MICA: A randomised, double blind, controlled mechanistic study of obinutuzumab versus rituximab in ANCA-associated vasculitis (ObiVas)
Lead Research Organisation:
University of Cambridge
Department Name: Medicine
Abstract
What is vasculitis?
Vasculitis is a rare medical condition that affects around 250 per million people in the UK. It is characterised by inflammation and damage to the walls of blood vessels. Blood vessels carry blood around the body supplying our organs with oxygen and nutrients. Thus, any organ can be affected by vasculitis, but some organs are affected more than others. For example, the kidneys, lungs, ear nose and throat regions are commonly affected.
Vasculitis is a so-called 'auto-immune' disease where the body's own immune system attacks itself (blood vessels in this case) instead of defending them against infection. Without treatment, inflammation causes the affected organs to stop working. Patients can become very unwell and can die if proper treatment is not started quickly.
Research has shown that a certain type of immune cell (B cell) produces Y-shaped proteins (antibodies called ANCAs) which are important in starting the inflammation. We also know that another cell type (T cell) seems to be overactive and misbehaving in patients with vasculitis.
The problem.
The current best treatment is a medicine called rituximab, which is given directly in the vein by a drip. Rituximab gets rid of B cells from the blood. Patients feel better quite quickly after rituximab, but after about 6-12 months, the inflammation starts up again, so more and more rituximab is needed, which can cause unwanted effects to the immune system in the long-term.
Our solution.
We have looked at samples of tissue taken from the inside of the nose in patients who have received rituximab. We have shown that B cells are still present, suggesting that rituximab is not working as well as we need it to. Furthermore, we have used cutting-edge genetic analysis to show that B cells in the nose are interacting with the T cells. Our theory is that the inability of rituximab to get rid of the B cells in the tissues, allows the mechanisms driving the disease to continue which is why rituximab cannot make the vasculitis go away for a very long time.
There is a new medicine called obinutuzumab that also targets B cells but has been engineered to use slightly different mechanisms. Animal studies show greater reductions of B cells in tissues compared to rituximab, and clinical trials in humans have shown that obinutuzumab works well for some blood cancers and another autoimmune disease (lupus). We think that using obinutuzumab in patients with vasculitis will lead to better targeting of B cells in the tissues, resulting in less interaction between B cells and T cells, and better control of vasculitis and inflammation.
We propose a small experimental study of rituximab versus obinutuzumab in patients with vasculitis. We will give 6 patients the normal medicine and 6 patients the new medicine. Each patient will have a biopsy of the inside of the nose before treatment and 3 months after treatment. We will be able to assess the effects of the two medicines in terms of their ability to get rid of the B cells inside the nose and the indirect effect this has on the T cells. We will then follow patients up for 2 years by which time the B cells should have returned in the blood. Through regular blood tests, we will be able to examine the type of the returning B cells, and whether or not obinutuzumab has made them less likely to cause the vasculitis and inflammation to return.
Importance and wider use.
This study will let us assess and compare the mechanism of action of these 2 medicines, and also dig deep into the processes that drive inflammation in the disease tissue. This is an important study because finding a better treatment than rituximab will improve the lives of patients with vasculitis. Furthermore, targeting B cells is a commonly used approach for many other diseases, so the findings of this study may improve the understanding and treatments of other autoimmune diseases.
Vasculitis is a rare medical condition that affects around 250 per million people in the UK. It is characterised by inflammation and damage to the walls of blood vessels. Blood vessels carry blood around the body supplying our organs with oxygen and nutrients. Thus, any organ can be affected by vasculitis, but some organs are affected more than others. For example, the kidneys, lungs, ear nose and throat regions are commonly affected.
Vasculitis is a so-called 'auto-immune' disease where the body's own immune system attacks itself (blood vessels in this case) instead of defending them against infection. Without treatment, inflammation causes the affected organs to stop working. Patients can become very unwell and can die if proper treatment is not started quickly.
Research has shown that a certain type of immune cell (B cell) produces Y-shaped proteins (antibodies called ANCAs) which are important in starting the inflammation. We also know that another cell type (T cell) seems to be overactive and misbehaving in patients with vasculitis.
The problem.
The current best treatment is a medicine called rituximab, which is given directly in the vein by a drip. Rituximab gets rid of B cells from the blood. Patients feel better quite quickly after rituximab, but after about 6-12 months, the inflammation starts up again, so more and more rituximab is needed, which can cause unwanted effects to the immune system in the long-term.
Our solution.
