CAR T-cells as a treatment for MS
CAR T-cells as a treatment for MS
Using the military analogy, it is like brainwashing your T-cells to become assassins, with only one mission to go around your body and kill all B-cells.
Case study
Dear Prof Giovannoni, I have very active multiple sclerosis; in fact, one of my neurologists referred to me as having malignant MS. I was initially treated with dimethyl fumarate, followed by natalizumab. When I failed natalizumab, I underwent AHSCT, but sadly had a further brainstem and spinal cord attack 14 months after the transplant. I am now on ocrelizumab. I note your Tweet about anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Is this a treatment I should explore for my MS? Thank you.
Prof G’s opinion
I am really sorry to hear you failed AHSCT and your case illustrates that AHSCT is not a panacea and that a significant minority of patients with MS treated with AHCT develop breakthrough disease activity after AHSCT. A meta-analysis of AHSCT trials shows the 2-year NEDA (no evident disease activity) rate is only about 80% with AHSCT, and it falls with time (see figure below).
The term malignant MS is a term we don’t like to use anymore. In the past, some neurologists used to refer to patients with very active MS, for example, patients who go from diagnosis to wheelchair within 2-5 years, as having malignant MS. Others refer to patients with very active scans, for example, having 50 or more Gd-enhancing lesions as having malignant MS. In reality, malignant simply means the disease is very virulent. I would prefer to refer you to your disease as being refractory to treatment. However, it now seems as if you have now responded to ocrelizumab or at least the inflammatory component of your MS.
The anti-CD19 CAR T cells trial in systemic lupus erythematosus (SLE) is very exciting and is very relevant to MS. In fact, in a review paper from 2019 (see table), we include targeting intrathecal or CNS B cells using anti-CD19 CAR T cells.
What are CAR T cells?
Chimeric antigen receptor T cells are autologous (your own) T cells genetically engineered outside your body to express an artificial T cell receptor that typically targets a self-antigen, in this case, CD19, that is expressed on B-cells. When these cells are infused into your body, they find CD19-expressing cells and kill them. Using the military analogy, it is like brainwashing your T-cells to become assassins, with only one mission to go around your body and kill one particular type of cell in your body. In this case, it is the B-cell. The reason why anti-CD19 CAR T cells are better than anti-CD20 therapy is that they can penetrate the central nervous system and kill the B-cells in the brain, spinal cord and meninges. The monoclonal antibodies are too big for a sufficient amount to get into the CNS because of the blood-brain barrier to kill B-cells.
Please be aware that as plasma cells don’t express CD19, anti-CD19 CAR T cells won’t scrub the CNS clean of long-lived plasma cells. For this, you would need to use anti-CD38 CAR T cells. CD38 is a protein or antigen found on the surface of plasma cells. We hypothesize that you need to target both B-cells and plasma cells to tackle one of the components of smouldering MS. This is why we are exploring Ixazomib, a second-generation proteasome inhibitor in our SIZOMUS trial (ClinicalTrials.gov Identifier: NCT03783416).
A dirty little secret?
For CAR T-cells to work, you have to create space in the immune compartment to allow them to expand and work. Yes, there is such a thing called an immune compartment, and it is of a defined size. If the compartment is full and you infuse new cells, they can’t engraft, proliferate, and are then culled. This is why a conditioning protocol precedes all CAR T cell protocols to deplete the compartment before the engineered cells are infused. This immunodepletion can be quite profound. The following is from the methods section:
"To allow homeostatic CAR T cell expansion, all patients received a lymphodepleting chemotherapy with fludarabine 25mg/m2/d intravenously (i.v.) from day −5 to day −3 and cyclophosphamide 1,000mg/m2 /d. i.v. on day −3 before CAR T cell infusion."
I would have to ask whether or not the chemotherapy or CAR T cells resulted in these patients with SLE doing so well. Please note the paper suggests these patients may be cured of having SLE. This is quite remarkable and is why this treatment strategy is so exciting.
I am aware of a group of researchers in the US who were exploring anti-CD19 CAR T cells as a treatment for MS. I contacted them yesterday. They came back to me that their plans had been put on hold, but they would now be revisiting this as a potential treatment for MS. Please be aware that tisagenlecleucel (anti-CD19 CAR T cells) costs over $350,000 per treatment, which means it will not become a routine therapy for MS.
So if you want to be treated with anti-CD19 CAR T cells, you will need to be very wealthy, and I would suggest doing this under a well-defined study protocol. If you live in the US and want these investigators’ contact details, please email me. I am saying yes, anti-CD19 CAR T cells are a viable therapeutic option that needs to be explored in MS, but at the moment, it needs to be done under a research protocol.
Would you be interested in being treated with anti-CD19 CAR T cells as part of a clinical trial?
Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease characterized by adaptive immune system activation, formation of double-stranded DNA autoantibodies and organ inflammation. Five patients with SLE (four women and one man) with a median (range) age of 22 (6) years, median (range) disease duration of 4 (8) years and active disease (median (range) SLE disease activity index Systemic Lupus Erythematosus Disease Activity Index: 16 (8)) refractory to several immunosuppressive drug treatments were enrolled in a compassionate-use chimeric antigen receptor (CAR) T cell program. Autologous T cells from patients with SLE were transduced with a lentiviral anti-CD19 CAR vector, expanded and reinfused at a dose of 1 × 106 CAR T cells per kg body weight into the patients after lymphodepletion with fludarabine and cyclophosphamide. CAR T cells expanded in vivo, led to deep depletion of B cells, improvement of clinical symptoms and normalization of laboratory parameters including seroconversion of anti-double-stranded DNA antibodies. Remission of SLE according to DORIS criteria was achieved in all five patients after 3 months and the median (range) Systemic Lupus Erythematosus Disease Activity Index score after 3 months was 0 (2). Drug-free remission was maintained during longer follow-up (median (range) of 8 (12) months after CAR T cell administration) and even after the reappearance of B cells, which was observed after a mean (±s.d.) of 110 ± 32 d after CAR T cell treatment. Reappearing B cells were naïve and showed non-class-switched B cell receptors. CAR T cell treatment was well tolerated with only mild cytokine-release syndrome. These data suggest that CD19 CAR T cell transfer is feasible, tolerable and highly effective in SLE.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
I would be interested in being treated with car T cells if this is something even long term MSlers might have an improvement chance with…
I would love to learn more. Let's leave the money question on the side for now. What kind of risks are we talking about here?