Study in focus 1: CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-up

CART-cell therapy is the latest buzzword in the treatment of autoimmune rheumatic diseases.  This seminal publication reports the long-term efficacy and safety data of CD19-CAR-T-cell therapy in 15 patients (SLE – 8, IIM – 4, SSc – 3) with refractory rheumatic disease.

A single infusion of CD19 CART-cells was given to all patients after preconditioning with fludarabine and cyclophosphamide. At a median follow-up of 15 months, all patients with SLE attained DORIS remission, all IIM achieved ACR–EULAR major clinical response and all SSc had a reduction in EUSTAR activity index score, with discontinuation of immunosuppressive therapy (including glucocorticoids) in all patients. The side effects were predominantly mild – grade 1 cytokine release syndrome (CRS)was seen in 10 patients, while one patient had grade 1 immune effector cell–associated neurotoxicity syndrome (ICANS). One patient each had grade 2 CRS and grade 4 neutropenia. Infections were mostly mild.  No deaths were reported. No patient had prolonged (>28 days) bone marrow suppression or significant hypogammaglobulinemia.

Thus, this case series demonstrates the feasibility, safety, and efficacy of CD19 CAR T-cell therapy in severe, refractory autoimmune disease and paves the way for their investigation in future RCTs. Deep depletion of B cells and “resetting” the immune system through this strategy offers hope for sustained drug-free remission (“cure”) in autoimmune rheumatic diseases, a goal that is currently a distant dream. However, notwithstanding these promising results, it is still early days for CAR-T cell therapy in general, and much remains to be understood and optimized.

Study in focus 2: Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial

Whether the development of rheumatic disease in at-risk individuals is preventable or notremains a million-dollar question for the rheumatology fraternity. The second clinical study in focus for this quarter reports on the much-awaited results of the APIPPRA study that studied the role of abatacept in preventing the development of RA in high-risk individuals. 213 individuals with inflammatory joint pain and sero positivity for ACPA and RF were randomly assigned (1:1) to receive weekly injections of subcutaneous abatacept 125 mg for 12 months or placebo, followed by an observation period of 12 months. The primary outcome was the time to development of clinical synovitis in >3 joints or definite RA as per ACR/EULAR 2010 classification criteria. During the initial treatment period, there was a 23% difference (6% abatacept vs 29% placebo) in the number of individuals meeting the primary outcome in the two groups, which reduced to 12% at the end of the observation period. Sustenance of effect difference at 2 years makes abatacept somewhat superior to other agents. The planned long-term extension of the APIPPRA study will throw more light on whether this brief intervention leads to true disease “prevention” or a clinically significant delay in disease development. About two-thirds of patients, despite being seropositive and high-risk, did not develop RA over 2 years. No difference in the incidence of serious adverse events was seen in the two groups.

The readers are also encouraged to go through the results of the ARIAA trial (another study of abatacept in pre-RA with different entry criteria and primary endpoint)published in the same issue of The Lancet. Together, the results of the APIPPRA and the ARIAA trials suggest the potential efficacy and safety of T-cell costimulation blockade in at-risk RA.
 

References:

1. Müller F, Taubmann J, Bucci L, Wilhelm A, Bergmann C, Völkl S, et al. CD19 CAR T-Cell Therapy in Autoimmune Disease – A Case Series with Follow-up. N Engl J Med. 2024;390(8):687-700.
2. Cope AP, Jasenecova M, Vasconcelos JC, Filer A, Raza K, Qureshi S, et al. Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial. Lancet. 2024;403(10429):838-849.