The meticulous balance of our immune system, which allows it to combat infections and cancer while preventing autoimmune reactions, is regulated by co-inhibitory and co-stimulatory immune checkpoint complexes (ICCs). These complexes have become significant drug targets, driving rapid advancements in cancer immunotherapy with antibodies that block inhibitory ICCs. Meanwhile, antibodies that block stimulatory ICCs are in clinical trials for treating autoimmune diseases. Surprisingly, but likely fueled by the current focus on IC inhibitors, the field has largely ignored that ICCs are genuine transmembrane receptors that transmit signals upon binding of an extracellular protein ligand. This oversight leaves unexplored therapeutic avenues that we are now addressing by validating Nanobodies (Nbs) as first-in-class allosteric modulators of inhibitory immune checkpoint complexes. By applying innovative immunization and bio-selection techniques, we have discovered and characterized the first-ever positive allosteric modulators (PAMs) of a clinically relevant inhibitory ICC that enhance receptor signaling with pathway-specific and spatio-temporal precision. These ICC PAMs open up novel therapeutic modes of intervention that ensure patient safety, even in cases of overdose, and may outperform current inhibitor-based immunotherapies, which often cause significant side effects.

The study explores combining myeloid checkpoint blockade with IgA antibodies against CD19, CD20 or CD38 to enhance killing of acute lymphoblastic leukemia (ALL). By recruiting macrophages and PMN and harnessing IgA's unique Fc receptor engagement, this strategy aims to improve tumor clearance. Preclinical results with anti-CD38 IgA2 and CD47 blockade show synergistic effects in vitro and in vivo, suggesting this combination may become a novel immunotherapeutic approach for more effective ALL treatment strategies.

We have developed a novel tumour-selective immuno-virotherapy, TROCEPT, based on adenovirus serotype 5 (Ad5). TROCEPT has been engineered not to enter normal human tissues by disabling (de-targeting) all three of the major capsid proteins (fiber knob, hexon and penton). The removal of normal tissue tropisms addresses the main limitations of other intravenously delivered viral therapies, which are rapidly sequestered in the liver and other healthy tissues. TROCEPT has been further engineered to specifically bind to αvβ6 integrin (re-targeting), a tumour marker expressed at high frequency on most carcinomas. The TROCEPT platform can be armed with transgenes encoding potent protein-based therapeutic drugs for in-tumour expression.

We report findings from the VENEZOLUNG trial, assessing autologous dendritic cell (DC) vaccination plus atezolizumab in ES-SCLC. Expansion of circulating XCR1+ DCs and CXCR5+PD-1+ CD8+ T cells correlated with improved survival, while reductions in Tpex and DC subsets predicted poorer outcomes. These results highlight the relevance of XCR1+ DCs in enhancing immunotherapy efficacy in SCLC. Final data will be presented at the meeting.

Both CAR-T and CAR-M have a great potential to eradicate malignant cells, however, convincing evidence in solid tumours is missing. Macrophages have an intrinsic potential to migrate into solid tumours, and, if kept in an anti-tumoural state, can re-shape the tumour micro-environment, enabling CAR-T to persist and remain active within a solid tumour. By combining the different properties of CAR-M and CAR-T, we thus hope to overcome the hurdles of conventional mono-immune therapy and make CAR immunotherapy effective in solid cancers.

Single-domain antibodies (sdAb, VHH) offer advantages over single-chain variable fragments (scFv) in biophysical properties such as stability and aggregation propensity, making them a favoured antibody format for antigen recognition for chimeric antigen receptor (CAR) T cells. We compared 10 affinity-matched VHH and scFv-CAR pairs targeting CD123, assessing differences in performance in vitro and in vivo. The VHH-CARs had an improved biophysical profile and sensitivity to low antigen density targets, with enhanced cytokine secretion compared to scFv-CARs. Following these findings, we propose a triple VHH-CAR strategy simultaneously targeting CD123, CLL-1, and CD33, addressing critical challenges in acute myeloid leukemia (AML) treatment.

InCephalo’s compartment lock (C-Lock) toolbox allows to confine the activity of antibodies or antibody Fc-fragment fusion proteins to the brain. InC01 is a C-Locked IL-12-based biologic which InCephalo develops for local treatment of brain cancer. Preclinical data on the development and proof of concept in murine and human ex vivo models will be presented with a focus on local, intratumoural effector cells and a locally sustained anti-glioma immune response.

• Tumor heterogeneity
• Different resistance mechanisms
• Immunosuppressive cell types, immunosuppressive factors
• Immunosuppressive ligands
• Large impenetrable tumor mass
• Lack of nutrients, exclusion of immune cells
• Hard to tip the equilibrium balance to immune control by overcoming tumour immune suppression

• Innovative payloads and linker strategies for non-cytotoxic applications.
• Target selection challenges (membrane-bound vs. soluble targets).
• Efficacy, safety, and biodistribution outside the oncology paradigm.
• Regulatory and translational considerations in non-oncology ADCs.

The talk would give an overview of Bright Peak PD1 based immunoconjugates pipeline with specific focus on the clinical program of PD1-IL18. We will share unique insights from technology used to construct PD1-IL18 based immunocytokines to preclinical characterisation of 'first-in-class' molecules and an overview of the clinical plans.

SOT201 is a novel cis-acting immunocytokine consisting against PD-1 antibody fused to RLI-15 complex consisting of an attenuated human IL-15 mutein and the high-affinity binding site of the IL-15Ralpha, the sushi+ domain. SOT201 targets PD-1+ TILs with a balanced cytokine potency to revive exhausted T cells in tumours in comparison to PD1-IL-2v. SOT201 is currently being evaluated in Phase I clinical study VICTORIA-01 (NCT06163391) in metastatic advanced cancer patients.

Although cytokines activate many cell types, only a subset drives anti-tumor activity, while others may reduce efficacy or cause toxicity. This talk will present preclinical data showing that restricting IL-2 and IL-21 signaling to CD8+ T cells via cis-targeting can decouple anti-tumor effects from toxicity, expanding the therapeutic window. Clinical evidence of highly effective cis-targeting will also be discussed, including findings with etakafusp, a CD8-targeted IL-2 therapy.