1971 
Roberta di Blasi MD PhD is a haematologist at Saint Louis Hospital in Paris where she is a specialist in CAR-T cell therapy for lymphoma. Hospital Healthcare Europe had the pleasure of hearing her thoughts and perceptions on CAR-T therapy and its role in treating patients with lymphomas.
Prior to her appointment in Paris, Dr Roberta di Blasi completed her residency in haematology at the Catholic University School of Medicine, Policlinico Universitario Agostino Gemelli in Rome. Towards the end of her residency, she moved to Paris, initially working at CHU Henri Mondor in Créteil, where she became involved in bone marrow transplantation and acute leukaemias and developed a special interest in infections among haematology hosts. In 2018, she moved to Saint Louis to take part in the CAR-T cell project.
Saint Louis is a large, specialist haematology hospital with seven wards dealing with different haematological malignancies. Dr di Blasi is part of a team of seven clinicians, of whom two are based in the outpatient or day-care centre, caring for patients with lymphoma and chronic lymphocytic leukaemia. The unit has 16 beds and treats patients with chemotherapy and CAR-T cell therapy. It is a busy department, which, according to Dr di Blasi, took care of 661 patients, including 450 new patients, in 2021.
CAR-T therapy and lymphoma
Dr di Blasi described how CAR-T therapy is ‘a form of immune therapy that makes use of the patient’s own T lymphocytes that are engineered to express an antigen that can recognise a target in the tumour cell.’ Although this target can vary depending on the pathology, she explained that ‘with lymphomas, our target is CD19, which is expressed on the cell surface of lymphomas.
Consequently, the T cells are modified to express a receptor that can recognise the CD19 on tumour cells, link to the tumour cell, and ultimately destroy it.’ Dr di Blasi explained how CAR-T therapy is a relatively new approach to the treatment of lymphomas, but while it was only introduced into clinical practice in Europe in 2018, the technology had been investigated in clinical trials for a much longer period of time prior to this.
Dr di Blasi said that her own interest in CAR-T cell therapy began in 2017 when clinicians at the hospital became more attracted to the technology, especially for patients with refractory malignancies. Given her prior experience and knowledge of allogenic bone marrow transplantation, she believed it was a natural fit, particularly as there are some complications that can arise from CAR-T cell therapy that bear similarities to those experienced by patients undergoing allogeneic bone marrow transplants. And she remains fascinated by the technology to this day.
National patient registry
Although her department does have strong links to the pharmaceutical industry and participates in clinical trials, an equally important part of its work involves the examination of the findings held in a national patient registry. The registry (termed DESCAR-T) collates data from patients across France and enables a much greater understanding of the impact of real-world experience of CAR-T cell therapy.
In addition, other areas of research within the hospital include basic biological science and translational research, which are designed to better understand CAR-T.
Although diffuse large cell B lymphomas and the family of related lymphomas are treated with CAR-T cell therapy, Dr di Blasi pointed out that ‘recently, the centre had received authorisation to treat mantle-cell lymphoma and follicular lymphoma’.
Dr di Blasi felt that the patient registry outcome data, in particular, treatment efficacy seen in real-world data derived from registry data, are comparable to that observed in the clinical trials, adding that the extent of toxicities was probably lower with the registry data, which was likely a reflection of how clinicians were better able to manage these adverse effects in practice.
Nevertheless, she stressed that because the production of products differed, it was not always easy to compare the effectiveness seen in the trials with the registry data although, broadly speaking, the two datasets provided similar results.
CAR-T authorisation and use
Although a novel and promising therapeutic approach, Dr di Blasi explained that CAR-T is not currently a first-line treatment option and that her hospital is only authorised to use the therapy third-line after two unsuccessful chemotherapy regimens.
She mentioned how the department currently uses two CAR-T cell products aggressive B cell lymphoma or transformed follicular lymphoma. Despite the constraint of having to use CAR-T cell therapy third-line, this might change over time, and she noted that clinical trials are starting to report on the value of CAR-T cell therapy as a second-line option in either refractory patients or in those who relapse within the first year of chemotherapy.
She also added that ‘axi-cel CAR-T cell therapy will hopefully be used as a second-line treatment for patients with lymphomas who relapse within the first year of treatment as well as refractory patients and hopefully, by the end of the year, axi-cel will be available for follicular lymphoma too.’ She revealed how the department is likewise eagerly ‘waiting for liso-cel (another CAR-T cell product) to be available for large-cell B lymphoma as well as some other entities, such as transformed marginal zone lymphoma, that were not covered by the older CAR-T cell products.’
Although CAR-T cell therapy makes use of a patient’s own cells, Dr di Blasi explained that because the cells undergo modification, it is designated a ‘product’ and therefore subject to all the standard regulatory approvals required for drugs.
Dr di Blasi explained that in her department, after a single infusion, patients were monitored for the first 10 days and, if there are no problems, discharged home but contacted daily until day 21. After 28-30 days, patients revisit the centre for efficacy assessment by a clinician.
Following this, patients are reviewed after three months, as any relapse is likely to occur at this point, and then every 90 days. She described how there were no specific criteria for choosing CAR-T cell products and this relied solely on the availability of the manufacturer to produce the product.
