Penn Medicine’s Human-in-the-Loop AI Framework Discovers GPNMB as a New CAR T Cell Therapy Target for Solid Tumors

On June 25, 2026, Penn Medicine researchers led by Daniel Baker, Carl June, and Zoltan Arany published a landmark study in Cell describing a human-in-the-loop AI framework that integrates large language models (LLMs) with single-cell RNA sequencing data to systematically discover and prioritize new CAR T cell therapy targets . Their top candidate antigen was GPNMB (glycoprotein non-metastatic melanoma protein B), and GPNMB-directed CAR T cells showed significant anti-tumor activity in mouse models of melanoma, leukemia, and colorectal cancer . The framework is designed to be modular, disease-agnostic, and adaptable to any LLM, with the goal of dramatically accelerating target discovery for solid tumors and beyond — reducing what can take months or years to just a few weeks .

How the Human-in-the-Loop AI Framework Works

The research team developed a multi-step pipeline that combines computational power with expert biological oversight. Here’s how it works:

• Data Integration: The team combined four publicly available single-cell RNA sequencing skin cancer datasets with data from public databases, then applied specific biological guidelines to prioritize more than 10,000 potential surface antigens for CAR T-relevant features (e.g., tumor-specific expression, surface accessibility) .
• LLM-Based Nomination: Several frontier large language models were used to nominate ideal targets from that prioritized list .
• Repetition to Reduce Hallucination: The entire nomination simulation was independently repeated 1,000 times to mitigate known LLM risks such as hallucinations, and results were aggregated into a final shortlist .
• Human Expert Review: Scientists then reviewed the shortlist and performed biological validation — including surface expression confirmation, CAR construction, and preclinical testing .
• Speed: The entire AI-driven pipeline took less than a few weeks, compared to months or years with manual methods .

Top Antigen Identified: GPNMB

GPNMB (glycoprotein non-metastatic melanoma protein B) emerged as the top candidate from the framework’s rigorous nomination process . GPNMB is a type I transmembrane glycoprotein involved in melanogenesis and tissue repair. Targeting GPNMB with CAR T cells produced significant anti-tumor activity in mouse models of:

• Melanoma (skin cancer)
• Leukemia (blood cancer)
• Colorectal cancer

This multi-cancer efficacy suggests GPNMB-directed CAR T cells could have broad therapeutic potential across different solid and hematologic malignancies .

How This Approach Aims to Accelerate Target Discovery Beyond Blood Cancers

CAR T cell therapy has been revolutionary for certain blood cancers like leukemia and lymphoma, but progress in solid tumors has been slow due to the difficulty of finding safe, effective surface targets. This new framework was explicitly built to overcome that bottleneck:

• Disease-Agnostic Design: The framework is modular and generalizable to any cancer type or disease, not limited to the skin cancer datasets used for proof-of-concept .
• Works with Public Data: It runs on publicly available datasets, democratizing target discovery beyond institutions with access to clinical samples or proprietary sequencing technology .
• LLM-Agnostic: The framework is not tied to any specific large language model, meaning it can be applied to future, more advanced models as they emerge .
• Goal: The researchers explicitly designed the approach to break the bottleneck — finding safe, effective surface targets for solid tumors — which is the major barrier to expanding CAR T therapy beyond the blood cancers for which it is currently FDA-approved .

Why GPNMB Matters for Solid Tumor CAR T Therapy

Solid tumors present unique challenges for CAR T therapy: they are more difficult to penetrate, have a more hostile microenvironment, and frequently lack tumor-specific surface antigens. GPNMB is expressed on multiple solid tumors but has limited expression on healthy tissues, making it a promising candidate for targeted therapy. The Penn team is now positioned to advance this target toward clinical testing .

The Role of AI in the Study

This study is part of a broader trend where AI and machine learning are being applied to accelerate every stage of CAR T development — from target identification to vector design, manufacturing, and personalized clinical decisions . The Penn framework specifically uses LLMs to prioritize candidates from a large pool of potential surface proteins, then relies on human experts for the final validation and testing. This human-in-the-loop approach ensures that computational results are checked against real-world biology.

What This Means for the Future of Cancer Immunotherapy

By reducing the target discovery timeline from years to weeks and by making the process open to any research group with access to public data, this framework could significantly speed up the development of CAR T therapies for solid tumors. If GPNMB-directed CAR T cells perform in human clinical trials as they have in mouse models, this approach could open a new chapter in the treatment of cancers that have historically been resistant to immunotherapy.