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ALLoRIGHT: A Tool for Predicting Allograft Risk of GvHD After Hematopoietic Transplant

  • Diagnostics

Project Overview

  • The identification of minor histocompatibility antigens (mHAgs) has the potential to improve outcomes in allogeneic hematopoietic cell transplantation (allo-HCT) by reducing graft-versus-host disease (GvHD) and enhancing graft-versus-leukemia (GvL) effects. 
  • Researchers at Dana-Farber Cancer Institute have developed the foundational components of the ALLoRIGHT platform, which integrates advanced computational methods to identify mHAgs and predict transplant outcomes.  
  • The technology could eventually have applications beyond allo-HCT, including solid organ transplantation, and may transform donor selection processes in the future.  
  • Opportunities for collaboration, development, and licensing are available to further advance this innovative approach. 

Background

Allogeneic hematopoietic cell transplantation (allo-HCT) is a powerful treatment for various hematological malignancies, leveraging donor immune responses to target and eliminate cancerous cells. 

Despite its curative potential, allo-HCT is often accompanied by graft-versus-host disease (GvHD), a condition where donor immune cells attack the recipient’s healthy tissues. GvHD affects a significant proportion of patients, leading to considerable morbidity and impacting quality of life. Current strategies to mitigate GvHD focus on human leukocyte antigen (HLA) matching and broad prophylactic measures, but these approaches have limitations in fully preventing adverse outcomes. 

The identification and understanding of minor histocompatibility antigens (mHAgs) have emerged as a promising avenue to refine allo-HCT outcomes. mHAgs are genetic variations between donor and recipient that can trigger immune responses, playing a dual role in both GvHD and the beneficial graft-versus-leukemia (GvL) effect. Historically, identifying mHAgs has been labor-intensive, involving single-cell cloning and biochemical methods. Further, establishing a consistent connection between patient-specific mHAg repertoires and clinical outcomes has been challenging. 

Technology

The ALLoRIGHT platform, developed through collaboration between Dana-Farber Cancer Institute and the Broad Institute, is an analytic tool designed to improve the identification and prediction of mHAgs in allo-HCT. 

Led by Nicoletta Cieri, MD, PhD, from the Department of Medical Oncology and a member of Catherine Wu, MD’s laboratory, the ALLoRIGHT platform aims to predict detrimental GvHD in blood cancers following hematopoietic transplant. The approach focuses on mHAgs derived from genetic differences between patients and donors, which influence both beneficial GvL and harmful GvHD effects. 

At the core of ALLoRIGHT is its AI-driven pipeline, which begins with whole-exome sequencing of germline DNA from both donors and recipients. This sequencing data is integrated with single-cell datasets and processed through advanced computational methods to systematically discover mHAgs while minimizing false positives. The AI component is designed to interpret the vast amount of genetic data, allowing for the identification of mHAgs relevant to each individual transplant case. 

While the foundational components of ALLoRIGHT have been developed and published in a 2024 Nature Biotechnology paper, the AI-driven aspects of the platform are still in development. Through collaboration with the Center for International Blood & Marrow Transplant Research (CIBMTR), which provided a curated repository of biospecimens from alloHCT donor-recipient pairs treated across all north American transplant centers, the team is refining their computational models to better learn patterns associated with GvHD and GvL outcomes.  

Once fully developed, the platform is expected to analyze organ-specific transcriptional and proteome-level expression to differentiate between mHAgs that may contribute to adverse effects like GvHD and those that enhance the beneficial GvL response. The ultimate goal of this project is to provide clinicians with improved donor-recipient matching tools for allo-HCT. 

ALLoRIGHT offers several advantages over traditional methods, significantly reducing the time and labor required for mHAg identification and providing faster, more accurate predictions. The tool’s ability to personalize treatment strategies based on individual genetic profiles represents a major advancement in transplant medicine, offering the potential to tailor prophylaxis and identify targets for post-transplant immunotherapy.

Team Members: Nicoletta Cieri, Catherine Wu, Yiren Shao

Applications

The primary application of the ALLoRIGHT platform is in the context of allo-HCT, where approximately one million procedures are performed annually worldwide. By optimizing donor selection and personalizing treatment strategies, the tool has the potential to significantly improve patient outcomes. 

In the future, the technology may also be adapted for use in solid organ transplantation, expanding its clinical utility. With around 170,000 solid organ transplants conducted annually, the potential impact of ALLoRIGHT could be substantial. 

Opportunities

Dana-Farber Cancer Institute is actively seeking development and commercial partners to further advance the ALLoRIGHT platform. Licensing opportunities are available for organizations interested in contributing to the development and integration of this promising technology. 

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Team Members