Chimeric antigen receptor (CAR) T cell therapies have made remarkable strides in treating high-risk B-cell malignancies since the first CAR-T, Novartis’ Kymriah (tisagenlecleucel), was approved in 2017. As of March 2025, seven CAR-T therapies have received US Food and Drug Administration (FDA) approvals across several indications, but there have been significant barriers to the uptake and commercialisation of these novel assets. During the 11th Annual Immuno-Oncology 360 (IO360) Summit held in Boston in the US state of Massachusetts from 24 to 26 March 2025, much of the focus was on ongoing research addressing existing challenges, and ways to expand the efficacy, safety and accessibility of CAR-T therapies across a broader range of diseases were discussed.
Harnessing immunosuppressive tumour microenvironment for a durable response in solid tumours
While CAR T-cell therapy has revolutionised blood cancer treatment, its application to solid tumours has been limited. Recent innovations include engineering CAR T-cells to overcome the immunosuppressive tumour microenvironment (TME) and enhancing their ability to infiltrate solid tumours. In the keynote talk, Dr Crystal Mackall from Stanford University presented data from the ongoing Phase I, open-label, single-centre clinical trial of GD2-CAR cells in diffuse midline gliomas (DMG) and diffuse intrinsic pontine glioma (DIPG) patients (NCT04196413). Systemic and locoregional delivery of GD2-CAR-T into H3K27M-mutated DMG led to a significant reduction in tumour volume and resolution of symptoms, but the improvement was not durable. Clinical samples provided evidence for macrophage-mediated CD47-dependent phagocytosis of CAR-T cells, further supported by a patient-derived xenograft model of DMG relapse following a low-dose intracerebroventricular injection of GD2-CAR-T cells.
In a xenograft mouse model, microglia and myeloid cell depletion during a specific time window following CAR-T administration enhanced the durability of tumour control. Cell surface protein CD47, which is present on T cells and over-expressed on tumour cells, sends a “do not eat me” signal to the signal regulatory protein alpha (SIRPα) receptor on the surface of macrophages. Adding an anti-CD47 antibody masks the “don’t eat me” signal, inducing tumour cell and T cell phagocytosis [the ingestion and elimination of particles]. CAR-T cells that are engineered to express a CD47 variant (47E) that ablates anti-CD47 antibody binding but retains SIRPα interaction were protected from phagocytosis and demonstrated synergistic anti-tumour activity with anti-CD41 antibody.
The presented data supported overcoming tumour immune surveillance evasion with a CD47-targeting immune checkpoint inhibitor (ICI) in combination with “armoured” CAR-T cells as a potential approach to achieving a durable response in solid tumours. There are 12 fusion proteins and antibodies targeting CD47 in clinical development for solid tumours and haematological malignancies globally, including one in Phase III (ALX Oncology Holdings’ evorpacept), eight in Phase II and seven in Phase I. The companies with Phase II assets include AbbVie (lemzopalimab), Akeso (ligufalimab), KAHR Medical Ltd (DSP-107), Centessa Pharmaceuticals (LB-101), Pfizer (maplirpacept) and Planes Therapeutics (PT-886).
CAR-T cell therapies’ potential in autoimmune disease
Since 2023, several academic groups have demonstrated the potential of CD19-CAR-T in patients with systemic lupus erythematosus (SLE), myositis and systemic sclerosis (SSc). At the IO360 Summit, Dr. Georg Schett from Friedrich-Alexander University presented long-term follow-up data from 15 patients with CD19-CAR T. Patients with refractory SLE (n=8), idiopathic inflammatory myositis (IIM) (n=3) and SSc (n=4) were treated with Miltenyi Biomedicine’s MB-CART 19.1 cells via an expanded access programme. Dosing with CAR-T leads to a rapid loss of B cells in circulation and lymph nodes, resulting in the complete depletion of B cells within the first 10 days after treatment and a recurrence of B cells 50–150 days after the CAR-T infusion. No major toxicity, good tolerability and a good safety profile were reported, with limited incidence of low-grade cytokine release syndrome and no immune effector cell-associated neurotoxicity syndrome (ICANS). At the time of the analysis (14 to 40 months follow-up), 14 out of 15 patients had achieved drug-free remission with no disease progression.
Cabaletta Bio presented its lead asset, an autologous CD19-targeting CAR-T therapy, rese-cel (CABA-201), in clinical development in multiple Phase I/II trials (RESET) for B-cell mediated autoimmune disorders (AIDs) (myositis, SLE, SDc, myaesthenia gravis, multiple sclerosis and pemphigus vulgaris). CABA-201 is a fully human CAR with a 4-1BB co-stimulatory domain, similar to a dual CD19xCD22 CAR-T construct successfully employed in academic reports. Early efficacy and safety readouts from the first 10 patients were reported. All patients had active, refractory disease, and most had failed B cell-targeting therapies. CABA-201 showed a tolerable safety profile with minimal adverse events, except for one Grade 4 ICANS in a lupus nephritis (LN) patient, possibly due to an underlying occult infection. Clinical responses in highly active and refractory autoimmune patients without immunosuppressants showed a favorable pharmacokinetic (PK)/pharmacodynamic profile with CAR-T peak expansion between weeks 1 and 2, rapid contraction at one month and B cell repletion by months 2 to 3, with evidence for deep tissue B cell depletion.
Several companies are racing to establish an early presence in the CAR-T cell therapies AID market. With encouraging safety and efficacy data from early clinical studies and a larger affected population, AID presents as an attractive expansion opportunity for the developers of CAR-T therapies. According to GlobalData’s Pharma Intelligence Center, out of the 25 CD19-targeting CAR-T cell therapies for AID that are in clinical development (Phase I and II) globally, 21 therapies are in trials for SLE. GlobalData’s recent patient-based forecast model estimates the prevalence of SLE and LN across the seven major pharmaceutical markets (7MM: France, Germany, Italy, Japan, Spain, the UK and the US) to increase and result in a larger addressable patient population, reaching 424,000 treated cases and $3.5 billion in sales by 2031.