In a world first, the Australian COMMITTAL trial uses CAR T-cell therapy to improve survival for people with B-cell ALL who have an allogeneic stem cell transplantation (SCT).
Dr Ken Micklethwaite, a clinical haematologist and bone marrow physician, who runs the CAR T-cell program at The Westmead Institute of Medical Research (Sydney), describes the study as “completely revolutionary and very exciting”.
“It’s Professor David Gottlieb’s baby. He’s been talking about this idea–a transplant that eliminates all the things that cause death and complications in transplant patients–as long as I’ve known him, and that’s more than 15 years,” said Dr Micklethwaite, Medical Director of the Sydney Cellular Therapies Laboratory.
Relapse is the major cause of death; followed by infection and graft-versus-host disease (GVHD) which affects two-thirds of transplant recipients.
“What we are trying to do is prevent these complications from occurring,” said Dr Micklethwaite.
“The whole idea of the COMMITTAL study is to make the transplant better.”
Allogeneic stem cell transplant
With a standard of care allogeneic SCT, the donor harvest given to the recipient is a combination of stem cells and a host of other cells that have both positive and negative effects. And normally the immune cells can cause GVHD, a graft-versus-tumour effect, and also prevent infection.
Dr Micklethwaite described the transplant on the COMMITTAL trial, as a “special sort of transplant”.
“It’s a CD34-selected transplant where the recipients are given stem cells that have a marker on their surface for CD34.
“With a CD34 transplant, we specifically isolate the stem cells that are the ‘good stuff’ and leave out the cells that do the ‘bad stuff’,” said Dr Micklethwaite.
This process involves removing the immune cells that cause GVHD and making immune cells that can prevent infection and prevent relapse.
“It’s a very sophisticated and highly engineered transplant where we give immune cells to fight infection, then we give the CAR T-cells,” said Dr Micklethwaite.
“We’re trying to prevent the three major causes of why people die after a transplant.
“This is a world first. It’s completely revolutionary and very exciting.”
COMMITTAL trial
Dr Micklethwaite said bone marrow specialist, Dr Emily Blyth, who has been involved in cell therapies for the last 10 years “has been central to the success of the CAR T-cell transplant program, from the clinical side of things”.
In January, the first two patients – both adults with B-cell ALL in first remission – received this treatment protocol on the COMMITTAL pilot trial.
“The results are pretty exciting, but it’s early days,” said Dr Micklethwaite.
“No-one has used CAR T-cells in this context before… where they are given as a preventative therapy after transplant.
“So far, we’ve seen the CAR T-cells grow in the blood, which is really very interesting because normally, when you give CAR T-cells in the relapsed setting, the amount of CAR T-cell growth in the blood depends on how much disease the patient has.
“If they have a lot of leukaemia, you see a large increase in the CAR T-cells in the peripheral blood, whereas if they only have a little bit of leukaemia, they don’t get a large increase,” he explained.
CAR T-cells
The first two patients on the COMMITTAL trial didn’t have any detectable disease when they received the CAR T-cells.
“In this setting, I wasn’t expecting to see a lot of CAR T-cell growth but what we’re seeing is this quite nice expansion of the CAR T-cells,” said Dr Micklethwaite.
“And we’re getting the toxicity we’d expect with that degree of expansion. Both patients have had mild cytokine release syndrome (systemic inflammation with fevers) and are doing reasonably well now.
“We are monitoring them for incidents of infection, persistence of the CAR T-cells in the long-term, GVHD, and potential relapse.
“We hope the CAR T-cells will kill off any leukaemia that might still be around, even if it’s below the limit of our detection, and that they will persist for quite some time and prevent any relapse from occurring, and do that without causing GVHD.
“It’s pretty cutting-edge stuff, this whole idea of a completely engineered graft. It’s a very high tech and refined transplant,” said Dr Micklethwaite.
Clinical trials
The CAR T-cell therapy program at The Westmead Institute of Medical Research has two clinical trials underway–the CARTELL and COMMITTAL studies.
And there are plans for a third study to go ahead in the next two months, pending TGA approval.
Dr Ken Micklethwaite said this ‘local’ program arose out of The Westmead Institue’s immunotherapy program and in response to the “very expensive cost” of current technologies used in international studies and commercial CAR T-cell production.
“Over the last eight years we’ve developed a non-viral vector technique for making the CAR T-cells at a tenth of the cost, so this markedly reduces the overall cost of CAR T-cell production,” said Dr Micklethwaite.
“Our clinical trials are about demonstrating that this method for producing CAR T-cells also produces similar efficacy and safety results for patients with leukaemia and lymphoma as the overseas trials.”
Leukaemia or lymphoma
The first two trials are specifically in the setting of allogeneic stem cell transplantation (SCT).
The first–the CARTELL study–treats people who have relapsed or persistent B-cell leukaemia or lymphoma after a matched brother- or sister-related SCT. So far, there are 10 patients on the study who have had the same sort of responses as the international studies.
“Most of our patients have gone into remission early after receiving the CAR T-cells. Half of them have persisted in remission and we’ve had some relapses, which is the same as the results of the international multi-centre studies overseas,” said Dr Micklethwaite.
The second study is the revolutionary COMMITTAL trial and the third trial is being reviewed by the TGA.
“The third trial will assess our home-grown CAR T-cells outside the stem cell transplant setting, in patients who have relapsed or persistent leukaemia or lymphoma, but who haven’t had a transplant,” said Dr Micklethwaite.
“The first two studies use a healthy donor to get the CAR T-cells, but in the third trial, we make the CAR T-cells from the actual patient themselves, which is what most other studies have done.”
