Tissue tropism of PD-1 therapy in ulcerative colitis and rheumatoid arthritis
Lead Research Organisation:
University of Oxford
Department Name: Kennedy Institute
Abstract
Background:
Immune-mediated inflammatory diseases (IMIDs) such as Rheumatoid Arthritis (RA) and ulcerative colitis (UC) are characterized by an aberrant immune response which leads to chronic inflammation and damage to organs. They affect 5-7% of the Western population with numbers rising. While there are effective treatments available, medications lose their effect in almost half of patients treated, and there is no cure for these diseases.
IMIDs runs in families and people with disease in one organ such as the gut often get disease in another, such as the joints or skin, or even eyes. Why this happens is not clear but similarities in the types of side effects from patients treated with a drug that helps "cure" cancer called a PD1 antagonist, have given tantalizing clues as to the mechanisms that drive tissue tropism (i.e. which organs are affected by which diseases).
One molecule central to moderating inflammation is PD-1. Programmed cell death protein 1 (PD-1) is an immune checkpoint inhibitor present on immune cells (T and B cells) which upon activation dampens inflammation to promote immune tolerance. Dysregulation of PD-1 is thought to promote inflammation in both UC and RA and is thus a potential therapeutic target In the Phase 2 PARIS trial I am part of, we are testing the effect of a PD-1 agonist across UC, RA and Sjogren's syndrome.
However, there are several questions that cannot be addressed within the design of the PARIS trial. For example, the early direct effects of PD-1 therapy cannot be determined in this clinical trial setting, as the extended time interval between before and after therapy (3 months) gives room for indirect effects to take place. The proposed DPhil project will overcome this limitation and provide complementary insights on the mechanism of action of PD-1 therapy.
Aims and Objectives:
The aim of this fellowship is to map the direct effects of PD-1 therapy across UC and RA. New technologies are emerging which allow intact tissues, or individual cells and inflammatory molecules, to be studied in an experimental dish, using biopsies taken from patients' intestines and the joint. We will use these to determine the early cellular and molecular alterations that are a direct result of PD-1 therapy. To provide a complete insight into PD-1 biology in IMIDs, we will compare the effects of activating PD-1 with inhibiting PD-1. These tests will be extended to the tissue level, comparing effects of PD-1 therapies in inflamed and non-inflamed tissue of the intestine and joints.
Potential Applications and Benefits:
Potential benefits include insight into early mechanistic activities associated with therapeutic response and non-response to PD-1 therapy and inform therapeutic strategies to minimise possible adverse effects. Immunotherapies like PD-1 antagonists have revolutionized oncological management, but in some patients cause adverse events like gut or joint inflammation. PD-1 is also important in immune tolerance against infection and allergy. The findings form this fellowship will provide the insights required to tailor PD-1 therapeutic approaches to the individual setting. By this the project will not only benefit research into IMDIs, but also extend to research into cancer therapy, infections and allergies.
Immune-mediated inflammatory diseases (IMIDs) such as Rheumatoid Arthritis (RA) and ulcerative colitis (UC) are characterized by an aberrant immune response which leads to chronic inflammation and damage to organs. They affect 5-7% of the Western population with numbers rising. While there are effective treatments available, medications lose their effect in almost half of patients treated, and there is no cure for these diseases.
IMIDs runs in families and people with disease in one organ such as the gut often get disease in another, such as the joints or skin, or even eyes. Why this happens is not clear but similarities in the types of side effects from patients treated with a drug that helps "cure" cancer called a PD1 antagonist, have given tantalizing clues as to the mechanisms that drive tissue tropism (i.e. which organs are affected by which diseases).
One molecule central to moderating inflammation is PD-1. Programmed cell death protein 1 (PD-1) is an immune checkpoint inhibitor present on immune cells (T and B cells) which upon activation dampens inflammation to promote immune tolerance. Dysregulation of PD-1 is thought to promote inflammation in both UC and RA and is thus a potential therapeutic target In the Phase 2 PARIS trial I am part of, we are testing the effect of a PD-1 agonist across UC, RA and Sjogren's syndrome.
However, there are several questions that cannot be addressed within the design of the PARIS trial. For example, the early direct effects of PD-1 therapy cannot be determined in this clinical trial setting, as the extended time interval between before and after therapy (3 months) gives room for indirect effects to take place. The proposed DPhil project will overcome this limitation and provide complementary insights on the mechanism of action of PD-1 therapy.
