Nicolás Triantafilo C.

Can we prevent CAR-T exhaustion before it drives treatment failure? CAR-T therapy has transformed treatment for relapsed/refractory large B-cell lymphoma, but chronic tumor-cell engagement can drive progressive T-cell dysfunction and loss of tumor control. Using single-cell RNA sequencing of tumors at CAR-T progression, investigators identified clonally expanded, proliferating CAR-T cells showing transcriptional features of dysfunction and reduced IL-2 signaling. They then modeled repeated tumor-cell exposure in vitro, finding that chronic rechallenge progressively impaired CAR-T function. A potential solution emerged with pegenzileukin, a non-alpha IL-2 receptor agonist. Rather than simply increasing stimulation, it helped preserve CAR-T expansion and function, improving tumor control in vitro. The findings were even more striking in vivo: CAR-T alone produced only a transient response before tumor progression and CNS relapse, whereas CAR-T + pegenzileukin completely eradicated tumors in the model. The broader lesson: CAR-T failure may not simply reflect too little CAR-T activity—it may reflect sustained antigen engagement pushing the cells into dysfunction. Targeting the biology of exhaustion alongside the tumor itself could offer a new strategy to make CAR-T responses more durable. ashpublications.org/blood/ar… #CART #CellTherapy #Lymphoma #Immunotherapy #TCellExhaustion #Hematology #CancerResearch

What if bridging radiotherapy before CAR-T does more than control the tumor? Systemic inflammation before CAR-T therapy has been associated with impaired CAR-T function and inferior outcomes in patients with relapsed/refractory B-cell lymphoma. Bridging therapy is often used during CAR-T manufacturing to reduce or stabilize disease. But how different bridging approaches affect the inflammatory environment before lymphodepletion has been less clear. A new analysis of 421 patients treated with CAR-T used the validated INFLAMIX serum-based inflammatory signature to evaluate changes between apheresis and lymphodepletion. Overall, the proportion of patients classified as inflammatory decreased from: 🔹 44% at apheresis → 29% at lymphodepletion The change was most pronounced when bridging therapy included radiotherapy: 🔹 RT-containing bridging: 41% → 13% inflammatory 🔹 Systemic therapy alone: 44% → 35% Conversion to an inflammatory phenotype after RT bridging was uncommon, occurring in only 4% of patients. The findings also linked inflammation with tumor response: 🔹 86% of patients who converted to a non-inflammatory phenotype had a reduction in metabolic tumor volume 🔹 Compared with 47% of those who remained or became inflammatory 🔹 Non-inflammatory status at lymphodepletion and decreasing MTV were each associated with improved survival The broader implication is that radiotherapy may be doing more than providing local disease control before CAR-T. It may also be reshaping the systemic inflammatory environment in which the infused CAR-T cells will function. This challenges the traditional assumption that RT necessarily amplifies inflammation. In the pre-CAR-T setting, effective cytoreduction with RT may instead reduce systemic inflammation by lowering tumor burden. If confirmed prospectively, bridging RT could become more than an option for bulky or symptomatic disease. It could serve as a form of pre-CAR-T conditioning, optimizing both tumor burden and the host inflammatory state before infusion. The next question is whether inflammatory biomarkers and metabolic tumor volume can be used dynamically to determine who should receive RT, when it should be delivered, and what optimal bridging therapy looks like. #CART #CAR #Lymphoma #RadiationOncology #CellTherapy #Immunotherapy #DLBCL #TranslationalResearch sciencedirect.com/science/ar… sciencedirect.com/science/ar…