Bridging Radiotherapy May Decrease Inflammation Prior to CAR-T Cell Therapy
Authors: Patel Roshal R. , Tward Alexander , Fregonese Beatrice , Hubbeling Harper , Lapen Kaitlyn , Mankuzhy Nikhil P. , Raj Sandeep S. , Perales Miguel-Angel , Shouval Roni , Yahalom Joachim , Imber Brandon S. 
Published: December 2024

Introduction: Correlative studies from large, randomized trials have demonstrated that systemic inflammation, as measured by biomarkers such as LDH, CRP, ferritin, IL-6, and TNF-α, has been associated with worse outcomes to chimeric antigen receptor T-cell (CAR-T) therapy. Bridging radiotherapy (BRT) may improve CAR-T responses through proposed mechanisms such as tumor cytoreduction and modulation of the immune microenvironment. Radiotherapy has classically been thought to increase short-term inflammation, which may counterbalance decreases in inflammation from cytoreduction. To study this, we evaluated known parameters of inflammation to characterize the effect of BRT on the systemic inflammatory environment prior to CAR-T infusion.

Methods: We identified patients with B-cell malignancies treated with BRT, defined as radiotherapy delivered during the period between apheresis and CAR-T infusion, from March 2017 to May 2024. We examined lab markers associated with systemic inflammation. Baseline labs were identified within 30 days prior to BRT (median 9 days prior) and compared to labs post-completion of BRT, but pre-lymphodepletion (median 8 days after BRT). Pair-wise Mann-Whitney U testing was conducted to compare lab values before and after BRT.

Results: We identified 109 patients treated with BRT. Lymphoma histologies included diffuse large B-cell (86%), mantle cell (6%), follicular/marginal zone (5%), and Burkitt (3%). During the bridging period, 63% received BRT alone, whereas 37% received combination systemic therapy and BRT. Radiation doses ranged from 4Gy to 54Gy (median 30Gy) with the most common radiation regimens being 30Gy in 10 fractions (32%) and 20Gy in 5 fractions (24%). Twelve patients (11%) were treated with investigational CD19 agents, while the remaining patients were treated with axicabtagene ciloleucel (41%), lisocabtagene maraleucel (30%), tisagenlecleucel (14%), or brexucabtagene autoleucel (4%).

Of 105 patients with LDH collected before and after BRT, there was a significant decrease after BRT (median 271 U/L, IQR 202 - 409 vs 207 U/L, IQR 170 - 280; p&lt;0.001). Seventy-three patients (70%) had a reduction in LDH (median decrease of 72 U/L), while 32 patients (30%) saw an increase (median increase of 38 U/L). Radiation doses ≥30Gy were associated with larger reductions in LDH (median reduction of 59 U/L for ≥30Gy vs 17 U/L for &lt;30Gy; p=0.014). Seventeen patients had evaluable CRP before and after BRT, noting a significant reduction (0.58 mg/dL, IQR 0.23 - 3.98 vs 0.32 mg/dL, IQR 0.15 - 1.69; p=0.032). Only two patients had an increase in CRP after BRT. Linear regression analysis demonstrated a correlation between changes in LDH with changes in CRP (p&lt;0.001, 95% CI 0.004 - 0.009, R2=0.69).

Ferritin was non-significantly decreased in 26 patients with evaluable labs (336 ng/mL, IQR 63 - 1,092 vs 162 ng/mL IQR 59 - 914; p=0.77). Ferritin was reduced in sixteen patients and increased in ten. Only 12 patients had IL-6 and TNF-α collected pre/post-BRT. There was a non-significant reduction in IL-6 post-BRT (8.5 pg/mL, IQR 2.6 - 46.0 vs 5.1 pg/mL, IQR 0 - 8.1; p=0.26). Three patients had an increase in IL-6 after BRT. There was a small, but significant reduction in TNF-α (10.5 pg/mL, IQR 9 - 18.8 vs 9.0 pg/mL, IQR 8 - 17; p=0.02). One patient had an increase in TNF-α after BRT.

Conclusions: BRT may reduce systemic inflammation prior to CAR-T infusion as suggested by reductions in pro-inflammatory biomarkers known to be associated with poorer CAR-T outcomes. This may in part explain why BRT can benefit patients undergoing CAR-T therapy. Further work is planned to study this in a larger cohort and to equate these findings with outcomes.