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Manipulating the Immunopeptidome for Rapid Tumor Elimination

  • Therapeutics
  • 2025

Despite major advances in immunotherapy, many cancers still evade immune attack. Ellis L. Reinherz, MD, a researcher at Dana-Farber and Professor of Medicine at Harvard Medical School, and his team aim to change that by rethinking how T cells recognize tumors. Backed by a SPARK Accelerator grant, they’re leveraging decades of expertise in T cell biology—along with chemical synthesis and structural biology—to design a novel strategy that strengthens the immune system’s ability to target cancer. Their approach focuses on enhancing the role of T lymphocytes, particularly cytolytic T cells (CTLs), which recognize and destroy tumor cells displaying “foreign” antigens. These antigens are short protein fragments presented by HLA molecules—specialized proteins on the cell surface that show these fragments to T cells so they can detect and respond to threats. By improving this recognition process, the team hopes to overcome key limitations of current immunotherapies and expand their reach to more patients.

This work builds on a central principle in cancer research: harnessing the immune system to eradicate tumors. T lymphocytes have been at the heart of many immune-based therapies, including checkpoint inhibitors—drugs that release the “brakes” on T cells and have transformed treatment for cancers like melanoma and lung cancer. Reinherz’s strategy seeks to push this paradigm further by improving how T cells identify and attack cancer cells, opening new possibilities for tumors that currently resist even advanced immunotherapies.

Understanding Tumor Immune Evasion

Understanding why tumors evade immune detection is critical to this effort. Many cancers manipulate the peptides they display to avoid recognition. Some suppress potential foreign targets from the outset, while others adaptively restrict mutant peptide expression once CTLs begin their attack. Using mass spectrometry, the team analyzed data from more than 5,000 patient samples and found that few, if any, tumor-associated antigens—or neoantigens—they assessed are displayed. This means the immune response is severely limited for most cancers, underscoring the need for new strategies to overcome this barrier.

Modifying the Immune Response to Cancer

To address the stealthiness of cancer cells, the team is developing a method to increase the diversity ofpeptides associated with HLA molecules on tumor cells, thereby improving the likelihood that our immune system can recognize tumors as foreign and mount an immune attack. Their approach involves the identification of drug-like small molecules that can bind to HLA molecules and dramatically alter the array of peptides presented to CTLs. This increases the chance that immunogenic peptides will be expressed and subsequently recognized and killed by our immune system. Hundreds of new peptides may be expressed on tumor cells following treatment with novel small molecules identified by Reinherz’s team, potentially generating a large, diverse T cell response and increasing the probability of therapeutic benefit.

Preclinical data indicate that treatment with newly identified small molecules can cause a significant shift in the immunopeptidome—the full set of peptides presented by HLA molecules—on cancer cells. Proof-of-concept has been achieved with one HLA molecule. Using AI-guided drug design, the team plans to extend this approach to a total of 40 HLA molecules, covering virtually all racial and ethnic populations globally.Targeted Delivery with Antibody-Drug Conjugates

To ensure the specific delivery of these compounds only to tumor cells, the team is developing antibody-drug conjugates (ADCs) designed to bind to specific cancer cell surface markers and release the small molecule as a pharmaceutical payload. This targeted delivery system will alter peptide display selectively on tumor cells. By creating ADCs that target the 12 most common cancers, the team is building a generic toolkit for cancer therapies.

Toward a Broadly Applicable Therapeutic Platform

With this conjoint approach—combining peptide modulation and targeted delivery—the team aims to change the landscape of cancer treatment. In particular, the researchers hope to make cancers generally thought to not respond to immune–based therapy such as glioblastoma, pancreatic, ovarian, and breast cancers, among others, immunotherapy-responsive. The project benefits from Dana-Farber’s broad cancer expertise and collaborative research environment, involving oncologists and researchers across multiple cancer types. 

Team Members