Circulating exosomes have emerged as means for a multitude of cancer applications including early detection, tumor molecular classification, prediction of therapeutic response, and monitoring of tumor progression and regression. The informative value of circulating exosomes across several types of solid tumors will be presented that are indicative of the value of circulating exosomes as a liquid biopsy approach.

Circulating tumor cells (CTCs) and DNA (ctDNA) in blood have received enormous attention as new "liquid biopsy" biomarkers. Broad clinical usage will depend on standardization of both pre-analytical and analytical procedures as performed in the European Liquid Biopsy Society (ELBS) consortium (www.elbs.eu). Clinical applications of liquid biopsy analyses include early cancer detection, improved cancer staging, early detection of relapse, real-time monitoring of therapeutic efficacy, and detection of therapeutic targets and resistance mechanisms. 

Over the past 10 years, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) and exosomes have received enormous attention as new biomarkers and subjects of translational research. Although these biomarkers are already used in numerous clinical trials, their clinical utility is still under investigation with promising first results. The development of cancer immunotherapy led to new challenges for the development of relevant biomarkers. Additionally, as the treatment needs to be tracked over time, the development of liquid biopsy-based robust biomarkers is urgently needed. Current challenges of liquid biopsy research, from discovery to clinical application in Immuno-Oncology will be highlighted.

Demonstrating antigen availability on the surface of tumor cells is crucial for the success of cancer immunotherapeutic approaches. We detail in this presentation the quantitative mass spectrometric strategy that we developed to measure generically MHC-I peptides of interest after initial characterization. We present two representative examples for which we demonstrated and quantified MHC-I peptide receptor complexes in relation to in vitro treatment effect.

Combination immune checkpoint inhibitor therapy has shown promising results in treating various cancer types. However, recent studies in HNSCC patients have shown no significant differences in overall survival between durvalumab (aPD-L1) or durvalumab + tremelimumab (aCTLA-4) therapy compared to standard of care. To understand immune landscape dynamics of these patients, we designed a CyTOF panel to broadly identify all major immune cell types and deeply profile regulatory T cells.

Preclinical safety testing of novel immune-oncology therapeutics require assessment of pharmacology driven cytokine release syndrome and on-target off-tumour risk where standard toxicity models are often not applicable. To address these challenges we are applying tumour bearing humanised mouse models, primary cell screens and membrane protein arrays to safety assessment. The benefits and challenges of these approaches will be discussed.

CRS is one of the major safety liabilities associated with treatment with T cell engaging therapies in the clinic, including CAR T cells and T cell engagers. A series of in vitro and in vivo preclinical studies were conducted to gain a better understanding of the biological mechanisms inducing CRS, providing new avenues for the mitigation of the same. 

The role of Tregs in glioblastoma remains controversial and their depletion has the potential to open the door to new treatment strategies for this devastating disease. By combining the analysis of human datasets, the use of a novel Treg targeting antibody and a newly developed mouse model of glioblastoma we have found that Treg depletion leads to deep changes in the adaptive and innate compartments allowing for the rational design of novel combination therapies targeting the glioblastoma microenvironment.

Microbiotica’s precision microbiome profiling and the MELRESIST clinical study has allowed us to identify a consortium of bacteria, MB097, strongly linked to immune checkpoint inhibitor response across multiple melanoma cohorts. MB097 synergises with anti-PD1 in vivo to inhibit tumour growth. The bacteria also demonstrate multiple interactions with primary human immune cells in vitro, leading to tumour cell killing. MB097 is being scaled up for clinical trials as a novel co-therapy with anti-PD1 in melanoma.

We have developed several bispecific antibody programs targeting the innate immune checkpoint CD47 for different indications in oncology. Two clinical-stage programs aim at selectively blocking CD47 at the surface of malignant cells. In addition, we are also developing two CD47/PD-L1 bispecific antibodies with differentiating mechanisms of action, affording either independent blockade of the immune checkpoints or targeted CD47 inhibition to PD-L1+ cells. The different rationales, key characteristics, and development status of these four CD47 targeting programs will be discussed.  

In contrast to many oncolytic viruses that are attenuated by either gene deletion or mutation and the armed with immunomodulatory transgenes to promote anti-tumor immune responses, CodaLytic is a novel virotherapeutic that is synthetically engineered to use alternative codons. We will describe its design, efficacy, holistic modulation of the tumor microenvironment, and ability to stimulate potent anti-tumor immune responses in preclinical models. This will support the utility of the virus as a monotherapy and in combination with checkpoint inhibition.

Activation of CD40+ antigen-presenting cells (APCs) aims at generating anti-tumor T cell responses. So far, dose limitations due to on-target systemic toxicity restrict the amount of systemically administered CD40 agonists that can be delivered to the tumor to activate APCs locally. We developed a fibroblast-activation-protein-a (FAP)-CD40 antibody, which activates CD40 solely in presence of the tumour stromal antigen FAP. FAP-CD40 enables safe administration of higher doses, essential for inducing antitumor immunity.

NT-I7, a long-acting IL-7, has shown promising early anti-tumor activity in two immune-cold tumor types. In MSS CRC, where pembro had 0% ORR, 3 PR/iPR were observed in 17 evaluable pts treated with NT-I7+pembro, for an iORR of 18%. Furthermore response was also observed in pancreatic cancer, where pembro also had 0% ORR, despite short followup. Responses, once occurred, are durable and continue to deepen over time.

The successes with immune checkpoints and CAR T cells in treating multiple cancer types have established immunotherapy as a powerful curative option for patients. Unfortunately, many patients do not derive benefit or long-term responses, highlighting a pressing need to perform complete investigation of the underlying mechanisms. We will show how high-plex single-cell functional proteomics can help to deliver new insights into biomarker discovery and guide the rational design of next-generation immunotherapies.

We have developed BsAbs engineered to preferentially target tumor rather than normal tissue and that demonstrate potent activity in xenograft models of hematologic and solid tumors, both as monotherapy and in combination with other agents. The tumor-selective activity is mediated by simultaneously masking an IO target while antagonizing an efflux transporter, thereby inducing an enhanced immune response and counteracting drug resistance. The potent activity of this dual targeting on tumors and the lack of binding to normal tissue provides for enhanced efficacy with the additional benefit of reduced toxicity.

The role of Tregs in glioblastoma remains controversial and their depletion has the potential to open the door to new treatment strategies for this devastating disease. By combining the analysis of human datasets, the use of a novel Treg targeting antibody and a newly developed mouse model of glioblastoma we have found that Treg depletion leads to deep changes in the adaptive and innate compartments allowing for the rational design of novel combination therapies targeting the glioblastoma microenvironment.