A common basis for cancer immunotherapy treatment failure appears to be the suppressive tumor microenvironment (TME). We are investigating the B cell repertoire of cancer patients who have successfully responded to immunotherapy to identify antibodies that can relieve immunosuppression in the TME. We have discovered several antibodies that are directed at modulating immunosuppression of the tumor microenvironment. I will present data on OR2805, a clinical-stage anti-CD163 antibody, that relieves immunosuppression caused by macrophages, and discovery and preclinical characterization of LILRB2/ILT4 antibody that rescues T cells from macrophage-mediated suppression and induces anti-tumor responses.

Evaluation of Fc effector mechanisms of therapeutic antibodies is an important regulatory requirement. Eurofins DiscoverX’s MOA-reflective KILR cytotoxicity assays enable precise quantitation of multiple effector-mediated MOA’s including ADCP & ADCC applications. These dye-free, radioactivity-free assays measure direct target cell killing. Here we share phase-appropriate data for several KILR bioassay models demonstrating these assays are fit-for-purpose for screening, characterization, & relative potency applications in lot-release testing.

Targeting oxMIF, the disease-related isoform of MIF, enables the inhibition of different MIF-mediated pro-tumorigenic effects. Our clinical candidate anti-oxMIF antibody ON203 shows modulation of the immune contexture of patient-derived colorectal cancer tumoroids towards enhanced immune cell responses. These findings are in line with in vivo data from xenograft cancer models. ON203 has a high potential to become a new treatment option for patients with solid tumors, either as standalone therapy or in combination with checkpoint inhibitors that could generate more durable responses and contribute to the prevention of tumor resistance.

Mucin 4 (MUC4), a transmembrane glycoprotein, shields trastuzumab epitope on HER2 molecule inducing resistance, and also it is a biomarker of poor disease-free survival in HER2+ breast cancer treated with trastuzumab. TNFα neutralization downregulates MUC4 expression sensitizes cells and tumors to trastuzumab and triggers an antitumor immune response. MUC4 expression is associated with immune desert HER2+ breast cancer. Knowing MUC4 status of a patient’s tumor will improve clinical decision-making and should benefit patient outcomes.

• What tumor types have prevalent mechanisms of antigen presentation defects?
• How to increase antigen presentation through MHC class I?
• How to increase antigen presentation through MHC class II?
• How to develop clinical biomarkers for tumors with antigen presentation defects?
• Why don't NK cells kill cancer cells with MHC Class I defects?​

Although there has been advancement in the treatment of head and neck cancers with immunotherapy in recurrent metastatic disease the response rates still remain low, especially in platinum-refractory head and neck cancers. So far, combination of radiation therapy and immune checkpoint inhibitors has also not been shown to be effective. I would like to discuss the novel immunotherapy combination strategies in head and neck cancer.

In the highly competitive immune-oncology (I-O) space, effective identification and differentiation of potential therapeutics requires a detailed understanding of mechanism of action (MOA). To maximize the value of sophisticated antibody discovery technologies, MOA needs to be understood at the earliest stages of drug discovery. In these initial stages, candidate numbers can measure in the thousands and precious sample quantities are stretched thin across numerous discovery platforms. This talk will focus on a strategy of I-O therapeutic selection supported by high-throughput surface plasmon resonance (HT-SPR) to increase the potential for efficacious and commercially differentiated antibodies. By front loading characterization efforts in the discovery phase, this approach enables an evolving selection of therapeutic leads dependent on program objectives, biological discoveries, and commercial pressure.

More than a decade ago, a new class of immune therapy called immune checkpoint inhibitors (ICI) revolutionized cancer research. Since their debut, ICIs have achieved many successes but have also led to many challenges both in term of toxicity and efficacy. In this talk, we will discuss novel preclinical approaches that can guide the development of the next-generation of immune-oncology (IO) agents and the design of rational combination strategies.

Oncolytic virotherapy ONCOS-102 demonstrated 35% ORR in a phase I trial in 20 patients in PD1 r/r melanoma. Following local delivery of ONCOS-102, systemic tumor responses were observed in >50% of patients, including 2 examples where a non-injected lesion completely disappeared. Tumor responses were associated with strong increase in T cell infiltration, which persisted and strengthened over time. Broad immuno-modulation was demonstrated by RNAseq gene expression analysis, confirming cellular IHC observations. A randomized multi-cohort phase II trial is being set up to test ONCOS-102 further in PD1 r/r melanoma in various IO combinations.

TANK-binding kinase 1 (TBK1) is a versatile innate immune protein kinase nominated as a candidate immune evasion gene in a number of pooled genetic screens. Using genetic and pharmacologic tools across multiple experimental model systems, we have confirmed a role for TANK-binding kinase 1 (TBK1) as an immune evasion gene. Taken together, our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy.

Patients with Kras-driven lung adenocarcinoma have benefited from T cell targeted immunotherapies, but response rates vary based on the presence of various genetic co-mutations. Importantly, the link between cancer genetics and the anti-tumor T cell response is not understood. Therefore, we generated mouse models of lung cancer harboring different mutations commonly found in human disease but expressing the same neoantigen, allowing us to determine the mechanisms behind this therapeutic disparity.

Antigen presentation defects in tumors are prevalent mechanisms of adaptive immune evasion and resistance to immune checkpoint blockade, but how these tumors escape NK cell attack is unknown. Using CRISPR screens, we discovered a novel NK checkpoint on cancer cells. An antibody that blocks this target enhances NK killing of cancer cells in vitro, and increases antigen presentation, tumor infiltrating lymphocytes, and NK-mediated cytotoxicity in vivo.

Colorectal cancer (CRC) is one of the most common cancers globally. Beyond MSI-H (Microsatellite Instability High) tumors, CRC is largely resistant to immune therapies and is considered "cold." In this talk, we will discuss chemokine modulation as a potential strategy to increase intratumoral CD8+ T cell infiltration in metastatic colorectal cancer, thereby turning it from a "cold" to a "hot" tumor.

Current therapies are ineffective against pancreatic cancer. Our lab has developed a microbial-based immunotherapeutic treatment for selective delivery of a highly immunogenic tetanus toxoid protein (TT856-1313) into tumor cells by attenuated Listeria monocytogenes, which reactivates pre-existing TT-specific memory T cells, generated during childhood, now killing infected tumor cells. This resulted in a strong reduction in pancreatic cancer and improvement of survival of KPC mice, which may lead to new treatment modalities against pancreatic cancer where other types of therapies fail.