Neutralizing the IL-12/IL-23 p40 subunit prevents immune checkpoint blockade toxicity without compromising antitumor efficacy
(1) Groeneveldt C (2) Vadgama D (3) Onrust-van Schoonhoven A (4) Whyte D (5) Hofman MM (6) Rozendaal NEM (7) van Nimwegen M (8) Eterman M (9) Dumoulin DW (10) Mathijssen RHJ (11) Joosse A (12) van der Veldt AAM (13) Boon L (14) Doukas M (15) Samsom JN (16) Stadhouders R (17) Dammeijer F (18) Aerts JGJV (19) Joosse ME
Groeneveldt et al. investigated mechanisms driving early-stage immune-related adverse events (irAEs) in patients with metastatic melanoma treated with combination ICB (anti-PD-1 and anti-CTLA-4). Proteomic analysis of serum identified an early, significant increase of p40, a subunit of IL-12/I-23, prior to the onset of clinically apparent irAEs, which was not associated with ICB efficacy. In mouse models that mimic irAEs in patients, p40 neutralization prevented ICB-induced toxicity, without compromising antitumor T cell immunity, including the establishment of tumor-specific responses, suggesting distinct mechanisms that can be uncoupled.
Contributed by Katherine Turner
(1) Groeneveldt C (2) Vadgama D (3) Onrust-van Schoonhoven A (4) Whyte D (5) Hofman MM (6) Rozendaal NEM (7) van Nimwegen M (8) Eterman M (9) Dumoulin DW (10) Mathijssen RHJ (11) Joosse A (12) van der Veldt AAM (13) Boon L (14) Doukas M (15) Samsom JN (16) Stadhouders R (17) Dammeijer F (18) Aerts JGJV (19) Joosse ME
Groeneveldt et al. investigated mechanisms driving early-stage immune-related adverse events (irAEs) in patients with metastatic melanoma treated with combination ICB (anti-PD-1 and anti-CTLA-4). Proteomic analysis of serum identified an early, significant increase of p40, a subunit of IL-12/I-23, prior to the onset of clinically apparent irAEs, which was not associated with ICB efficacy. In mouse models that mimic irAEs in patients, p40 neutralization prevented ICB-induced toxicity, without compromising antitumor T cell immunity, including the establishment of tumor-specific responses, suggesting distinct mechanisms that can be uncoupled.
Contributed by Katherine Turner
ABSTRACT: Immune checkpoint blockade (ICB) has markedly improved overall survival in various cancers, but is associated with severe and sometimes fatal immune-related adverse events (irAEs). Current management of irAEs involves discontinuation of ICB therapy and administration of immunosuppressive drugs, such as corticosteroids, which have been associated with decreased antitumor efficacy. Although irAE development is associated with ICB response, it is currently unknown whether their underlying mechanisms are shared or distinct. To identify early and targetable drivers of irAEs, we performed proteomic analyses on the serum of patients with cancer treated with anti-PD-1 and anti-CTLA-4 combination ICB. We identified a significantly increased concentration of p40, a subunit of IL-12/IL-23, shortly after the start of ICB but before the onset of clinically apparent irAEs. Importantly, increased p40 levels were not associated with ICB efficacy. Neutralizing p40 mitigated ICB-induced toxicity in various mouse models without impairing ICB-induced antitumor efficacy. In conclusion, we demonstrated that IL-12/IL-23p40 is a key mediator of ICB-induced toxicity while being redundant for ICB antitumor efficacy. This shows that the mechanisms underlying ICB toxicity and efficacy can be uncoupled and provides a rationale for p40 blockade in clinical trials with ICB treatment to prevent irAEs in patients.
Author Info:
(1) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (2) Erasmus MC Cancer Institute Rotterdam, South-Holland Netherlands. ROR: https://ror.org/03r4m3349 (3) Erasmu
s MC Netherlands. ROR: https://ror.org/018906e22 (4) Cancer Research UK Scotland Institute United Kingdom. ROR: https://ror.org/03pv69j64 (5) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (6) Erasmus MC Cancer Institute Netherlands. ROR: https://ror.org/03r4m3349 (7) Erasmus MC Rotterdam Rotterdam Netherlands. (8) Erasmus MC Cancer Institute Netherlands. ROR: https://ror.org/03r4m3349 (9) Erasmus MC Rotterdam Rotterdam Netherlands. (10) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (11) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (12) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (13) University of Warsaw Poland. ROR: https://ror.org/039bjqg32 (14) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (15) Erasmus MC - Sophia Children's Hospital Rotterdam, South Holland Netherlands. ROR: https://ror.org/047afsm11 (16) Erasmus MC Rotterdam Netherlands. ROR: https://ror.org/018906e22 (17) Erasmus MC Rotterdam Rotterdam Netherlands. (18) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349 (19) Erasmus MC Cancer Institute Rotterdam Netherlands. ROR: https://ror.org/03r4m3349
Citation: Cancer Immunol Res 2026 Aug 31 Epub08/31/2026
