Expert Series: Dr Cameron Curley on transplantation and CAR-T therapy
Dr Cameron Curley describes CAR T-cell therapy as “arguably the biggest breakthrough in the treatment of many blood cancers in the last decade”.
“It’s an exciting time, when we have new evolving cellular therapies which offer hope for our patients,” said the Acting Director of Haematology and Bone Marrow Transplantation Cancer Care Services at the Royal Brisbane and Women’s Hospital (RBWH).
“CAR T-cell therapy is a real focus of our research unit because we see it as the future of treatment.”
And “the great hope” that bone marrow transplantation offers patients, when all other treatments had potentially failed, and “the connection that we form with our patients over long periods of time” is what initially drew Dr Curley to this challenging treatment.
At the end of his haematology training, during his fellowship at the RBWH, Dr Curley spent a year covering all aspects of transplant care, including research in this area of medicine.
“It’s a difficult, often very challenging treatment for our patients, but it comes at a time when people really need our help,” he explained.
Dr Curley stayed on at the RBWH, gained experience in treating a range of blood cancers, and joined the transplant team which he said, “has a lot of expertise in different aspects of transplantation”.
He developed an interest in managing relapse, which led to research to answer the question, “how do we manage relapse when a transplant doesn’t work?”, and to driving better ways of preventing graft versus host disease (GVHD) – “one of the major toxicities and risks of an allogeneic transplant”.
“Unfortunately, stem cell transplantation is not always successful, and it comes with great risks, so we’ve always been keen to find ways to better treat patients and prevent relapse.”
“We’ve been lucky, here at the Royal Brisbane, to be able to be a site where we can offer CAR T-cell therapy to our patients and to drive a whole suite of research around CAR-T, which we think represents a major pillar of cellular therapies for blood cancers moving forward.
“It’s an area that we’re heavily investing in, both people and research, moving forward.”
What is the difference between a bone marrow transplant (BMT) and a stem cell transplant (SCT)?
“That’s a common question, and a really good question,” said Dr Curley ,“because the name is quite different and the source of where the cells comes from is slightly different”.
“But the general basis of the treatment – its mechanisms, how it’s given, and the long-term outcomes – are not particularly dissimilar.
“The difference really comes down to where the donor cells come from. Does the donor donate bone marrow or peripheral blood stem cells?”
Over the last 20 years, Dr Curley said there had been “a great move” towards using less bone marrow as a donor source and instead, using stem cells collected through the peripheral blood.
“This is a far easier process for our donors and involves a less invasive procedure, so it does make some big differences to the donor,” he explained.
“And for the patient, it offers a greater number of stem cells to set up a new bone marrow to fight the blood cancer we’re trying to treat.
“So there is a key distinction and there are subtle differences in the procedure.”
“While we may choose a different source of where the cells come from – the bone marrow or the peripheral blood – overall, it’s a very similar procedure and process for the patient in the end.
“Traditionally, bone marrow transplant was the name of this procedure because, at the start of initiating this type of therapy around the world, bone marrow was the only source where the cells could be harvested from,” said Dr Curley.
“It was only with developments, that we increasingly started to use stem cells, but the procedure is very similar, so the name BMT has still remained at many centres around the world.
“Technically, most transplants done now are peripheral blood progenitor cell transplants.”
The different types of transplants
Dr Curley said that autologous stem cell transplantation is the most effective therapy for specific types of blood cancers, particularly for myeloma and many forms of lymphoma, but is used less frequently in other blood cancers.
“An allogeneic stem cell transplant, by its nature, is an immunotherapy that uses someone else’s immune system to target and fight an underlying blood cancer. It is most commonly needed and most effective in acute leukaemia,” he said.
“Whilst it can be used in myeloma, an allotransplant seldom is used in that scenario, given the presence of many other effective therapies now.
“And there are three stem cell sources for an allogeneic transplant – umbilical cord blood, peripheral blood or bone marrow.
“With the advent of newer and modern ways of doing allogeneic SCT, we’re increasingly using less cord blood,” said Dr Curley.
“The major concern with cord blood transplantation (CBT) now is the quite small number of stem cells that can be harvested from this donor source, and the risk of non-engraftment.
“These stem cells function very well for their numbers but often there’s a huge mismatch in the number of stem cells in the cord blood to the weight of a large recipient (80-90kg) who needs a far greater number of stem cells to achieve engraftment.
“This has been the major limitation when it comes to cord blood transplantation across the world and consequently it represents only a small minority of all transplants done today,” he said.
“CBT remains one of the many options but is reserved for rare circumstances, primarily in the treatment of children, nowadays, where it still has its best results.
“The number of recipients is often quite low and usually two umbilical cords are needed to do a transplant.”
Dr Curley said, “there are lots of different ways to describe a SCT and the first generally pertains to where the donor may have come from; the donor source”.
A SIB, is from a sibling, a VUD is from a voluntary, unrelated donor, and a haploidentical transplant is from a child, parent, or someone who is only half-matched at the key HLA proteins that are important for this procedure. Modern techniques using novel ways of preventing GVHD have enabled us to have similar outcomes with haploidentical and fully matched transplants.
“The intensity of conditioning can vary greatly depending on the disease we’re treating, the age of the patient, and whether they have other medical problems that make them more vulnerable to the toxicity of the chemotherapy.”
The least intense form of conditioning is called non-myeloablative and the most intense form is called myeloablative and that is usually reserved for younger people with acute leukaemia. In between we have reduced intensity conditioning. This is suitable for older patients with acute leukaemia who need slightly less intensive chemotherapy to make the procedure feasible for this patient group.
What qualifies someone for a BMT?
Dr Curley said the answer to this question is based on what is technically feasible from a safety point of view for a patient.
“That’s what really drives the decision about who should have a transplant or not. Unfortunately, there is a key relationship between age and mortality from the transplant itself,” he said.
“The risks of complications that frequently occur post-transplant and lead to a bad outcome increase as we get older.
“There are lots of modifications on how we do transplantation to find ways around this problem, and that’s where reducing the intensity of the conditioning has played a big role.
“When we’re deciding whether someone should have allogeneic SCT, we try to balance the risks of their disease against the risks of the procedure, which involves lots of different factors.
“Age is just one factor, but it’s really just a number as we get older. We’re increasingly more interested in the physiological age of our patient, which factors in an understanding of their comorbid health problems and baseline organ function,” said Dr Curley.
“How do they function in their life in lots of different areas; physically, mentally, and socially, and do they have support and the structures around them to keep them safe through a complicated procedure like this?
“Then lastly, a key thing is the assessment of organ function, to make sure it is sufficient to deal with the stress of the transplant procedure, because what is common during an allogeneic stem cell transplant is that the body at different times needs to overcome significant challenges,” explained Dr Curley.
“That requires the body to function in different organs well above what it would normally do to overcome those hurdles.
“These vulnerabilities tend to creep in more with age, but we are more interested in this concept of physiological age – how has life impacted on the patient and what is their ability and resilience to overcome the hurdles that come with transplantation?”
What are the risks of transplantation?
The risks of having an allogeneic stem cell transplant are “very much linked to the new immune system that the patient receives from their donor”, explained Dr Curley.
“That new immune system offers the hope of cure, with that new immune system fighting the underlying blood cancer.”
“But that new immune system also has the potential to recognise its new host (recipient) as foreign, and we call that reaction graft versus host disease, which still to this day represents one of the most significant challenges and is the number one risk of allogeneic stem cell transplant.
“It can cause a range of different symptoms, from a skin rash to significant inflammation of the gastrointestinal system (gut) or inflammation of the liver.
“We have a number of ways of trying to prevent GVHD including using medicines to suppress the new immune system and the absolute best donor care,” said Dr Curley.
“The best donor is the best matched at these key HLA proteins, so we match a younger, potentially male donor in some circumstances, and a related donor. These are all factors that minimise that risk.
“But sadly, despite finding what we think is the perfect donor and using all the therapies we know to prevent GVHD, a significant proportion of people still do develop this illness that needs quite intensive therapy to manage.
“The other risk that is linked to GVHD is infection, and that follows this procedure because our immune system is replaced with a new one, which needs to be kept quiet, and in that scenario, we’re very susceptible to infection. Surprisingly, this is often infection from within the body,” said Dr Curley.
“We live with a host of millions of bacteria every day, and the reason they cause us no harm is because we have a competent immune system. When we take away that, we do tend to see bugs from within causing issues that we need to manage.”
And there are risks from the potential late effects of the transplant procedure.
“Unfortunately for some people, the cure does come at some cost with potential effects on fertility, on the function of different organs, and the risk of secondary cancer.
“It is particularly important to offer our survivors comprehensive surveillance care to look out for these issues that can emerge, sometimes decades down the road.”
What are the latest advancements in transplantation?
It’s the ability to find a donor for almost every patient, that is the biggest advancement in transplantation.
“If we went back over a decade ago, sadly, there was a group of patients for whom, despite our best efforts, we could not find a suitable donor to do the procedure,” said Dr Curley.
“Luckily today, the advances in finding new ways of preventing GVHD, which have become far more effective, have allowed us to use donors that 10-15 years ago we could never have dreamed of potentially considering.
“This means that finding a donor for the vast majority of people is not a barrier today to having a stem cell transplant.”
“New and potent ways of preventing GVHD have allowed us to use donors that increasingly are not well-matched, to achieve a similar long-term outcome as a fully matched donor, which is a major breakthrough.
“The other is the vast improvement in supportive care and the treatment of graft versus host disease, which is translating into improved outcomes for our patients, and survival.”
The outcomes of stem cell transplantation
Dr Curley said it was very hard to generalise about what the outcomes of allogeneic SCT may be.
“This is because it relates to the specific type of blood cancer, what stage it’s at, and what therapy patients may or may not have had before.
“We’re increasingly recognising that each blood cancer has within it an increasing complexity about its genetic basis; the mutations that may have occurred that led to this cancer or have occurred in the progression of this cancer.
“All those factors have profound impacts on the success of the procedure,” he said.
“The other big factor that’s quite variable, is the health of the transplant recipient.
“The risks of autologous stem cell transplantation though, are a magnitude less than that of allogeneic SCT, and whilst infection can occur, the vast majority people survive the procedure and have engraftment of their stem cells, which is wonderful.
“Sadly though, for all forms of transplantation, relapse of the underlying cancer for which the SCT is being undertaken still is a major problem.
“Recurrence of the underlying disease is the most common reason for an autologous stem cell transplant to not be successful long-term.
“For allogeneic SCT, the risks of succumbing to the toxicities of the transplant have significantly reduced, but still range anywhere from 10% to as high as 25% for some patients.”
The decision to have a stem cell transplant
There’s a very individualised discussion that happens for each patient who comes in for this procedure, where a team of specialists assesses that risk and comes up with what they estimate the outcome will be, said Dr Curley.
“That’s a very important part of every discussion about whether patients wish to proceed with a stem cell transplant. This discussion between the specialist and the patient is about balancing the risks in the short-term and the consequences in the long-term balanced against the risks of not having the procedure.
“The decision about doing a stem cell transplant has to come from an exceptionally well-informed patient and family deciding that they are compelled to do this treatment, understanding the risks and benefits.”
The role of genomic testing in BMT
“We can use genomic testing to find the absolute best donor for a patient,” said Dr Curley.
“Today, we’re able to match our donors at an extremely high resolution by matching the HLA genes that are important in stem cell transplantation, and we believe that’s a significant contribution to the improved outcome for our patients. Previously, we looked at the proteins these genes express, which wasn’t able to achieve the same degree of high-level matching.
“The other use of genomics is in assessing patients’ blood cancers, looking for mutations that have occurred in the cancer itself,” he said.
“We call these somatic mutations (not inherited mutations) that develop within the cancer as it grows.”
Somatic mutations can provide a thorough understanding of the behaviour of that blood cancer after therapy, whether it has a high potential of recurring, or if it’s a condition that doesn’t need therapy, could it turn into a more aggressive condition such as an acute leukaemia?
“This means we’re now able to better estimate the risk of not having a transplant for our patients, so patients can be assured that the risk of an allogeneic stem cell transplant is worth taking when absolutely necessary,” said Dr Curley.
“Genomics is being used widely, particularly in the myeloid malignancies – acute myeloid leukemia, myelodysplastic syndromes, and myelofibrosis – to improve our understanding of prognosis and to guide timing around when is the best time to have a transplant.
The importance of a graft versus host response
Dr Curley said the reason why patients have an allogeneic SCT is to give them a new immune system to fight their blood cancer.
“We know that if patients have a degree of graft versus host disease, their immune system is recognising and mounting some reaction against their healthy tissues, and it’s more likely to be having a therapeutic reaction against the leukaemia itself.
“That is the irony here… that potentially having some form of GVHD means a patient is less likely to experience a relapse of their blood cancer. Mild forms of GVHD, thankfully, appear to have just as strong an effect against underlying blood cancer as more severe forms, but they have very limited effects on quality of life and are rarely likely to be a threat to a patient’s health,” said Dr Curley.
“Mild GVHD may be something as simple as a mild rash or a mild change in liver function tests that the patient may not have any symptoms of, but that is a reflection that this process is going on within the body.
“It can be of great benefit without any great sacrifice to the patient.
“At the other end of the spectrum, severe GVHD is quite a serious condition,” he explained.
“If it occurs in the first three months after a transplant and is not responsive to treatment, sadly, it can be fatal. If severe chronic GVHD occurs later, it has a potential risk of affecting a patient’s independence and quality of life through different impacts on mobility, endurance, or physiological reserves.
How is GVHD treated?
The treatment of GVHD depends on its severity.
“Very mild forms might only need a topical cream such as topical steroid,” said Dr Curley.
“When it becomes moderate to severe, it generally requires some form of immune-suppressing medicine that will work throughout the body. The most effective is corticosteroids which have a great benefit in treating GVHD for the vast majority of people.
“Unfortunately, they don’t work for all patients but there have been major developments with new therapies that have been shown to be more effective at managing GVHD when steroids fail, and that thankfully improves the outcome for our patients in this scenario.
The importance of immunoglobulin therapy
Dr Curley said immunoglobulin therapy is an important treatment for some patients with blood cancers, offering the opportunity of reducing the frequency and severity of some infections, and is most effective in combatting bacterial infections.
“Some patients who have had an allogeneic or autologous stem cell transplant may be deficient in many of the important antibodies we usually have that keep us well by preventing recurrent bacterial infections that can lead to hospitalisation,” he said.
“In that scenario, providing intravenous or even subcutaneous immunoglobulin can be quite beneficial.
“It’s important to note that not all patients should have or need immunoglobulin therapy because many patients, post stem cell transplant and after a brief period of immune system suppression have a very good recovery of immune function,” said Dr Curley.
“We call that immune reconstitution.
“We find a lot of patients gain no benefit from prophylactic immunoglobulin, so it should be reserved for people whose immune system is having trouble recovering. That’s where it can offer a bridge to a safer place for patients.”
Research underway in transplantation and CAR T-cell therapy
The prevention and treatment of GVHD is a key area of research for studies in allogeneic stem cell transplantation.
“We are part of an important national study, called CAST, across all the transplant centres in Australia, looking at finding novel ways of preventing graft versus host disease for our most successful transplant – matched sibling transplants,” said Dr Curley.
The aim of the study is to gain a “better outcome, longer-term, through use a novel way of preventing graft versus host disease”.
“We’re also involved in a multi-centre international randomised control trial utilising other new ways of preventing graft versus host disease for our transplants for patients with unrelated donors,” he said.
“And in the CAR T-cell therapy space, we are involved in a suite of investigator-initiated trials looking at different aspects of need. The most exciting is an important novel Phase I clinical trial, called the CARTEY trial, where we are producing CD-19 CAR T-cells in-house, for patients with relapsed/refractory B-cell malignancies who have no option of access to CAR T-cells in Australia.
“At the RBWH, we are fortunate to have local expertise to produce effective CAR T-cells onsite. They are not commercially manufactured internationally but are manufactured as part of a research project within our facility, here in Queensland,” said Dr Curley.
“And, flowing from that, we have a suite of studies looking at different aspects around CAR T-cell therapy, including assessments of how the immune system functions after CAR T-cell therapy, and a study looking at the neurocognitive effects of CAR T-cell therapy, both short-term and long-term.
“There’s a paucity of evidence about the long-term impacts of CAR T-cell therapy, and we think it’s crucial that we understand this important treatment.”
“We also have a study looking into patient-reported outcomes, to better understand what it really is like for the person who is going through CAR T-cell therapy.
“Other areas of study include looking specifically at the immune responses patients are experiencing to COVID vaccines, which overlaps with CAR T-cell therapy, to better understand when and how to vaccinate our patients. There are concerns about patients’ ability to mount immune responses to COVID vaccines after this therapy.
“Lastly, we have a number of international CAR trials that we’re participating in,” said Dr Curley.
“One, called NKARTA, is an important Phase I study using genetically modified natural killer (NK) cells. This therapy doesn’t require collection of patient cells prior to manufacture as donor NK cells can be provided off-the-shelf with some matching of key proteins, we call HLA.
“That’s a very exciting trial and we’re one of several global sites that are participating.”
Dr Curley mentioned there are other CAR-T trials open to recruitment locally including a “potentially practice-changing trial”, called CARTITUDE 5, that is currently recruiting in myeloma. This international randomised study is looking at the role of CAR T-cell therapy as part of frontline treatment in patients with myeloma who aren’t suitable for a stem cell transplant.
“It’s an important study and we are very excited about the ability to offer our myeloma patients this novel therapy as part of frontline treatment,” said Dr Curley.
“We have a team of basic science researchers, clinical researchers, and cellular therapy scientists all with interest and expertise in CAR T-cell therapy, who are driven to provide this treatment for our patients and doing this locally, here in Queensland, which is really important.”
About CAR T-cell therapy
Dr Curley described CAR T-cell therapy as “a potentially curative treatment”, saying it “definitely is not given as a palliative treatment”.
“The evidence is strongest for patients who have exhausted all other treatments but we are increasingly seeing signs that the earlier in the treatment course that CAR-T can be provided potentially will lead to better outcomes,” he said.
“At this time, when used as the last line of therapy in some lymphomas, for the majority of people, unfortunately, it is not effective, but still, a significant proportion of people who have no other options do experience very long-term remissions from this treatment.
“We’re hopeful that if we’re able to modify the way we give these CAR T-cells, modify the types of these cells, and use them at different stages of the treatment course, potentially in combination with other therapies, that we may be able to significantly improve those outcomes. That’s the hope of our unit in the coming years.”
And whether CAR T-cell therapy moves into the front line or standard of care setting is an important area of research which Dr Curley said, “we really need to answer”.
“There are many conditions we treat in hematology,” he said.
“For many lymphomas, the standard therapy is highly effective for most people so it may be unnecessary to change this. And it may be difficult to justify the risks of CAR T-cell therapy as an initial treatment for some blood cancers, where our [existing] treatments are very effective.
“But I think if we get better at identifying those conditions that we know have a high potential of failing our standard treatment, that’s where I think CAR T-cells can potentially be used earlier in the treatment course and lead to the best outcome for patients.”
Types of CAR T-cell therapies and their availability
In Australia, the blood cancers for which CAR T-cell therapy is predominantly used are the B-cell malignancies where the CD-19 protein is ubiquitously expressed, making it a widespread target in many different blood cancers of that lineage.
And in myeloma, the BCMA protein, has been demonstrated to be an important target for CAR T-cell therapy, for good responses.
Globally, Dr Curley said CAR T-cell were being tried in other cancers, including Hodgkin lymphoma, and there have been early efforts in other conditions such as myeloid malignancies.
“But I think we’re a long way off being able to offer safe and effective therapies for those conditions as yet,” he said.
Kymriah® (tisagenlecleucel) and Yescarta® (axicabtagene ciloleucel) are the CAR T-cell immunotherapies that are currently licensed, funded, and available for use in Australia for lymphoma and young patients with acute lymphoblastic leukemia.
“A significant proportion of Kymriah is manufactured in Australia,” said Dr Curley.
“Another product, Tecartus® (brexucabtagene autoleucel), is not currently funded and available, but Dr Curley said, “we’re hopeful of the availability of that product within the year to treat a specific type of lymphoma, mantle cell lymphoma”.
Dr Curley said these cellular therapies were not funded through the Pharmaceutical Benefits Scheme system. Instead, there is a different arrangement, through the Medical Services Advisory Committee, for CAR T-cells funding and reimbursement that is essentially an arrangement through the Federal government along with each State jurisdiction.
The importance of ongoing research
“We have to keep driving research to find new and better ways of treating our blood cancers,” said Dr Curley.
“That means we need to improve our chance of cure, but we also need to find ways of reducing the impacts on patients and their families.
“That’s a really key part of all this – we need to find ways to achieve the outcome with the least harm to our patients and that will come through our ongoing commitment to research, and high quality, compassionate and comprehensive care,” concluded Dr Curley.