receptor (CAR) T cells.

Dr. Heczey and team engineered armored CAR T and natural killer T cells to overcome immunosuppressive conditions by producing multiple cytokines such as IL-15 and IL-21 that boost survival, expansion and effectiveness of the therapeutic cells. Armored CAR T cells expressing IL-15 and also targeting glypican 3 (GPC3), which is overexpressed in many cancerous but not noncancerous cells, have been tested in clinical trials. The team found that the expression of IL-15 alone in GPC3-CAR T cells significantly increased their expansion and antitumor activity in children and adults with solid tumors.

To promote longer-term persistence and function of immunotherapy cells, Dr. Heczey is developing two technologies to regulate the expression of survival signals that overcome the limiting conditions of the tumor microenvironment. One strategy uses gene expression systems that respond to the presence or absence of small molecules. These compounds could be administered to patients to raise or lower production of protective cytokines or factors from other engineered genes introduced into immunotherapy cells. A second strategy uses cell-state dependent, bidirectional modulation of positive and negative regulators of T-cell function. The systems will sense changing conditions and respond by increasing or decreasing production of proteins that protect immunotherapy cells and counteract suppressive proteins.

To identify the most effective autonomous regulatory systems, the Heczey Lab developed an ORFeome library with open reading frames (ORFs) of all human transcription factors and epigenetic modifiers. The researchers are screening the library for the ORFs that are most effective at stimulating CAR T-cell therapeutic activity. The candidates with the most promise as disease-independent master T-cell regulators will be used to create synthetic gene expression regulator switches, or SynGERS, that can be tested for their ability to autonomously regulate CAR T cells under specific conditions.

The Heczey Lab is also collaborating with immunologist and virologist Bruce Torbett, PhD, to advance in vivo engineering of cells. Most current cell-based immunotherapies require a time-consuming process of extracting a patient’s cells, adding elements such as CAR and cytokine genes, expanding the engineered cells, and delivering them to the patient. This process, which can delay treatment for patients, is expensive, requires special facilities for manufacturing, and generates differentiated cells with potentially lower therapeutic capacity. The Heczey and Torbett Labs are creating modified viruses that will introduce packages of cell-modifying genetic components directly into cells within the human body (via injection or infusion) to engineer an immune cell population into therapeutic agents.

As the Scientific Director of Translational Research, Cell, Gene and Protein Therapeutics at Seattle Children’s Research Institute, Dr. Heczey is interested in partnerships that use his expertise in moving technologies from exploration and preclinical testing through multisite clinical trials.

Stage of Development

• Preclinical in vitro
• Preclinical in vivo
• Clinical trials

Partnering Opportunities

• Collaborative research and development
• Sponsored research agreement
• Consultation agreement
• Licensing agreement
• Clinical trials
• Investigator-initiated clinical trials

Publications

Caraballo G LD, Cevher Zeytin I, Rathi P … Heczey AA. DRIMS: A synthetic biology platform that enables deletion, replacement, insertion, mutagenesis, and synthesis of DNA. ACS Synth Biol. 2025;14(2):485-496.

Steffin D, Ghatwai N, Montalbano A … Heczey A. Interleukin-15-armored GPC3-CAR T cells for patients with solid cancers. Res Sq [Preprint]. 2024; rs.3.rs-4103623.

Heczey A, Xu X, Courtney AN, et al. Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results. Nat Med. 2023;29(6):1379-1388.

Batra SA, Rathi P, Guo L … Heczey A. Glypican-3–specific CAR T cells coexpressing IL15 and IL21 have superior expansion and antitumor activity against hepatocellular carcinoma. Cancer Immunol Res. 2020;8(3):309–320.