In several models and functional evaluations, anti-tumour IgE immunotherapy can restrict cancer growth by immune effector mechanisms employed by this antibody class against parasites. IgEs recognizing tumour-associated antigens potentiated re-activation of monocytes and recruitment of stimulated macrophages into the tumour microenvironment. We will discuss the clinical development of a first-in-class IgE and the mechanisms by which IgE can reconfigure the tumour microenvironment and activate previously untapped immune mechanisms against tumours.

Macrophages are critical for the anti-tumour activity of direct targeting antibodies, such as rituximab. Here, we will present recent preclinical and clinical experience on how T cell stimulation with CD27 agonists can modulate the activity and enhance the anti-tumour activity of macrophages.

Despite the clinical breakthroughs achieved with checkpoint blockade, the overall proportion of patients experiencing durable responses remains relatively small. Therefore, the real promise for most cancer patients lies in complementary combination therapies, combining checkpoint blockade with the immune-promoting/supporting properties of other therapeutic modalities, which help breach physical barriers, overcome immunosuppression, and improve immune cell infiltration in tumors. This talk will compare and highlight two of the latter categories: antibody-drug conjugates and oncolytic viruses

We have developed new bioluminescent tools that expedite the development of T cell-redirecting cancer therapies. We will describe how TCRαβ-null reporter cells can be used to screen TCRs against tumor antigen, and NanoBiT-based assay platforms that quantitatively measure the potency of CD3 bispecific antibodies to induce T cell-dependent effector functions.

Many efforts have been devoted in recent years towards reconditioning the tumor microenvironment to mount an immune response against the tumor. While holding promises, our understanding of the manipulation of the immune system remains limited and has to be addressed with other technical challenges, such as tumor penetration, off-target systemic toxicity, and simultaneous co-engagement of several tumor progression pathways. We will be sharing our strategy to answer these different challenges using the Nanofitin scaffold, with examples of multispecific constructions directed against several tumor progression pathways (angiogenesis, T cell population, and macrophage differentiation).

Fine-tailoring antibody Fv- and Fc- interactions is needed to optimize anti-TNFRs antibodies’ activity. Here, the potent antitumor activity of isotype-optimized ligand-blocking, or agonist, antibodies to the T cell co-stimulatory receptor TNFR2 is described. Both types of mAbs eradicated large solid tumors through mechanisms involving intratumoral Treg-depletion and/or CD8+ T cell expansion, alone or in combination with anti-PD-1. BI-1808 has completed GLP toxicology and is scheduled to enter the clinic in 2020.

There is growing appreciation of the depth of interaction between tumour cells and their microenvironment serving to modulate tumour growth, proliferation and immune suppression. Although these interactions have long been known to limit responses to conventional treatments such as chemotherapy, their impact on antibody immunotherapy is less clear. This presentation will discuss several key interactions between the host and the tumour that impact antibody immunotherapy and how they might be targeted to improve treatment efficacy.

Systemic administration of some agonistic anti-CD40 antibodies has shown some signs of activity in cancer patients, but dose-limiting toxicity has prevented the exploration of the full dose range, and possibly has impaired clinical efficacy. To overcome this issue, we developed a multispecific DARPin® therapeutic candidate, MP0317, intended to activate CD40 receptor locally, rather than systemically, in the tumor microenvironment through cross-linking with fibroblast activation protein (FAP). In vitro and in vivo data will be presented showing that MP0317 is able to activate the CD40 receptor locally in FAP-positive tumors, producing significant antitumor activity in the absence of systemic toxicity.