Hyper-fractionated radiotherapy as a bridging strategy to enhance CAR-T efficacy by regulating T-cell co-stimulatory molecules in relapsed/refractory diffuse large B-cell lymphoma

Abstract

Background: Bridging therapy can prevent patients from disease progression while waiting for CAR-T cell preparation. Hyper-fractionated radiotherapy can achieve an effective target dose within a short period, minimize radiation damage, and may modify immune environment compared to conventional radiotherapy.

Aims: This study aims to investigate the efficacy and safety of bridging hyper-fractionated radiotherapy in combination with CAR-T therapy for relapsed/refractory diffuse large B-cell lymphoma. The potential mechanisms were explored.

Methods: This is a prospective pilot study. After T-cell collection, the patients underwent hyper-fractionated radiotherapy at lesion sites with 1.5 Gy twice daily for 10 days before CAR-T cell infusion. Peripheral blood immune cell subsets and quantitative serum proteomics were assessed before radiotherapy and after radiotherapy before CAR-T cell infusion.

Results: A total of 13 patients have been enrolled. The median follow-up time was 6 (3-24) months after CAR-T infusion. At 3-month follow-up, 9/13(69%) patients had CR, 1/13(8%) patient had PR, 1/13(8%) patient remained SD, and 2/13(15%) patients died of disease progression. The local recurrence rate was 1/13(8%). Seven patients have been followed up for more than 6 months, and they remain in CR. The median PFS and OS were not reached. No grade 3-4 CRS or ICANS were reported. After hyper-fractionated radiotherapy, peripheral PD1+CD8+T/T ratio significantly decreased while quantitative serum proteomics profiling showed a decrease in sCD28.

Conclusion: Hyper-fractionated radiotherapy can rapidly control tumor progression sites without delaying the infusion time. This approach can improve the ORR and does not increase the incidence of CRS and ICANS. The mechanism may be related to the regulation of T-cell co-stimulatory molecules, which demands further exploration.

Keywords: CAR-T; DLBCL; T-cell co-stimulatory molecules; bridging therapy; hyper-fractionated radiotherapy.

Figure 1

(A–C) A case of bulky left cervical disease. (A) Baseline PET/CT scan showed a 13.1 cm × 8.4 cm × 10.5 cm mass with SUVmax to be 20.5 at the left side of the neck and pushing the trachea to the right. (B) The mass quickly shrank to 6×2.6 cm after hyper-fractionated radiotherapy. (C) After CAR-T cell infusion at 1 month, PET/CT scan showed a 3.2 cm × 1.9 cm mass with SUVmax of 3.2. (D–F) A case of CNS lesion. (D) Baseline contrast-enhanced MRI showed a 2.5-cm enhanced nodule with peripheral edema in the left frontal lobe. (E) After radiotherapy, the lesion shrank to 0.75 cm with ring-like enhancement. (F) After CAR-T cell infusion at 1 month, the lesion was 0.5 cm with ring-like enhancement. (G) The lesion had no enhancement on the contrast-enhanced MRI at 3-month after CAR-T cell infusion.

Figure 2

The Kaplan–Meier survival curves for progression free survival and overall survival of the 13 patients in our study.

Figure 3

Significantly decreased CD8+PD1+T/T (15% vs. 8%, p=0.017), decreased granulocyte/WBC (73% vs. 58%, p=0.049), and increased monocyte/WBC (9% vs. 13%, p=0.029) ratio were observed after hyper-fractionated radiotherapy.

Figure 4

Paired t-test showed significantly decreased sCD28 (p=0.016), CXCL12 (p=0.013), NOS3 (p=0.003), and PTN (p=0.034) and increased Gal1 (p=0.009) after hyper-fractionated radiotherapy.