We have recently reported the identification of novel, dominant ILC2-dependent circuits of immunosuppression in cancer patients. Therefore, ILC2 may represent attractive cell targets to reprogram the immunosuppressive tumor microenvironment. By decoding the transcriptional programs of ILC2, we have identified candidate targets for ILC2 functional reprogramming. By therapeutically interfering with these circuits, we are exploring the impact of these discoveries in preclinical mouse models, in view of Phase I clinical trial.

The TNFSR14 (herpes virus entrymediator/HVEM) delivers a negative signal to T cells through the B and T lymphocyte attenuator (BTLA) molecule and has been associated to a worse prognosis in various malignancies. Here, we show in humanized mice that HVEM/BTLA is a novel immune checkpoint and that a mAb targeting HVEM acts on tumor growth in part through activation of myeloid cells. 

Antigen-presenting cells, in particular dendritic cells, play a central role in the cancer-immunity cycle. Alligator Bioscience develops therapies targeting CD40, which is the key activating receptor on dendritic cells. Mitazalimab is a Phase 2-ready monoclonal CD40 agonist that activates antigen-presenting cells, such as B cells, dendritic cells and macrophages, which can expand the tumor-specific T cell repertoire and remodel the tumor microenvironment.

This presentation will cover the fundamental aspects of the CD47-SIRPɑ axis, with a focus on our own contribution, including the discovery, history and current status, with respect to clinical developments.

Activating NK cell receptors represent promising trigger molecules on natural killer cells to modulate anti-tumor NK cell responses. In the presentation different strategies to modulate the NKG2D or NKp30 receptor by antibody derivatives will be presented.

Macrophages can adopt different functional roles in response to signals from their environment, including the ability to direct pro-inflammatory and anti-inflammatory immune responses. Verseau is utilizing its proprietary, all-human, drug discovery and translation platform to develop a pipeline of Macrophage Checkpoint Modulators. The lead monoclonal antibody program, targeting PSGL-1, reprograms macrophages to a pro-inflammatory state, activates T cells, and attracts other immune cells to generate a powerful antitumor response.

Chimeric antigen receptor (CAR)-based approaches have shown promise in hematologic malignancies, but responses in solid tumors have been minimal. This presentation will focus on the novel approach of genetically engineering primary human myeloid cells, such as monocytes and macrophages, and how this advance may overcome many of the challenges cell therapies face in the solid tumor setting.

Arch Oncology, Inc. is a privately held, clinical-stage immuno-oncology company focused on the discovery and development of best-in-class antibody therapies for the treatment of patients with cancer. Preclinical data will be presented about its lead product candidate, AO-176, that is in a Phase 1 clinical trial for the treatment of patients with select solid tumors. AO-176 is a highly differentiated, anti-CD47 antibody that in addition to inducing phagocytosis of tumor cells, binds preferentially to CD47 on tumor versus normal cells, directly kills tumor cells while inducing damage-associated molecular patterns, and shows enhanced binding under acidic conditions as found in the tumor microenvironment.

The CD47/SIRPɑ axis has recently been validated as an exciting clinical target, and importantly, its blockade could enhance antigen cross-presentation in the setting of immune-neglected (anti-PD1 refractory) tumors. The subset of dendritic cells which are the most potent antigen cross-presenters, express CD40, and its stimulation enhances CD8+ lymphocyte activation by these cells. SIRP ɑ-Fc-CD40L can simultaneously block immunosuppressive signals and activate innate immune cells, inducing a potent anti-tumor adaptive immune response.

Chronic inflammation via the inflammasome pathway plays a key role in carcinogenesis by accelerating tumor invasiveness, growth, and metastatic spread by promoting an immunosuppressive tumor microenvironment. Our work highlights the pathophysiological role of NLRP3 downstream mediator, IL-1b in tumor immunomodulation, and that IL-1b blockade might have important consequences on T cell function and checkpoint blockade in cancer.

Dendritic cells (DCs) play a major role in both inflammatory diseases and cancer. DCs within tumors are inefficient in taking up, processing, and presenting the tumor antigens effectively. This presentation will discuss the reprogramming of DC metabolism and targeting of the tumor antigens via surface receptors to improve anti-tumor immune response.