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.

Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking. We identified the innate immune kinase TANK-binding kinase 1 (TBK1) as a candidate immune evasion gene in a pooled genetic screen. Using a suite of genetic and pharmacologic tools across multiple experimental model systems, we confirm a role for TBK1 as an immune evasion gene. Our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy.

• Are immune cells programmed distinctly in different organs?
• Cross talk between suppressive myeloid cells and CAR T cells
• Combinatorial approaches to create a more favorable TME for CAR T cells​

• ​Can viruses "go it alone" or are they "the opening act?"
• Intravenous vs. intratumoural delivery —Targeted intravenous delivery of cancer-killing viruses is a viable treatment strategy for hard-to-reach, immunologically cold tumours?
• Beyond liposomes — platforms for oncolytic virus delivery
• Clinical translation of nanomedicines
  

The B cell response may contribute to clinical outcomes, especially in immunogenic tumours such as melanoma and subsets of breast cancers. While isotype-switched B cells with distinct immunoglobulin isotype profiles form part of the immune infiltrate, inflammatory Th2-biased conditions in the tumour microenvironment promote B cell maturation as a mechanism to divert humoral immunity in solid tumours. Dissecting B cell profiles can uncover tumour-associated immune suppression signatures with prognostic relevance.

I will discuss targeting neutrophils with IgA triggers trogoptosis of cancer cells, checkpoint inhibitors on neutrophils, synergy with IgA, and how to attract neutrophils as killer cells to the TME.

Most aggressive solid tumors and hematological malignancies express certain extracellular matrix components (e.g., splice variants of fibronectin and of tenascin-C), which are virtually undetectable in most normal adult tissues. In this lecture, I will show how certain antibody-cytokine fusions, specific to alternatively-spliced extracellular matrix components, can be used to effectively treat patients with aggressive forms of cancer.

Primary and metastatic liver tumors are among the most lethal malignancies. While immunotherapy represents one of the greatest advancements in cancer treatment over the past 50 years, unfortunately, patients with tumors in the liver are less likely to respond relative to most other cancer types. Immunological and physical barriers within the organ and the tumor microenvironment (TME) often limit the efficacy of immunotherapies in the liver.

Challenges in developing new immuno-oncology therapies has led to emerging strategies that attempt to correct immunological defects in the tumour microenvironment (TME) by targeting specific cell phenotypes known to contribute to tumorigenesis and immunosuppression. By using improved methods in AI, chemogenomics, computational biology and more advanced translationally relevant in vitro screening, we attempt to identify targets capable of causing a reprogramming in the TME towards a more inflammatory phenotype.

At Candel Therapeutics, we are developing immunotherapies that induce immunogenic cell death in cancer cells, unmasking tumor neo-antigens within an activated microenvironment. This process leads to a systemic, durable immune response against the injected tumor and uninjected metastases, with the potential to change disease outcomes across a variety of solid tumors. Candel’s investigational medicines are designed to improve survival while maintaining quality of life – from early- to late-stage disease.

High expression of the CD270 on tumors strongly correlates with poor survival and an immunosuppressive TME. Anti-CD270 antibodies were selected that specifically inhibit the interaction with immune suppressive ligands CD160 and BTLA but do not inhibit the immune-stimulating CD270-LIGHT interaction. This turns CD270 expressing tumors from immune suppressive to immune stimulatory.

Clinical trials with CAR T cells have had limited efficacy in patients with solid tumors. CAR T cell persistence and tumour-mediated immune suppression are key hurdles. To address these issues, we created (1) a novel CAR T cell with a stem-like phenotype, increased persistence and tumour control in vivo; (2) switch CAR T cells which bind to mediators of immune suppression and convert T cell suppression to activation to increase tumour control in vivo.

• Hurdles to CAR T cell efficacy
• Engineering CAR T cells to address a resistance is now feasible
  
• Combination therapy with CAR T cells may be needed to achieve objective clinical responses in patients?

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 optimisation. Here we discuss the salient properties of monoclonal antibodies (mAb) required to strongly agonise these receptors and discuss potential strategies for leveraging them optimally for immune activation and anti-tumour efficacy.

We have generated camelid-derived single domain antibodies targeting different Natural Cytotoxicity Receptors for the conditional activation of NK cells. Combined with a humanized Fab version of Cetuximab for tumor targeting, resulting NK cell engagers (NKCEs) trigger potent NK cell-mediated killing of EGFR-overexpressing tumor cells. By modulating valencies of incorporated binders as well as via engineering the spatial orientation of individual paratopes, killing capacities of constructed NKCEs can be augmented significantly.

We are developing next-generation antibodies, such as Fc-engineered antibodies with enhanced immune function or antibody-drug conjugates (ADCs), for the treatment of breast cancer. Our lab has developed a novel ADC against triple-negative breast cancer (TNBC) which greatly restricts growth of human TNBC xenograft tumours in vivo. We have also engineered novel Fc-enhanced antibodies against HER2-positive breast cancer and TNBC which induce significantly greater direct cell killing by antibody-dependent NK cell-mediated cytotoxicity (ADCC) and reprogramming of macrophages towards a more pro-inflammatory, anti-tumoural phenotype.