Award Title: Identifying autoimmune signatures in patients receiving checkpoint immunotherapy
Funder: Cancer Research UK

Abstract: Background: Fighting cancer with immunotherapy represents a fundamentally different strategy to other treatment modalities. Its power lies in the ability to tap into the immune system's diverse antigen recognition potential and relax regulatory checkpoints that normally control immune activation. This results in the immune system attacking the tumour. The principle checkpoints that are targeted in cancer immunotherapy (CTLA-4, PD-1) are the very same that we have studied in the context of preventing autoimmunity. It is therefore unsurprising that a significant side-effect of cancer immunotherapy is the emergence of autoimmune adverse events. While some of these are easily treated using anti-inflammatory drugs, with the advent of combination therapy more severe side effects are evident, including the development of chronic conditions with significant patient impact such as autoimmune diabetes. There are presently no reliable ways to tell whether a patient receiving immunotherapy will develop autoimmune side-effects, and up to 40% of patients on combination therapy are forced to discontinue treatment due to adverse reactions.  Aim: The aim of our project is to take knowledge of T cell phenotypes obtained from patients with autoimmunity, including patients with CTLA-4 deficiency, and test whether this can be used to predict the development of autoimmune side-effects in cancer patients receiving immunotherapy. A major focus for the work is analysis of follicular helper T cells (Tfh) since we have extensive data suggesting that these T cells are modulated by immune checkpoints, particularly CTLA-4.   Methods: Fresh blood samples from 30 patients with advanced melanoma will be analysed at baseline then 3wk, 6wk and 12wk and after combined CTLA-4/PD-1 immunotherapy. Optimised flow cytometry panels will be used to provide detailed immunophenotyping information on peripheral blood cells, serum will be frozen for autoantibody and cytokine analysis and clinical data will be recorded. We will test defined hypotheses based on our expertise in CTLA-4/PD-1 biology and use in vivo models to help us dissect the therapy-induced changes we see.  How the results of the research will be used: A major challenge in the field of cancer immunotherapy is distinguishing desirable clinical responses from adverse events at an early stage. Predicting individuals who will benefit and those who may experience life-threatening side-effects is critical. The results will be used to help clinicians to make informed choices about which patients will benefit from continued immunotherapy and which show the hallmarks of burgeoning autoimmunity and might best be served by discontinuing or changing therapy.

Lay Abstract: Background: Fighting cancer with immunotherapy represents a fundamentally different strategy to other treatment modalities. Its power lies in the ability to tap into the immune system's diverse antigen recognition potential and relax regulatory checkpoints that normally control immune activation. This results in the immune system attacking the tumour. The principle checkpoints that are targeted in cancer immunotherapy (CTLA-4, PD-1) are the very same that we have studied in the context of preventing autoimmunity. It is therefore unsurprising that a significant side-effect of cancer immunotherapy is the emergence of autoimmune adverse events. While some of these are easily treated using anti-inflammatory drugs, with the advent of combination therapy more severe side effects are evident, including the development of chronic conditions with significant patient impact such as autoimmune diabetes. There are presently no reliable ways to tell whether a patient receiving immunotherapy will develop autoimmune side-effects, and up to 40% of patients on combination therapy are forced to discontinue treatment due to adverse reactions.  Aim: The aim of our project is to take knowledge of T cell phenotypes obtained from patients with autoimmunity, including patients with CTLA-4 deficiency, and test whether this can be used to predict the development of autoimmune side-effects in cancer patients receiving immunotherapy. A major focus for the work is analysis of follicular helper T cells (Tfh) since we have extensive data suggesting that these T cells are modulated by immune checkpoints, particularly CTLA-4.   Methods: Fresh blood samples from 30 patients with advanced melanoma will be analysed at baseline then 3wk, 6wk and 12wk and after combined CTLA-4/PD-1 immunotherapy. Optimised flow cytometry panels will be used to provide detailed immunophenotyping information on peripheral blood cells, serum will be frozen for autoantibody and cytokine analysis and clinical data will be recorded. We will test defined hypotheses based on our expertise in CTLA-4/PD-1 biology and use in vivo models to help us dissect the therapy-induced changes we see.  How the results of the research will be used: A major challenge in the field of cancer immunotherapy is distinguishing desirable clinical responses from adverse events at an early stage. Predicting individuals who will benefit and those who may experience life-threatening side-effects is critical. The results will be used to help clinicians to make informed choices about which patients will benefit from continued immunotherapy and which show the hallmarks of burgeoning autoimmunity and might best be served by discontinuing or changing therapy.

Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);7.1 INDIVIDUAL CARE NEEDS
Health Categories: CANCER AND NEOPLASMS