We have looked at samples of tissue taken from the inside of the nose in patients who have received rituximab. We have shown that B cells are still present, suggesting that rituximab is not working as well as we need it to. Furthermore, we have used cutting-edge genetic analysis to show that B cells in the nose are interacting with the T cells. Our theory is that the inability of rituximab to get rid of the B cells in the tissues, allows the mechanisms driving the disease to continue which is why rituximab cannot make the vasculitis go away for a very long time.
There is a new medicine called obinutuzumab that also targets B cells but has been engineered to use slightly different mechanisms. Animal studies show greater reductions of B cells in tissues compared to rituximab, and clinical trials in humans have shown that obinutuzumab works well for some blood cancers and another autoimmune disease (lupus). We think that using obinutuzumab in patients with vasculitis will lead to better targeting of B cells in the tissues, resulting in less interaction between B cells and T cells, and better control of vasculitis and inflammation.
We propose a small experimental study of rituximab versus obinutuzumab in patients with vasculitis. We will give 6 patients the normal medicine and 6 patients the new medicine. Each patient will have a biopsy of the inside of the nose before treatment and 3 months after treatment. We will be able to assess the effects of the two medicines in terms of their ability to get rid of the B cells inside the nose and the indirect effect this has on the T cells. We will then follow patients up for 2 years by which time the B cells should have returned in the blood. Through regular blood tests, we will be able to examine the type of the returning B cells, and whether or not obinutuzumab has made them less likely to cause the vasculitis and inflammation to return.
Importance and wider use.
This study will let us assess and compare the mechanism of action of these 2 medicines, and also dig deep into the processes that drive inflammation in the disease tissue. This is an important study because finding a better treatment than rituximab will improve the lives of patients with vasculitis. Furthermore, targeting B cells is a commonly used approach for many other diseases, so the findings of this study may improve the understanding and treatments of other autoimmune diseases.
Technical Summary
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is rare, autoimmune disease with a UK prevalence of 250 per million. The immunopathogenesis includes neutrophil activation by B-cell-derived ANCAs, activation of the alternative complement pathway, and dysregulated T-cell responses that result in a necrotizing vasculitis of small blood vessels. The only licensed therapy, rituximab, depletes B-cells and induces remission in 60-80% of patients, but repeated doses are needed to prevent relapses.
There is a dissociation between peripheral B cell depletion and the persistence of B-cells in the tissue after rituximab, with evidence of ongoing B and T-cell interaction and antigen presentation, which we have demonstrated using a safe and reliable nasal biopsy technique to provide sequential fresh tissue samples of a disease-relevant site in AAV. Incomplete tissue B cell depletion drives lower response rates and high relapse rates with rituximab therapy. Obinutuzumab, a Type II mAb also against CD20, is a more potent B-cell depletor than rituximab with superior tissue B-cell depletion in primates, and superior clinical efficacy in the treatment of haematological malignancy (phase III) and lupus nephritis (phase II).
We hypothesise that obinutuzumab use in AAV will (1) result in more effective B-cell depletion in the tissue, (2) attenuate the aberrant T-cell response, (3) delay B-cell reconstitution. To investigate these hypotheses, we propose an experimental medicine study comparing the mechanistic effects of rituximab versus obinutuzumab in AAV. We will randomise up to 20 patients with active AAV to either rituximab or obinutuzumab. Patients will be followed up for 18 months. Baseline and 3-month nasal mucosal biopsies will enable evaluation of the extent of B-cell depletion in the tissue, which is the primary objective of this study. Differential effects on B-T-cell interaction, subsets and activation status in the tissue will also be examined.
There is a dissociation between peripheral B cell depletion and the persistence of B-cells in the tissue after rituximab, with evidence of ongoing B and T-cell interaction and antigen presentation, which we have demonstrated using a safe and reliable nasal biopsy technique to provide sequential fresh tissue samples of a disease-relevant site in AAV. Incomplete tissue B cell depletion drives lower response rates and high relapse rates with rituximab therapy. Obinutuzumab, a Type II mAb also against CD20, is a more potent B-cell depletor than rituximab with superior tissue B-cell depletion in primates, and superior clinical efficacy in the treatment of haematological malignancy (phase III) and lupus nephritis (phase II).
We hypothesise that obinutuzumab use in AAV will (1) result in more effective B-cell depletion in the tissue, (2) attenuate the aberrant T-cell response, (3) delay B-cell reconstitution. To investigate these hypotheses, we propose an experimental medicine study comparing the mechanistic effects of rituximab versus obinutuzumab in AAV. We will randomise up to 20 patients with active AAV to either rituximab or obinutuzumab. Patients will be followed up for 18 months. Baseline and 3-month nasal mucosal biopsies will enable evaluation of the extent of B-cell depletion in the tissue, which is the primary objective of this study. Differential effects on B-T-cell interaction, subsets and activation status in the tissue will also be examined.
