Which co-stimulatory domains are associated with a later average onset of Cytokine Release Syndrome (CRS) after Chimeric Antigen Receptor T-cell (CAR-T) therapy?

From the Guidelines

The 4-1BB co-stimulatory domain is associated with a later average onset of Cytokine Release Syndrome (CRS) after Chimeric Antigen Receptor T-cell (CAR-T) therapy compared to CD28. This is based on the most recent evidence from the 2022 NCCN clinical practice guidelines in oncology 1. The time to onset of fever, and therefore CRS, may be earlier in patients treated with CD28 costimulatory domain-containing products compared with 4-1BB costimulatory domain-containing products.

Some key points to consider when managing CRS after CAR-T cell therapy include:

• Hospitalization or extremely close outpatient monitoring at centers with CAR T-cell experience is recommended 1
• Close monitoring in the hospital is preferred with current products for adults; however, extremely close outpatient monitoring may be possible at centers with outpatient transplant experience 1
• Daily monitoring of complete blood count, complete metabolic panel, and coagulation profiles, as well as CRP and serum ferritin levels, is crucial for early detection of CRS 1
• The severity of CRS depends on multiple factors beyond just co-stimulatory domain, including disease burden, CAR-T cell dose, and patient-specific factors, and clinicians should be prepared for CRS management regardless of construct type 1

The distinct signaling properties of the 4-1BB and CD28 co-stimulatory domains may contribute to the difference in CRS onset timing. CD28 provides rapid but short-lived T cell activation, leading to faster proliferation and cytokine release, while 4-1BB delivers more gradual, sustained signaling that results in slower expansion but better persistence of CAR-T cells. The delayed CRS onset with 4-1BB constructs may provide a clinical advantage by allowing more time for monitoring and prophylactic interventions before symptoms develop. Clinicians should maintain vigilant monitoring throughout the expected risk period for each specific CAR-T product, with tocilizumab and corticosteroids readily available for CRS management.

From the Research

Co-stimulatory Domains and Cytokine Release Syndrome (CRS) Onset

• The co-stimulatory domains associated with CAR-T cells are CD28 and 4-1BB, with preclinical investigations exploring the utility of additional co-stimulatory molecules such as ICOS, OX40, and CD27 2.
• A study found that CD19-BBz(86) CAR T cells, which contain the 4-1BB co-stimulatory domain, produced lower levels of cytokines and expressed higher levels of antiapoptotic molecules, resulting in no neurological toxicity or CRS (greater than grade 1) in patients treated 3.
• Another study demonstrated that co-stimulation combining 4-1BB with an optimized form of CD28 enhances CAR T cell function, including expansion, persistence, and resistance to exhaustion 4.
• The 4-1BB co-stimulatory domain has been shown to promote CAR T cell survival through noncanonical NF-κB signaling, leading to longer persistence after adoptive transfer compared to CD28-costimulated CAR T cells 5.
• A comparison of anti-CD19 CAR T-cell therapy containing 4-1BB and CD28 co-stimulatory domains found that the 4-1BB co-stimulatory domain suggested a better benefit-risk ratio, with a lower incidence of neurotoxicity and a higher overall remission rate 6.

Association with Later Average Onset of CRS

• The evidence suggests that the 4-1BB co-stimulatory domain is associated with a later average onset of CRS, as it promotes CAR T cell survival and persistence, and reduces the incidence of neurotoxicity and severe CRS 3, 5, 6.
• In contrast, the CD28 co-stimulatory domain has been linked to a higher incidence of neurotoxicity and severe CRS 3, 6.
• The optimized combination of 4-1BB and CD28 co-stimulatory domains may also contribute to a later average onset of CRS, as it enhances CAR T cell function and reduces exhaustion 4.