Efficacy and Safety of Anti-CD19 and Anti-BCMA Chimeric Antigen Receptor (CAR) T-Cell Therapies in Patients with Autoimmune Disease and Lymphoma or Myeloma
Authors: Paruzzo Luca , Bouvier Riemke , Ghilardi Guido , Fardella Eugenio , Fulmer Bria , Cohen Ivan J , Chong Elise A. , Svoboda Jakub , Nasta Sunita D. , Landsburg Daniel J. , Patel Vrutti , Ziyu Li , Pajarillo Raymone , Waxman Adam , Cohen Adam D. , Vogl Dan T. , Barta Stefan K. , Porazzi Patrizia , Fraietta Joseph A. , Bhoj Vijay , Garfall Alfred L. , Stadtmauer Edward A. , Schuster Stephen J. , Carter Jordan S. , Apostolidis Sokratis A. , Susanibar-Adaniya Sandra , Ruella Marco 
Published: December 2024

Background: Chimeric antigen receptor T cell (CART) immunotherapy has shown promising efficacy in early-phase trials for patients with autoreactive B cell mediated autoimmune diseases (AD). However, these trials involve small, selected populations, and real-world data are lacking. Given the frequent co-occurrence of autoimmune diseases with lymphoproliferative disorders, such as B-cell non-Hodgkin lymphomas (B-NHL) and multiple myeloma (MM), we evaluated the clinical effect of commercially available CART targeting CD19 and BCMA (CART19 and CARTBCMA) on AD in pts with concurrent lymphoproliferative disorders. Furthermore, we assessed the efficacy and safety of commercial CART on B-NHL and MM in patients with AD compared to those without AD.

Methods: We retrospectively analyzed 442 pts with relapsed or refractory B-NHL or MM treated with commercial CART19 and CARTBCMA between January 2018 and October 2023. Data cutoff was May 31, 2024. AD was considered active if serologically positive or symptomatic, and an AD flare was defined as worsening AD clinical manifestations post-CART. AD response was assessed based on clinical manifestations and medication requirements. Serum autoantibodies (Aabs) were measured at baseline and month 3 in 90 pts (51 CART19, 39 CARTBCMA) using a multiplexed bead-based antigen array. Anti-tumor clinical efficacy and toxicity were assessed separately for B-NHL and MM. B-NHL and MM responses were evaluated using Lugano and IMWG criteria, respectively. Toxicities were graded per ASTCT or CTCAE v5.0 guidelines. Absolute lymphocyte counts were used as a surrogate for early CART expansion.

Results: The total cohort consisted of 442 pts, including 317 B-NHL and 125 MM. Forty-three pts (9.7%) had an AD history (34 B-NHL, 9 MM, 4 pts had more than one AD). Among these, 10 pts (23%) had rheumatoid arthritis (RA) or juvenile RA; 9 pts (21%) had autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia; 9 pts (21%) sarcoidosis; 4 pts (9%) had systemic lupus erythematosus (SLE) or undifferentiated connective tissue disease; 4 pts (9%) had autoimmune thyroid disorders; and 3 pts (7%) had inflammatory bowel disease (IBD). The remaining pts included 2 with psoriasis (4%) and 1 each (2%) with type 1 diabetes, ankylosing spondylitis, uveitis, polymyalgia rheumatica, or autoimmune colitis.

The patient characteristics (age, CART product, previous lines of therapy, diagnoses) were similar between the AD and no-AD cohorts for both B-NHL and MM. In the B-NHL cohort, the complete response rate was 58.8% in the AD group and 53.3% in the no-AD group (p=0.58) with comparable progression-free survival (PFS) and overall survival (OS). There were no differences in CRS (Grade &gt;/=2 AD: 20.6% vs. no-AD: 27.5%), ICANS (%ICANS any grade AD: 17.7% vs. no-AD: 17.6%), and lymphocyte expansion (p&gt;0.05 for all comparisons).In the MM cohort, overall response rates were comparable: 77.7% of AD pts and 69.5% of no-AD pts achieved at least a very good partial response (p=0.72). Similarly, PFS and OS were comparable. There were no differences in terms of CRS (Grade &gt;/=2 AD: 22.2% vs no-AD: 26.7%,), ICANS (%ICANS any grade AD: 11.1% vs no-AD: 18.9%), and lymphocyte expansion (p&gt;0.05 for all comparisons).

We then evaluated the clinical efficacy of commercially available CART on AD in pts with concurrent lymphoproliferative disorders. Of 43 pts with AD history, 23.3% were on AD treatment at apheresis. Two pts (4.6%), 1 with RA and 1 with SLE, had active AD before CART19 infusion while the others were in clinical remission. Both went into remission for 2.5 and 2.3 years, respectively. We then analyzed Aabs in 90 CART pts. Both CART19 and CARTBCMA reduced circulating Aabs. CARTBCMA showed a greater reduction than CART19 (Median fold change post-/pre-CART: CARTBCMA: 0.61 vs. CART19: 0.83, p&lt;0.001). Finally, 3 RA, 1 psoriasis, 1 IBD, and 1 AIHA pts experienced AD flares within 3 months after CART that resolved with systemic steroids (2 pts) or nonsteroidal anti-inflammatory drugs (1 pt) (RA), topical steroids plus phototherapy (psoriasis), mesalamine (IBD), and RBC transfusions (AIHA).

Conclusion: CART therapies show similar efficacy and safety in patients with or without concurrent AD. CART19 and CART-BCMA reduced the levels of Aabs, thereby confirming their potential therapeutic role for AD in a large, real-world cohort. However, early AD flares were observed, suggesting close early monitoring of AD after CART infusion.