Ovarian carcinoma (OC) is among the top five causes of cancer-related death in women. At odds with other neoplasms, OC is poorly sensitive to immune checkpoint inhibitors, correlating with a tumor microenvironment that exhibits poor infiltration by immune cells and active immunosuppression. Thus, novel strategies are needed to overcome the lack of pre-existing immunity, potentially including immunogenic chemotherapies, adoptive T cell transfer strategies, and/or vaccination approaches. As most immunotherapies only benefit a small percentage of patients, it is also imperative to discover biomarkers that prospectively identify patients potentially achieving benefits from specific immunotherapeutic regimens, in the setting of personalized cancer immunotherapy.

The tumour microenvironment is frequently immune suppressive and can negatively impact the efficacy of antibody therapies. Identifying and understanding key mechanisms of resistance to antibody drugs could be instrumental to enhancing and widening responses. Here, we will present examples of how the tumour microenvironment can suppress antibody therapy and discuss strategies to overcome this suppression to enhance outcomes.

Patients with “cold” tumors rarely benefit from immune checkpoint blockade (ICB). Seeking to bring clinical benefit of ICB to these patients, we assessed the potential of FcgR blockade and spatially restricted vectorized anti-CTLA-4 to help overcome resistance in the cold tumor microenvironment. We provide in vivo proof-of-concept that triplet aPD-1/aCTLA-4/aFcgRIIB and doublet vectorized aCTLA-4/aPD-1 induce cures in B16 melanoma-bearing mice resistant to systemic aCTLA-4/aPD-1 combination immunotherapy.

The immune system uses checkpoints to maintain immune homeostasis, but cancer cells copy this technique to defend themselves against it, resulting in immune escape. We have engineered a mutant of the T cell mobilizing chemokine CXCL10 that acts as a superagonist via its improved GAG binding affinity. In pathological conditions with impaired immunosurveillance, this decoy could help bypass the immune system blockade and re-install T cell response leading to tumor necrosis.

One of the main hurdles for CD3-bispecific antibody therapy for solid tumors is the lack of tumor-infiltrating T cells, which are essential for therapeutic efficacy. We found that systemic administration of tumor-aspecific vaccination increased T cell infiltration in solid tumors and engaging these T cells with CD3-bispecific antibodies delayed tumor outgrowth and improve survival in syngeneic mouse models. This strategy might be used to improve CD3-bispecific therapy responses for solid tumors in the clinic.

Cytokines are powerful regulators of the immune system and attractive therapeutic effector candidates – provided that their sites of action can be restricted to avoid systemic exposure and toxicity. To achieve such spatial control of cytokine bioactivity upon drug administration, we have evolved a proprietary biologics platform that integrates a strategic “plug-and-play” assembly of modular, biomolecular building blocks into therapeutic agents with unique conditional effector functions and cell target selectivity.

Myeloid cells like monocytes/macrophages and PMN constitute a major population of tumor cell infiltrates. Myeloid checkpoint blockade e.g. with CD47 antibodies or QPTCL inhibitors can improve the therapeutic efficacy of tumor-directed antibodies. Additionally, switching to IgA antibodies can improve myeloid effector cell recruitment. Thus, the future challenge will be to identify situations in which myeloid effector cells in the tumor microenvironment can be optimally recruited to contribute to antibody efficacy.

Agonistic antibodies directed to immunostimulatory receptors are a currently untapped source for immunotherapy. Whereas checkpoint blockers have translated into the clinic, the rules for agonistic antibodies have been more difficult to discern and these reagents await further optimization. Here we discuss the salient properties of monoclonal antibodies (mAb) required to strongly agonize these receptors and discuss potential antibody engineering strategies for the future. Using TNFR superfamily receptors as a paradigm the following key aspects will be discussed:

• Role of isotype
  
• Role of epitope
• Structure-function relationships
• Engineered Fc for greater agonism

Xilio Therapeutics, Inc., is a clinical-stage biotechnology company. We are using our proprietary geographically-precise solutions (GPS) platform to rapidly engineer novel molecules, including cytokines and other biologics, that are designed to optimize their therapeutic index. These molecules are designed to localize activity within the tumor microenvironment while limiting systemic effects, resulting in the potential to achieve increased dosing and enhanced anti-tumor activity. We will present an update on our pipeline of wholly-owned, tumor-selective, GPS-enabled cytokine and checkpoint inhibitor programs.

Allogeneic T cells have qualities that make them an ideal platform for treating disease. Evolution of CAR T designs and next-generation armoring technologies to overcome the hostile tumor microenvironment will be explored, including the promise of a platform that doesn’t require HLA or TCR gene editing and safety, expansion, and persistence implications. 

Immune checkpoint inhibitors have revolutionized cancer treatment, but only a minority of patients respond and there is a critical need to identify reliable predictive biomarkers. The tumor microenvironment holds key information to predict clinical outcomes. Notably, B cells and tertiary lymphoid structures (TLS) have recently been shown to predict immunotherapy efficacy in various malignancies. The latest developments regarding B cells and TLS will be discussed during this talk:

• B cells and TLS predict immunotherapy response in soft-tissue sarcoma, melanoma, and other malignancies
• TLS as determinants of the immune contexture and clinical outcome
  
• TLS generate and propagate anti-tumoral plasma cells?