Jérôme Avouac, EULAR 2023: Effects of B cell depletion by CD19-targeted CAR-T cells in a murine model of systemic sclerosis
touchIMMUNOLOGY spoke with editorial board member Jérôme Avouac (Hôpital Cochin, Paris, France) to discuss his highlights from the European Alliance of Associations for Rheumatology (EULAR) annual meeting in the field of rheumatoid arthritis, and his presentation on the potential of CD19-targeted CAR-T cell transfer for systemic sclerosis.
The abstract ‘Effects of B cell depletion by CD19-targeted CAR-T cells in a murine model of systemic sclerosis’ was presented at the European Alliance of Associations for Rheumatology (EULAR), 31 May – 03 June 2023.
Questions
- What were your highlights and the most prominent data from this year’s EULAR meeting in the field of rheumatoid arthritis? (00:20)
- Please describe the rationale and main objectives of your investigation into CD19-targeted CAR-T cell transfer for systemic sclerosis? (01:14)
- What was the methodology and study design? (02:05)
- Please summarize the results and main findings (03:20)
- What conclusions can be made, and what will be the focus of future investigations of CD19-targeted CAR-T cells in this clinical setting? (05:14)
Disclosures: Jérôme Avouac has no financial or non-financial conflicts of interest to declare in relation to this video.
Support: Interview and filming supported by Touch Medical Media Ltd. Interview conducted by Sophie Nickelson.
Filmed in coverage of the European Alliance of Associations for Rheumatology (EULAR) Annual Meeting
Click here for more content from EULAR.
Transcript
My name is Jérôme Avouac, I’m a rheumatologist in Paris at Cochin Hospital, and I’m working more precisely in the field of rheumatoid arthritis and systemic sclerosis, both from the clinical and basic point of view.
- What were your highlights and the most prominent data from this year’s EULAR meeting in the field of rheumatoid arthritis?
It’s a good point, I think my point of view, there was no revolution considering the treatment or the care of the disease. However, there were some very, very interesting data regarding some comorbidities, for instance, regarding the prevalence of cancer, which is really important for the patient with RA and also some interesting information regarding JAK-inhibitors regarding their cardiovascular and safety and also their safety regarding the risk of cancer and the data were I think quite reassuring. And also some interesting abstracts regarding the use of corticosteroids, but also I think very important for RA.
2. Please describe the rationale and main objectives of your investigation into CD19-targeted CAR-T cell transfer for systemic sclerosis?
As you know, there are some clinical and now experiments that have been done in Lupu, both in preclinical models, but also in the clinics. And as you know, systemic sclerosis shares some mechanisms, some of their pathogenesis, with lupus, and there is also an important implication of B cells. So our aim was to assess the efficacy and safety of CAR T-cell injection in a preclinical model of systemic sclerosis, an FRA-2 mouse model that mimics the main complication of the disease, so ILD and pulmonary artery-like hypertension. And so it was proof of concept study of the possibility to use this technology in a systemic crisis in the future.
3. What was the methodology and study design?
Yes. So to do so, we we do use this pre-clinical model of systemic sclerosis and we conducted experiments in three different group of mice. The first group of mice was untreated. The second group received anti-CD20 antibodies So that’s — I would say the standard of care we use in systemic sclerosis. And the third work received a combination of SIMAP, so CD20 antibodies and CD19 targeted CAR T-cells. And the idea was to give this treatment as an add on Rituximab or anti-CD20, because I think that the use will be used in the clinic in the future. And also what is very important to know that to work correctly, the CAR T-cells need to be, we have to deplete circulating B cells before injecting the CAR T. So it was very important to use this combination together. So three different group of mice receiving either nothing, either anti CD20 or combination of anti CD20 and CAR T-cells.
4. Please summarize the results and main findings
At the beginning, the results were very promising because we obtained a very good B-Cell depletion with a combination of anti CD20 and CAR T with almost a complete depletion of B cells in the blood and almost 80% of depletion in the, 80 to 90 percent of depletion of B cells in the lung. And it was much better with the use of CAR T compared to anti-CD20 alone. But what was quite unexpected, we observed that the disease was worsening in the mice, receiving the CAR T. So my mice lose weight, and then they had increased clinical scores and also higher mortality. And when we looked to the organs, they had increased interstitial lung disease with a lot of inflammation and also have worsening of the pulmonary potential. And so we observed that there was an accumulation of the CAR T cells in the lungs of mice and with some very prominent T cell infiltration in the tissue. And these T cells were activated and produced larger amounts of inflammatory cytokines. So probably the CAR T cells correctly depleted the B cells in the lung, but it activated all the T cells around when the CAR T is activating to to destroy the B cell. So they activated all the T cells around, and I think that this why the mice worsened and die. So CAR T affects the activation of the T cells because there is a lot of T cell infiltration rates in the length of the mice. So that was quite unexpected, but it give us some information for the future.
5. What conclusions can be made, and what will be the focus of future investigations of CD19-targeted CAR-T cells in this clinical setting?
The conclusions are are are quite important because as you may know, there is one patient that has been treated with systemic sclerosis with CD19 CAR T. It’s published on IRD – It’s from the team of Georgette in Herlingen. And it was quite successful, but the patients had very mild pulmonary fibrosis. And saw in our model, it’s a model of very severe ILD and PH. And I think what is important is to remind that there is T cell component in systemic sclerosis that is very important. B cells are important, but T cells are probably prominent in the disease. So the use of CAR T maybe I think it’s maybe considered, but the conditioning before using CAR T will be very important, so using a combination of immunosuppressive drugs to decrease the weight of the T cell infiltration before using the CAR T to deplete the B cells. So using the CAR T alone without conditioning, I think will be not possible. So I think it allies the importance of conditioning the patients with immunosuppressive drugs prior to injecting the efficacy. I think that’s the main conclusion and that may be translated to clinical practice for for the pre-tribune of CAR T.
