skip to content

 

Research Interests:

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).

Key Publications:

1. Lawless, D., Geier, C.B., Farmer, J.R., Lango, H.A… Thaventhiran, J., Walter, J.E., Savic, S.,  (2018). Prevalence and clinical challenges among adult primary immunodeficiency patients with RAG deficiency. J Allergy Clin Immunol.

 

2. Sng, C.C.T., O'Byrne, S., Prigozhin, D.M., Bauer, M.R., Harvey, J.C., Ruhle, M., Challis, B.G., Lear, S., Roberts, L.D., Workman, S.,…Thaventhiran, J.E.*, (2018). A Type III Complement Factor D Deficiency: Structural insights for inhibition of the alternative pathway. J Allergy Clin Immunol.

*Corresponding Author

 

3. Tuijnenburg, P., Lango Allen, H., Burns, S.O., Greene, D., Jansen, M.H., Staples, E., Stephens, J., Carss, K.J., Biasci, D., Baxendale, H.,…Thaventhiran, J.E*, Kuijpers, T.W*., (2018). Loss of function NFKB1 variants are the most common monogenic cause of CVID in Europeans. J Allergy Clin Immunol.

*Corresponding & Equal Contribution Authors

 

4. Staples, E., Morillo-Gutierrez, B., Davies, J., Petersheim, D., Massaad, M., Slatter, M., Dimou, D., Doffinger, R., Hackett, S., Kumararatne, D., Hadfield, J., Eldridge, M., Geha, R., Abinun, M.,Thaventhiran, J.E, * (2017). Diesseminated Mycobacterium malmoense and Salmonella infections associated with a novel variant in NFKBIA. Accepted in Journal of Clinical Immunology

*Corresponding Author

 

5. Dickinson, R.E., Milne, P., Jardine, L., Zandi, S., Swierczek, S.I., McGovern, N., Cookson, S., Ferozepurwalla, Z., Langridge, A., Pagan, S., et al. (2014). The evolution of cellular deficiency in GATA2 mutation. Blood 123, 863-874.

 

6. Thaventhiran, J.E.*, Fearon, D.T., Gattinoni. L. (2013). Transcriptional regulation of effector and memory CD8+ T cell fates. Current Opinion in Immunology. 25(3):321-8  *Corresponding Author.

 

7. Verma, N., Thaventhiran, A., Gathmann, B., Thaventhiran, J.E., Grimbacher, B., (2013). Therapeutic Management of Primary Immunodeficiency in Older Patients. Drugs and Ageing. 30 (7): 503-12

 

8. J.E. Thaventhiran, D. T. Fearon (2013) “Control of HIV infection: Escape from the shadow of Blimp-1”, Eur J Immunol. 43(2):323-6.

 

9. J.E. Thaventhiran, A. Hoffmann, L. Magiera,  M. de la Roche, H. Lingel,  M. Brunner-Weinzieri and D.T. Fearon (2012) “Activation of the Hippo pathway by CTLA-4 regulates the expression of Blimp-1 in the CD8+ T cell”,  Proc. Natl. Acad. Sci. USA. 109, E2223-2229 PMC3421161.

 

10. P.F. Yong, J.E. Thaventhiran, B. Grimbacher (2011) “A Rose is a Rose, but CVID is Not CVID Common Variable Immune Deficiency (CVID), What do we know in 2011.” Adv. Immunol. 111:47-107

 

11. M. Rizzi, C. Neumann, A.Fielding, R Marks, Si Goldacker, J. Thaventhiran, M.D. Tarzi, M. Schlesier, U. Salzer, H. Eibel, K. Warnatz, J. Finke, B. Grimbacher, HH Peter, M (2011) “Outcome of allogeneic stem cell transplantation in adults with common variable immunodeficiency.” J. Allergy Clin. Immunol. 128(6):1371-1374

 

12. J.M. Carr, M.J. Carrasco, J.E. Thaventhiran, P.J. Bambrough, M Kraman, A.D. Edwards, A Al-Shamkhani, D.T. Fearon, (2006) “CD27 mediates interleukin-2 independent clonal expansion of the CD8+ T cell without effector differentiation.”  Proc. Natl. Acad. Sci. USA. 103(51): 19454-9 PMC1697827
 

13. D.T. Fearon, J.M. Carr, A. Telaranta, M.J. Carrasco, J.E. Thaventhiran (2006) “The rationale for the Il-2 independent generation of the self renewing central memory CD8+ T cells.” Immunol Rev. 211:104-118

MRC Investigator

Contact Details

MRC Toxicology Unit
Gleeson Building
Tennis Court Road
Cambridge

CB2 1QR

Telephone and Email

+44 (0)1223 3 34492

Affiliations

Classifications: