Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) has significantly improved outcomes for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL). However, relapse after CAR19 therapy remains a major clinical challenge, with median overall survival (OS) of only six months. Improving the prognosis for these patients is an urgent unmet need.
A recent Phase I clinical trial conducted by the CARdinal-22 Investigator Group at Stanford University, and published online in The Lancet, evaluated the safety and efficacy of CD22-targeted CAR-T therapy (CAR22) in R/R LBCL patients who had relapsed after CAR19. A companion commentary from Heidelberg University in Germany highlighted the study’s significance. The results suggest that CD22 is a promising therapeutic target, particularly for patients who relapse after CAR19, and may pave the way for new immunotherapy approaches in this difficult-to-treat population.
Study Design
LBCL, the most common aggressive lymphoma, includes diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma. While many patients are cured with first-line chemoimmunotherapy, up to 30% experience early treatment failure, with poor prognosis and median survival of less than one year.
CAR19 therapies such as axicabtagene ciloleucel and lisocabtagene maraleucel have become standard salvage options, offering curative potential. Still, outcomes remain dismal for those relapsing post-CAR19.
CD22, a sialoglycoprotein expressed across nearly all B-cell malignancies, has emerged as an alternative target. In pediatric B-ALL patients, most of whom relapsed after CAR19, CD22 CAR-T therapy achieved complete remission (CR) rates of up to 70%. However, no CD22-targeting therapy has yet been approved for LBCL.
This single-center, open-label, dose-escalation Phase I trial enrolled adults (≥18 years) with histologically confirmed LBCL, ECOG performance status 0–2, and adequate organ function. Two dose levels were tested:
- DL1: 1×10⁶ CAR⁺ T cells/kg
- DL2: 3×10⁶ CAR⁺ T cells/kg
Primary endpoints included feasibility, safety (via adverse events and dose-limiting toxicities), and maximum tolerated dose (MTD). Exploratory endpoints included overall response rate (ORR), CR rate, progression-free survival (PFS), OS, and biomarker correlations.
Results
Of 41 patients screened, 40 underwent leukapheresis, and 38 (95%) had CAR22 successfully manufactured. Median age was 65, 45% were female, and patients had received a median of 4 prior lines of therapy (range 3–8). Nearly all (97%) had relapsed after CAR19.
- MTD: Determined at DL1 (1×10⁶/kg).
- Safety: No grade ≥3 cytokine release syndrome (CRS), ICANS, or HLH-like syndromes observed at MTD.
- Efficacy: ORR was 68% (95% CI 51–83%), with CR in 53% (36–69%).
- Survival: Median PFS was 3.0 months, median OS was 14.1 months. Estimated 1-year OS was 57% and 2-year OS was 52%.
No significant differences were noted across LBCL subtypes. Importantly, CAR22 expansion correlated with higher ORR and CR rates. Responders showed higher circulating CAR22 T-cell levels and cumulative exposure. Conversely, baseline low CD22 expression was associated with progression, and in 63% of paired relapse biopsies, CD22 expression had decreased.
Commentary
The study demonstrates that CAR22 is both feasible and tolerable, with encouraging clinical activity in heavily pretreated R/R LBCL, particularly after CAR19 failure. The favorable toxicity profile and significant responses position CD22 as a promising target.
In an accompanying commentary, German investigators emphasized that while CAR19 therapies have transformed R/R LBCL treatment, more than half of patients relapse or fail to respond. The emergence of CD22-targeted CAR-T offers “new hope,” though further studies are needed to validate efficacy, explore earlier-line use, and test combinations with other immunotherapies.
Conclusion
This first-in-human trial of CAR22 in LBCL patients resistant to CAR19 shows an ORR of 68% and CR rate of 53%, with a manageable safety profile. CD22 is validated as a viable target, providing a foundation for future development of novel immunotherapies for R/R LBCL.
