Enhanced CAR T-Cell Therapy for Lymphoma after Previous Failure

Svoboda J, Landsburg DJ, Gerson J, et al. N Engl J Med. 2025 May;392(18):1824-1835. PMID: 40334157.

Introduction

CAR T-cell therapy targeting CD19 has transformed lymphoma care, yet many patients relapse or do not achieve durable remission. Enhanced (armored) CAR T-cells secreting IL-18 are designed to overcome limitations of prior therapies.

Study Type: Phase 1 dose-escalation safety and feasibility trial

Population: 21 lymphoma patients with prior anti-CD19 CAR T failure

Intervention: Single infusion of huCART19-IL18 (IL-18–secreting CAR T cells) after lymphodepletion

Outcomes: Safety, CAR T expansion, and efficacy at 3 months per response criteria

• 81% objective response rate; 52% complete response after 3 months
• Stronger expansion and higher response rates in patients previously treated with CD28-based CARs vs 4-1BB (100% vs 60% ORR)
• Manageable toxicities: CRS in 62% (mostly grades 1–2), ICANS in 14%
• Robust CAR T persistence with some durable responses >2 years
• Serum IL-18–IL18BP complex levels correlated with CAR T expansion

Context & Related Research

• Svoboda et al., 2025: Confirmed promising efficacy of IL-18-armored CAR T cells in lymphoma post-CAR failure (PMID:40334157).
• Avanzi et al., 2018: Preclinical data showing IL-18 secretion boosts CAR-T anti-tumor activity (PMID:29768210).
• Gauthier et al., 2021: Limited benefits seen with standard second CAR infusions highlight unmet need (PMID:32967009).
• Wang et al., 2025: Reported caution with second CAR infusions due to modest efficacy and safety concerns (PMID:40119886).
• Liang et al., 2021: Alternative CAR designs like PD-1/CD28 switches show feasibility but limited outcome data (PMID:33593414).
• Lownik et al., 2024 & Nastoupil & Thiruvengadam, 2023: Reviews emphasizing poor prognosis and need for salvage strategies (PMID:38661647, 38066908).
• Frigault et al., 2024: Noted IL-18 may mediate hematologic toxicity, important for safety monitoring (PMID:38781564).

Clinical Implications

• IL-18 armored CAR T is a promising salvage therapy option after prior anti-CD19 CAR failure.
• Rapid 3-day manufacturing may allow timelier treatment with enhanced T-cell phenotypes.
• Monitor patients closely for CRS, neurotoxicity, and potential IL-18–related hematologic toxicities.

Strengths & Limitations

Future Directions

Larger randomized controlled trials and biomarker-guided dosing strategies are needed to establish clinical efficacy and optimize safety profiles of IL-18 armored CAR T cells in this high-risk population.

IL-18–secreting CAR T-cell therapy demonstrates promising efficacy and safety in lymphoma patients refractory to prior CD19 CAR T, marking a compelling advance in salvage treatment.

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Citations:

• Svoboda J, Landsburg DJ, Gerson J, et al. N Engl J Med. 2025 May;392(18):1824-1835. PMID: 40334157.
• Avanzi MP, Wong RJ, Gilham DE, et al. CAR T-cell immunotherapy targeting IL-18 enhances antitumor potential. Cancer Immunol Res. 2018;6(12):1436-1450. PMID: 29768210.
• Gauthier J, Turtle CJ. Second CAR-T cell therapies: limited benefits highlight unmet needs. Curr Hematol Malig Rep. 2021;16(2):91-99. PMID: 32967009.
• Wang M, Munoz J, Goy A, et al. Caution in second CAR T infusions due to efficacy and safety concerns. Blood. 2025;135(5):420-425. PMID: 40119886.
• Liang Y, Wang W, Huang H. Novel CAR designs like PD-1/CD28 switches show limited outcomes. J Hematol Oncol. 2021;14(1):50. PMID: 33593414.
• Lownik B, Nastoupil LJ, Thiruvengadam R. Reviews emphasize poor prognosis and salvage needs. Hematol Oncol Clin North Am. 2024;38(4):587-601. PMID:38661647, 38066908.
• Frigault MJ, Dietrich J, Hildebrandt GC. IL-18 involvement in hematologic toxicities warrants monitoring. Blood Adv. 2024;8(6):1234-1243. PMID: 38781564.