Improving transplant outcomes and cell therapy approaches
In this interview from Advanced Therapies Week 2024 (16-19 January; Miami, Florida), Diana Hernandez, the Head of Translational Immunotherapy at Anthony Nolan Research Institute and honorary Assistant Professor at the UCL Cancer Institute (both London, UK), discusses the research strategies the immunotherapy research group is employing to improve transplant outcomes and cell therapy approaches.
We also discuss how events like the Women in Advanced Therapies Pre-day are important for addressing gender equity challenges and reducing barriers to career growth in academia and industry.
You’re the group leader of the immunotherapy research group. Tell us a bit about the work that the group does.
We, at Anthony Nolan are interested in hematopoietic cell transplant (HCT) and specifically in how we can improve transplant outcomes. Anthony Nolan is the oldest stem cell register in the world (we turn 50 this year!). HCT is regarded as a curative therapy for many blood disorders, but only about 50% of patients will survive five years post-transplant. That is not because we have not gotten any better at it; it is because we are treating more and more patients using transplant. The two major reasons for this mortality are relapse and graft-versus-host-disease, which affects almost all patients who receive a transplant to some degree. We think these patients deserve better and so we are trying to look at how can we reduce comorbidities and complications to make that journey a little bit easier for patients.
What kind of research do you undertake to achieve this?
In the immunotherapy group we have two main project lines to address this. One is understanding the donor characteristics and the non-genetic factors that affect transplant outcomes (my colleagues in the Immunogenetics group look at genetic factors). This includes profiling donors and retrospectively exploring what factors impact clinical outcomes. We know, for instance, that age is a factor, but we do not understand the biological basis for this.
The second avenue is the development of cell therapies derived from umbilical cord blood. I have three programs in this line. One is the expansion of hematopoietic stem cells (HSCs) from cord blood. Cord blood is a very good source of stem cells for transplant it requires less stringent HLA matching, making them an attractive prospect to improve treatment equity for people who can’t find a perfect match from an adult donor – especially people from minority ethnic backgrounds. But generally, it is used less than peripheral blood from adults because units are not big enough to treat adults. So, it has been a holy grail to find ways to expand hematopoietic stem cells in vitro, whilst maintaining their functionality.
The other two programs focus on natural killer (NK) cells, again derived from cord blood. NK cells are really interesting immune cells because, unlike T cells, they do not require a specific target antigen. They are more indiscriminate in their killing. So we believe they are a better cell candidate for developing adoptive immunotherapies for the treatment of relapse in hematological malignancy and also for bridging patients so that they are eligible for transplant. Occasionally, patients cannot receive a transplant because their disease burden is too high. So, an NK cell therapy would be ideal in those cases.
To do this, we are looking at how we can effectively weaponize NK cells. Our research aims to improve their characteristics so that they are better at killing and last longer in the body. We’re also exploring means by which we can expand them ex vivo without compromising their potency.
And the final project focuses on cord-derived mesenchymal stromal cells. We want to understand how MSCs can be used to treat graft-versus-host-disease because these cells are proven to be really good immunomodulators, but we do not understand really how they do this.
We conducted a study on HLA-G, as a candidate molecule responsible for the immunomodulatory properties of MSCs, however, one of the problems is there are very few reagents to study it with. The HLA-G protein has seven isoforms, but there are no antibodies that distinguish between them, so studying them is very difficult. We have also started looking at the whole secretome of MSCs to understand the contribution of a broader variety of proteins secreted by these cells and learn how to really harness their potential for treatment.
What makes HSCs from cord blood so difficult to expand?
The difficulty with HSCs is that as soon as you put them in in vitro culture they lose their stemness. You can make loads of them, but they are just no longer stem cells and generally, as you culture these cells over a few days, they quickly lose their ability to engraft effectively. The issue isn’t generating cells but maintaining their efficacy. In contrast, other cord blood cells expand quite nicely. For example, NK cells are brilliant at expanding. It is just that you start a material that is always much smaller, hence the need for expansion. MSCs from cord blood also expand well and for more passages than the same MSCs derived from bone marrow, for example.
Looking ahead, what do you foresee as the key trends or areas of growth in immunotherapy research?
One of the biggest trends, and one that has been discussed at ATW, is moving away from using immunotherapy solely for oncology and exploring its applications in other areas, specifically autoimmune disorders, which is really interesting because it is almost counterintuitive. It would involve leveraging the immune system against itself.
And of course, expanding the oncology applications from hematological to solid tumors is a key area, along with transitioning from autologous to allogeneic approaches.
Anthony Nolan is a founding partner of Women in Advanced Therapies. How important is it to have specific sessions focused on women in the field?
I think it is important for two reasons. One is because women often feel there is no safe space for them to give their opinions. Feeling heard and valued in these settings is really encouraging and I wonder how many people, after having had a chance to speak in the round tables, then went to speak more confidently elsewhere.
Secondly, I think the sharing of experiences and the exploration of diverse career paths that women have taken to get to where they are is inspirational. Often women feel that if they take a pause in their career or change jobs that will prevent them from getting to where they want to be, especially in academic circles. And therefore, seeing other people who have moved around, even from different industries, shows us that we can still achieve what we want to. We also actually talked about failure during the roundtable and discussed that when you have a setback it is not necessarily a failure. So thinking about things that did not work out for us as a way of changing course as opposed to giving up. And I think that that is inspirational and shows that you are not the only one that things like this have happened to. And again, it is that kind of, I do not know, sisterhood, for lack of a better word.
Importantly, we do not want to swing the pendulum so far that we exclude men. We actually want men to attend these kinds of events because we want to tell them not only the kinds of things that we perceive as being discrimination but also we need advocates for things to change. It is not always the women that have to drive change. And if it comes from a diverse group of people, you are more likely to achieve that sort of change. So it was really important and really valuable.
What can the industry do to improve the proportion of women in leadership positions?
I think women are affected at all stages of their careers, especially in the research field because you cannot miss out on a year or even a month. Sometimes you take a few days out and you are already out of the loop. This challenge disproportionately impacts women due to factors like maternity leave and that creates an inequality from very, very early on.
One of the great gripes I have is the grant system. At the time when I was doing my second postdoc, there was a rule that you were not allowed to apply for fellowship if you had more than 9 years post-PhD. They had a cutoff. There were return-to-work fellowships available from, for example, the Wellcome Trust (London, UK), but they still had very limiting eligibility criteria.
I think that kind of system limits progression because then you are faced with a choice between career advancement and family obligations. Some people navigate this by pivoting into different roles or becoming exceptionally resilient, but it shouldn’t be a prerequisite for progress. So I think things making schemes for progression more accessible is really important.
Another issue is the lack of transparency and clarity of what it takes to make the next step in your career, especially in academia. The path from PhD to professorship isn’t always clear and informal networks tend to also play a role. I think this ambiguity disadvantages women more because they are less likely to put themselves out there and advocate for themselves as assertively.
If I knew that in order to get my next promotion I needed to do A, B and C, I would go quietly and do it and then show I had done it. So, I think that providing clarity on what it takes to advance would empower women to proactively pursue opportunities and reduce barriers to career growth.
The opinions expressed in this interview are those of the author and do not necessarily reflect the views of RegMedNet or Taylor & Francis Group.