Aims and Objectives:
The aim of this fellowship is to map the direct effects of PD-1 therapy across UC and RA. New technologies are emerging which allow intact tissues, or individual cells and inflammatory molecules, to be studied in an experimental dish, using biopsies taken from patients' intestines and the joint. We will use these to determine the early cellular and molecular alterations that are a direct result of PD-1 therapy. To provide a complete insight into PD-1 biology in IMIDs, we will compare the effects of activating PD-1 with inhibiting PD-1. These tests will be extended to the tissue level, comparing effects of PD-1 therapies in inflamed and non-inflamed tissue of the intestine and joints.
Potential Applications and Benefits:
Potential benefits include insight into early mechanistic activities associated with therapeutic response and non-response to PD-1 therapy and inform therapeutic strategies to minimise possible adverse effects. Immunotherapies like PD-1 antagonists have revolutionized oncological management, but in some patients cause adverse events like gut or joint inflammation. PD-1 is also important in immune tolerance against infection and allergy. The findings form this fellowship will provide the insights required to tailor PD-1 therapeutic approaches to the individual setting. By this the project will not only benefit research into IMDIs, but also extend to research into cancer therapy, infections and allergies.
Technical Summary
Ulcerative colitis (UC) and rheumatoid arthritis (RA) are immune-mediated inflammatory diseases (IMIDs) that are debilitating and have no cure. Primary or secondary loss of response to biologic therapies is seen in up to 40% of patients, suggesting that new approaches to treatment are needed.
An exciting new concept that is showing promise is antibody mediated agonism of checkpoint inhibitory molecules. One such molecule that is central to modulating inflammation in the gut and synovium is PD-1. Programmed cell death protein 1 (PD-1) is an immune-checkpoint inhibitor receptor expressed by many immune cells, in particular T cells. Agonising PD-1 may dampen inflammation and restore "immune tolerance" in both UC and RA by promoting the differentiation of regulatory T cells and restricting cytotoxic effects of peripheral (Tph) and follicular helper (Tfh) T cells and CD8+ T cells. However, the cellular changes that occur across different tissues, where the ratio of PD-1 expressing cells may differ significantly and where differences between PD1 agonism and antagonism may not be mirror images of each other has not been compared.
As a sub-investigator of the PARIS trial [ISRCTN31164692], a phase 2 basket trial, we are testing the the biological effects of a PD-1 agonist across UC, RA and Sjögren's syndrome. Through human ex-vivo perturbation studies using blood and precision-cut tissue slices from patients with UC and RA, this MRC Fellowship application will provide key mechanistic insights into the mode of action of PD-1 therapy that the clinical trial cannot answer.
Key objectives are:
1. Understand the early cellular and molecular alterations that are a direct result of PD-1 therapy
2. To contrast the biological effects of both PD-1 agonism and antagonism
3. To explore the differential effects of PD-1 therapy on inflamed versus non-inflamed parts of the intestine in UC and synovium in RA
An exciting new concept that is showing promise is antibody mediated agonism of checkpoint inhibitory molecules. One such molecule that is central to modulating inflammation in the gut and synovium is PD-1. Programmed cell death protein 1 (PD-1) is an immune-checkpoint inhibitor receptor expressed by many immune cells, in particular T cells. Agonising PD-1 may dampen inflammation and restore "immune tolerance" in both UC and RA by promoting the differentiation of regulatory T cells and restricting cytotoxic effects of peripheral (Tph) and follicular helper (Tfh) T cells and CD8+ T cells. However, the cellular changes that occur across different tissues, where the ratio of PD-1 expressing cells may differ significantly and where differences between PD1 agonism and antagonism may not be mirror images of each other has not been compared.
As a sub-investigator of the PARIS trial [ISRCTN31164692], a phase 2 basket trial, we are testing the the biological effects of a PD-1 agonist across UC, RA and Sjögren's syndrome. Through human ex-vivo perturbation studies using blood and precision-cut tissue slices from patients with UC and RA, this MRC Fellowship application will provide key mechanistic insights into the mode of action of PD-1 therapy that the clinical trial cannot answer.
Key objectives are:
1. Understand the early cellular and molecular alterations that are a direct result of PD-1 therapy
2. To contrast the biological effects of both PD-1 agonism and antagonism
3. To explore the differential effects of PD-1 therapy on inflamed versus non-inflamed parts of the intestine in UC and synovium in RA
