MICA: Regulatory T cells in Highly Sensitised Renal Patients to Improve Outcomes after HLA-Ab Incompatible Transplantation

Kidney transplantation is the best treatment for patients with kidney failure. Donor organs are allocated using various criteria, one of which is the presence of antibodies (Ab) against tissue antigens called HLA, which indicate whether potential recipients will mount an aggressive rejection response against a particular donor. Organs are not offered if any of the Ab react against a prospective donor. Dialysis patients with multiple Abs, who account for up to 1/3rd on the transplant list, can therefore wait a long time for a suitable donor. In our centre, we offer specialised treatment which allows Ab to be ignored by the allocation process. This involves use of more powerful drugs to suppress the immune system. Patients transplanted this way survive for as long as if they had chosen to wait on dialysis for a different organ, but still suffer high rates of rejection, and more of their transplants fail in the first few years, because of the more aggressive responses against HLA on the organ. Consequently, this approach is reserved for patients who need a transplant urgently and is offered by few other centres. A new approach is needed to improve outcomes for this group with multiple Ab. This study will test a new personalised approach, using the patient's own specialised white blood cells with natural suppressive properties (called 'regulatory T cells' (Tregs)) that we will purify and grow-up in the laboratory before infusing them back.
Our experience in patients with existing transplants suggests that Tregs are deficient in some, but when present, they can suppress aggressive responses to HLA. We have also taken out and expanded Tregs from several patients with kidney failure and given them back safely, shortly after transplantation, including the dose of cells we will use here. For this application we want to show that we can measure a suppressive effect of Tregs on responses to specific HLA before transplantation.
First, we will study the way that these patients respond to HLA, using lab tests that allow us to define whether Tregs are present and capable of suppressing the response. To continue beyond this point, we need to see a specific pattern of response in least 21 patients, but will recruit a few more to account for patients who want to drop out or who get offered a transplant. We will ask these patients to be randomly allocated to one of two groups. The first group of 12 will be administered Tregs immediately. The second group of 9 will get delayed Tregs, and whilst they are waiting, we will monitor them using our different immune tests, to try and understand how our measurements change with time and vary spontaneously, information that no-one has ever gathered before, but which is vital for us to be able to define a specific effect of Tregs. To generate the Tregs for treatment, recruits will undergo a dialysis-like treatment to isolate a large number of white cells from blood, from which we will isolate the Tregs, grow up in the lab, before we re-infuse them, in a single dose, a few weeks later. We will then describe the same immune monitoring measurements with reference to the controls, to determine whether our treatment changes the suppression of responses to HLA and changes the numbers and subtypes of Tregs. We have designed the trial so that we can stop the trial after treating the first group of 12 if Tregs appear to have minimal effect, but continue with treating the second group if Tregs appear to work, so that we can better define both the proportion showing suppression of HLA responses and the duration of the Treg effect. This study will inform whether a larger trial, which will need to include patients being transplanted, is feasible. If so, we hope we can then persuade other centres to get involved. Ultimately, we want to demonstrate that these Tregs will safely reduce rejection rates and prevent transplant failure, thereby helping more of these highly disadvantaged patients to get transplanted.

Kidney transplantation is the gold standard treatment for renal failure, offering better quality of life and survival compared to dialysis. 33% of patients awaiting a transplant are 'highly sensitised' to human leukocyte antigens (HLA), resulting in circulating HLA antibodies (Ab). For these patients, waiting time is doubled (to 6-7 yrs) compared to those without HLA Ab as organs are only offered when no Ab is present. Low levels of Ab can be ignored ('delisting'), or some Ab can be removed ('desensitisation') and we have shown that these approaches offer no survival disadvantage compared to waiting. However, the patients need more immunosuppression, have high rates of acute and chronic rejection and reduced graft survival, because alloreactive memory T and B cells specific for donor HLA are activated post-transplant.
We have shown that regulatory T cells (Tregs) can suppress memory responses in sensitised patients, and this associates with better graft survival. We have also confirmed the safety and favourable immunological effects of infusing ex vivo expanded polyclonal Tregs. Our ultimate aim, in a future trial, is to use autologous Tregs to improve rejection free-survival and post-transplant outcomes for sensitised patients. Here we will conduct an adaptive phase IIa trial in sensitised patients to demonstrate that we can use in vitro assays to show that Tregs can suppress CD4+ T cell memory responses to specific HLA. We will identify sufficient patients with such responses to dose with Tregs. Our design allows us to determine the spontaneous variation seen without treatment and to stop the treatment arm early if efficacy signals are weak. Defining the proportion in whom the treatment works and how long suppression lasts will directly inform the feasibility of a future larger trial comparing clinical outcomes after delisting or desensitisation using Tregs vs. standard care. We expect this future trial will show improved outcomes for this disadvantaged group.

The following groups will benefit from this research:

Patients: Patients with HLA Ab on the deceased donor organ waiting list should develop enhanced confidence in the fact that an organ they receive after delisting or desensitisation will be less likely to suffer rejection and may last longer. Importantly, those waiting a long time for a kidney transplant because of the presence of antibodies should feel reassured that work is being done to address their problems. We will continue our efforts - see below, to actively engage patients in all aspects of our research.

Transplantation scientists and clinicians: This research, if it shows efficacy of Tregs, will be of significant interest to scientists and clinicians interested in improving outcomes for other organs, including hearts, livers, lungs etc. We will continue to communicate our findings via the usual (and some unusual - see below) academic channels.

Organ Allocation agencies: This research will be of interest to organ allocation agencies as, if it promotes a wider use of delisting and desensitisation (as we expect), it may disrupt the modelling they have done around organ availability and equity of access. It is an integral part of our plans, to approach NHSBT to ask for assistance in modelling the impact of our findings on the waiting times for sensitised patients.

To ensure that above groups benefit from this research, information on the research will be disseminated via scientific engagement events, the MRC Centre for Transplantation website, publication in scientific journals, lectures, exhibitions, roadshows and online databases. We will regularly update the clinical trials ISRCTN registry and provide a link to the protocol and main results.

King's College London (KCL) has a robust track record of dissemination of information and communication with the public, through its high-quality comprehensive website which holds a "research portal", through which details of research and outputs are freely accessible. KCL embraces novel methods of disseminating information to the public such as through its Youtube channel, which showcases videos of wide-ranging activities, including a video dedicated to research in the MRC Centre for Transplantation.

Information about this research will be disseminated via scientific engagement events, the MRC Centre for Transplantation website, publication in scientific journals, lectures, exhibitions, roadshows and online databases. Another potentially important route will be via the Science Gallery (https://london.sciencegallery.com/), with whom we have had preliminary contact about the possibility of featuring our work in a future exhibition. We will regularly update the clinical trials ISRCTN registry and provide a link to the protocol and main results.

The MRC Centre for Transplantation has recently celebrated its 10th anniversary, in the form of a special edition of the course 'Frontiers in Transplantation - Clinical Excellence through Innovation'. This annual course, co-devised and co-hosted by the CI continues to showcase the innovative translational research taking place at KCL. In 2018, our programme of cell therapy for transplantation featured heavily and attracted a wide and international audience.

Guy's Hospital has one of the largest transplantation programs in the UK and is internationally recognised as a centre of excellence. We have established close links with the Guy's and St Thomas' Kidney Patients Association (GSTTKPA). The GSTTKPA has a website which features a page dedicated to research activities including specific details of Professor Dorling's research; a Facebook page and Twitter account; the "Kidneytalk" newsletter and a "MyKidneyCare" app for iPhone and Android devices.