In cases where CAR-T cell therapy was ineffective, patients would not be switched to an alternative CAR-T cell product because, as Dr di Blasi clarified, ‘one route of escaping the treatment – that is, therapeutic failure – is due to loss of the antigen and because the target is the same, there is little point in switching to another CAR-T product.’
Dr de Blasi outlined how she has seen some remarkable results for CAR-T cell therapy, noting how ‘we have seen response rates in real life of 40-60% and are comparable to those seen in the clinical trials.’
Potential for wider use
Dr di Blasi described how after a few years of clinical experience with CAR-T cell therapy, clinicians are now better able to identify specific risk factors, both clinical and biological, such as high tumour burden, that negatively affect the response to CAR-T cell therapy. Using this knowledge, she thinks that ‘for some patients, it might be logical to conceive CAR-T cell therapy earlier in the therapeutic line.’
She mentioned that the ZUMA-12 trial has produced some remarkable findings. This is a Phase II, multicentre, single-arm study evaluating axicabtagene ciloleucel as part of first-line treatment in patients with high-risk large B-cell lymphoma or with an insufficient response after two courses.
As a result, she thinks that ‘the therapeutic strategy might change according to the clinical features at diagnosis for the patients’. However, she felt that in practice, third-line CAR-T therapy would be best suited to those patients with limited disease who are likely to respond well to the treatment.
One important and limiting factor to the greater use of CAR-T cell therapy is cost. Currently, Dr di Blasi said, ‘the total hospitalisation costs for one patient receiving CAR-T therapy is approximately €480,000’. Despite this, she pointed out that health economic studies have been favourable for CAR-T cell therapy, especially if the patient goes into remission and that, currently, ‘the balance is still in favour of CAR-T cell use’.
A further limitation to wider use was that ‘not all centres are fully certified to administer CAR-T cells’, with currently only around 31 centres being able to provide the treatment in France. An important part of the CAR-T programme, therefore, is education and involved visiting and discussing the specific patient referral criteria with non-accredited sites.
CAR-T cell therapy safety profile
Dr di Blasi described how ‘the two well-known side-effects of CAR-T therapy – at least the ones that we have been concentrating on – are cytokine release syndrome and neurotoxicity syndromes, and these can vary substantially depending on the pathology being treated, the CAR-T cell product and even the different clinical trials.’
With the severity of these adverse effects graded on a scale from 1 to 5, Dr di Blasi mentioned that ‘grade 3 or higher [adverse effects] can vary from 8-10% and up to roughly 30% for axi-cel and from 2% to 20% for tisa-cel. Liso-cel, for which there is currently less real-world data, also has a favourable toxicity profile’.
Nevertheless, with greater clinical experience in using CAR-T cell therapy comes a better understanding of how best to manage these adverse effects. Despite advances in the management of the two key side-effects, Dr di Blasi feels that a better understanding of other emerging adverse effects was still required.
This included cytopaenia, for example, which might affect up to 10% of patients after one year, as well as the risk of infection and hypo-gammaglobulinaemia. Finally, she revealed how there is an ongoing continuing debate over whether autologous stem cell transplantation after second-line chemotherapy is more toxic than CAR-T cell therapy.
Furthermore, Dr di Blasi explained that the decision over whether to use CAR-T cell therapy for a patient was complex and involved a consideration of many different factors, but the existence of treatment algorithms had been of great value to clinicians.
Dr di Blasi thinks that immunotherapy would be the next step in the management of patients who fail to respond to CAR-T cell therapy and does not believe that such patients would benefit from further chemotherapy, a point already proven in trials. She added that in some tumours, if a second surface antigen – CD20 – is still expressed, then immunotherapy can help.
Future CAR-T developments
First and foremost, over the next five years, Dr di Blasi hopes to see patients with the longest possible remission and with no, or very few, long-term side effects. Future developments might enable a reduction in the level of side effects through alteration of the receptor on the CAR-T cells.
As she explained, ‘we know that toxicities are partially linked to the structure of the receptor on the surface of the CAR-T cells and to the expansion profile, so modification of this structure might lead to less toxicity, and we already have three available products which have different toxicity profiles’.
While modifying the receptor might be possible, this approach is not guaranteed to lessen the incidence of adverse effects as there are many other factors that can affect an individual’s risk of adverse effects, including the number of T cells infused and the microenvironment of the patient’s tumour, both before and after infusion, and such effects are not always predictable. In addition, she added that much more work is needed to understand why some, but not all, patients are prone to cytopaenia.
Although CAR-T cell therapy targets a particular antigen, Dr di Blasi thinks that it is theoretically possible to deploy the technology in the treatment of any form of cancer, including solid tumours, provided that a discriminatory antigen can be found, and this is an area of ongoing research. One possible therapeutic area she would like to see CAR-T cell therapy used is in the treatment of T-cell lymphomas.
Dr di Blasi concluded that CAR-T cell therapy has been a major advance in the treatment of lymphomas, but there was still much to learn, not just about the technology itself, but also about how it affects patients and what might be achieved in the coming years to maximise the benefits and minimise the adverse effects the patients in her care.
