Immunotherapy-Related Adverse Effects as Models for Fragile Tolerance in Humans

Using cancer patients experiencing immunotherapy-triggered autoimmunity as a unique human model, this project uncovers the molecular and epigenetic mechanisms by which self-reactive T cells escape immune tolerance.
Ongoing Other Adaptive Immunity Biological & Mechanistic Experimental Platforms & Models Functional Genomics & CRISPR Human Cohorts Immune Tolerance T Cell Biology

Funding Year: 2023

Project Overview

Under normal conditions, self-reactive T cells are eliminated through central immune tolerance — but in cancer patients receiving immunotherapy, this tolerance breaks down, triggering autoimmune adverse effects. This project uses that clinical phenomenon as a unique window into the mechanisms of fragile human immune tolerance. By comparing self-reactive T cells from affected cancer patients with those from healthy individuals, and applying gene editing to probe their activation, the team aims to identify the molecular and epigenetic changes that allow these cells to escape control — and ultimately find new ways to treat autoimmune diseases.

Impact & Innovation

A human model for tolerance breakdown

Cancer patients experiencing immunotherapy-related autoimmune effects offer a rare, clinically accessible window into how self-reactive T cells escape control — insights with direct relevance to autoimmune disease broadly.

  • Uncovers molecular and epigenetic mechanisms driving self-reactive T cell activation, with implications across multiple autoimmune conditions
  • Generates IP potential through CRISPR-based tools, blood-based diagnostics, and novel self-antigen identification via selection-based screening
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar by converting a clinical observation into a platform for autoimmune disease understanding and therapeutic development
Research Approach

Methods, sources, and focus

This project combines immunological profiling of patient samples with preclinical mouse modeling to investigate how glycosylation of anti-TNF biologics influences immune responses and drug efficacy in pediatric IBD patients. The work moves from patient cohort characterization through mechanistic analysis and in vivo validation.

Serum analysis of anti-glycan antibody responses in a large cohort of pediatric IBD patients treated with glycosylated biologics, comparative efficacy testing of human-sugar-coated versus mouse-sugar-coated drugs in a human-like mouse model, and statistical modeling to identify associations between glycan-specific immune responses and loss of drug response over time.

Serum samples from pediatric IBD patients treated with anti-TNF biologics including Infliximab, Adalimumab, and Golimumab; control healthy pediatric samples; anti-glycan antibody profiling datasets; and human-like mouse models for in vivo efficacy comparison of differentially glycosylated biologics.

Characterization of the relationship between foreign glycan recognition, anti-drug immune responses, and biologic efficacy in IBD, with the goal of generating clinical guidelines for personalized biologic therapy selection and dosing. Findings are designed to extend to broader applications in glycosylated biologic development across chronic inflammation-mediated diseases.

Investigators & Institutions

Powering the science

Principal Investigators

Asaf Madi, PhD, Colton Consortium Member

Professor, Gray Faculty of Medical and Health Sciences (Cancer Biology and Immunology), Tel Aviv University

Eric Shifrut, PhD, Colton Consortium Member

Assistant Professor, Pathology, Gray Faculty of Medical and Health Sciences, Tel Aviv Sourasky Medical Center, Tel Aviv University

Ido Wolf, MD, Colton Consortium Member

Professor, Oncology, Cancer Biology Research Center, Tel Aviv University

Colton Centers & Institutions

Colton Center for Autoimmunity at Tel Aviv University

Research Outputs

From insight to impact

  • Provisional patent submitted by Ramot (2025-022-01)