Zippelius Lab
Anti-PD1-IL18 immunoconjugate promotes effector T cell-mediated antitumor immunity
Oelgarth et al. (JITC 2026)
Immune checkpoint inhibitors have transformed cancer therapy, but resistance remains a major challenge. In this study, we developed a novel PD-1-targeted immunocytokine that combines checkpoint blockade with localized immune stimulation to enhance antitumor responses. The therapy promoted robust T-cell activation, inflammatory signaling, and tumor control across multiple preclinical models, including resistant tumors. Complementary studies in human tumor samples supported these findings and demonstrated the presence of similar immune cell populations across diverse cancer types. These results provide strong preclinical and translational support for this targeted immunotherapy approach.
Cytotoxic CD39+ tumor-associated NK cells respond to NKG2A blockade in lung cancer
Serger et al. (Sci Immunol. 2026)
This study maps the differentiation of tumor-associated natural killer (NK) cells in non–small cell lung cancer, identifying a CD39+ effector population as the dominant cytotoxic NK cell subset within tumors. The authors show that these cells possess enhanced tumor-killing capacity that can be further amplified by NKG2A blockade, highlighting a promising target for next-generation NK cell immunotherapies.
Unveiling the molecular and immunological drivers of antibody-drug conjugates in cancer treatment
Zippelius et al. (Nat Rev Cancer 2025)
Antibody-drug conjugates (ADCs) are complex therapeutics with multiple molecular interactions that determine their distribution, efficacy and toxicity. The multiple mechanisms of action of ADC payloads and antibodies make them ideal candidates for pairing with immunotherapeutics by controlling cancer cell versus immune cell delivery and stimulation.
In this review we aim to inform the rational design of combination therapies and guide the development of the next generation of clinically effective ADCs.
PD-1-targeted cis-delivery of an IL-2 variant induces a multifaceted antitumoral T cell response in human lung cancer
Fusi, Serger et al. (Sci Transl Med. 2025)
In this paper, we study the mechanism of action of PD1-IL2v , a new antibody-cytokine fusion designed to activate specific immune cells inside tumors. Using human tumor models, we show how this targeted IL-2 therapy functionally reprograms T cells, further supporting its development as a next-generation cancer immunotherapy.
Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy
Trefny et al. (Nat Commun. 2023)
In this paper, we identify SNX9 as a key mediator of T cell exhaustion, demonstrating that its deletion enhances T cell memory differentiation, increases IFNγ production, and improves the antitumor efficacy of adoptively transferred and CAR T cells. These results reveal a promising strategy to prevent exhaustion and strengthen T cell–based immunotherapies.
NK cells with tissue-resident traits shape response to immunotherapy by inducing adaptive antitumor immunity
Kirchhammer et al. (Sci Transl Med. 2022)
This study shows that effective T cell–based cancer immunotherapy depends on a specific population of tissue-resident natural killer (NK) cells that produce the chemoattractant CCL5, which recruits dendritic cells and enhances T cell–mediated tumor killing. Using an engineered adenoviral IL-12 therapy, we demonstrate how activating this NK cell–dendritic cell–T cell axis can overcome resistance to immunotherapies like PD-1 blockade, highlighting a key mechanism for boosting antitumor immunity and improving therapy outcomes.