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MRC Toxicology Unit

 

Definition of the differential proliferative, tissue damaging and transcriptional responses  in endogenously TCR-triggered lymphocytes versus foreign antigen stimulated lymphocytes induced by checkpoint blockade

Dr James Thaventhiran MD

Inhibitors of immune checkpoints (ICP) have revolutionised cancer treatment, leading to durable treatment responses in a proportion of patients suffering from previously incurable cancers.  The efficacy of this class of drugs is dependent on their ability to trigger the patient’s cytolytic CD8+ T cells targeting tumour cells.  However, the broad immune stimulatory capacity of ICP-blockade is associated with a high rate of immune related (irAE).  The unpredictability of both efficacy and AEs in response to these agents is a growing concern. There are limited data relating to this heterogeneity of response and the development of irAE following administration of these agents.  I will use the following approaches to define the mechanisms leading to the development of irAE.

 

  1. Assessment of rare-patients with monogenic immune dysregulation leading to similar phenotypes as irAE to define candidate genes and pathways.

     

  2. A unique and novel murine system that clonally tracks, self-antigen responsive cells that could cause irAE, in which we can disrupt prioritised pathways identified from our above screening.

 

The pathogenesis of irAEs and the determinant of efficacious treatment response may be biologically linked, as the development of irAEs is predictive of efficacy1, 2. A starting point in this fellowship has been our identification that haploinsufficiency of the NFKB13 locus leads to the expansion of the same B lymphocyte population that predicts responsiveness to ICP blockade4.

 

1.         Kim, H.I. et al. Development of thyroid dysfunction is associated with clinical response to PD-1 blockade treatment in patients with advanced non-small cell lung cancer. Oncoimmunology 7, e1375642 (2017).

 

2.         Freeman-Keller, M. et al. Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes. Clin Cancer Res 22, 886-894 (2016).

 

3.         Tuijnenburg, P. et al. Loss-of-function nuclear factor kappaB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans. J Allergy Clin Immunol (2018).

 

4.         Das, R. et al. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J Clin Invest 128, 715-720 (2018).