Dr. Kristian Moller, Principal Scientist at Atlas Antibodies, shares the top research highlights from the exciting science being presented at AACR 2019.
The Annual American Advancement for Cancer Research meeting (AACR) of 2019 was held in Atlanta, Georgia, USA. This meeting attracts every year more than 22,000 attendees from all over the world and features the latest discoveries across the spectrum of cancer research, from population science and prevention to basic, translational, and clinical studies to survivorship and advocacy.
1. Immunotherapy: T-cells and Humanized Antibodies
It has been known for a century that immunosuppression dramatically elevates the risk of cancer development. The immune system is hence truly critical for patrolling the body fighting off aberrantly proliferating cells. In fact, around 80% of all cancer deaths in metastatic carcinoma, non-accessible by available therapeutics, might be cured by effective immunotherapies.
“Immunotherapy, also called biologic therapy, is a type of cancer treatment that boosts the body's natural defenses to fight cancer. It uses substances made by the body or in a laboratory to improve or restore immune system function.”
Most of the anti-cancer effects elicited by the immune system are mediated by cytotoxic T-cells. One of the presenters at the AACR 2019, Professor Steven A. Rosenberg (NCI, Bethesda, MD, USA) shared encouraging progress on individualized T-cell transfer therapy of treatment-resistant carcinomas.
Figure 1. Dr. Kristian Moller
Professor Rosenberg stressed the critical importance of immunogenic mutated proteins specifically expressed within the patient´s own tumor cells, better known as neoantigens. For truly individualized anti-cancer immunotherapy, tumor -infiltrating T-cells (TILs) are extracted from each patient´s individual cancer. The tumor-reactive TILs are then selected, expanded ex vivo and reinfused into the patient with the hope that they will have become properly selected for their tumor aggressiveness with the ability to combat the tumor. One fascinating clinical case presented showed sustained regression of metastatic breast cancer and complete response after 39 months of treatment with T-cell transfer immunotherapy.
The development of biologics (humanized antibodies) to break immune checkpoint inhibition, mainly by blocking PD-1/PD-L1 has revolutionized the clinical progress of the field. As with most other oncological therapies, the enthusiasm has in part been moderated by the development of treatment resistance. Looking at the tumor-infiltrating T-cells it seems that their tumoricidal property is confined to a subtype of CD8+ T-cells with a “stem-cell-like” gene signature, producing IFN-γ and which is responsive towards anti-PD-1 treatment.
As for the innate of the tumor microenvironment, one of the presentations emphasized on the anti-tumorigenic M2 macrophages and their conversion into tumor-fighting M1-macrophages in vivo by the PI3K-γ inhibitor IPI-543 (Infinity Pharmaceuticals) presently in Phase I clinical trial against several solid cancers such as lung cancer and melanoma.
Much attention was given towards bi-specific humanized antibodies, that of hybrid antibodies able to target sites for concerted attack by effector T-cells. These synthetic antibodies have been engineered to simultaneously bind to the surface of the tumor cells and to a common component of the T-cell receptor making the killing of the tumor cells exceedingly efficient. One of several examples is that of CD20-TCB (RGG6026) which is a novel T-cell engaging bi-specific antibody which has been shown to induced complete remission in relapses non-Hodgkin lymphomas in an early clinical trial.
2. Mapping the Cell Content and their Individual Molecular Signatures in Normal and Cancer Tissues
The ability to molecularly phenotype the entire cellular content of any tissue at single-cell resolution, not least of solid tumors, has undergone dramatic progress during later years. Extraordinary progress in microfluidics, single-cell RNA sequencing, and smart bioinformatic algorithms has paved the way for this progress.
The chief rationale behind the complex cell mapping studies, of which several were presented at the AACR, is to decode and capture the complex cell diversity of normal tissues and apply this valuable knowledge to the corresponding neoplastic or cancer tissues. Major single-cell mapping initiatives that are the generation of “normal” cell compendia are coordinated by the Broad Institute at MIT, Boston, the publicly NIH-funded HuBMAP and several initiatives sponsored by the Chan-Zuckerberg Initiative, including a project run by Dr. Emma Lundberg at the Human Protein Atlas (HPA).
A particularly interesting initiative was presented by Dr. Nicholas Navin at MD Anderson Cancer Center, Austin TX, USA. He supervised the analysis of nearly 34.000 breast tissue cells from 10 healthy women, by single-cell RNA sequencing. He identified 2-5 subsets of each breast epithelial cell and fibroblasts including or cellular activation states for most cell types in the breast. Several of these newly characterized cell types showed importance in breast cancer development.
3. Multiplexed Imaging
The deconstruction of tissues and the subsequent analyses of their qualitative/quantitative RNA- and protein content makes poor biological sense in the absence of spatial and subcellular localization data, preferentially in a multiplexed format.
A high-throughput technology capable of simultaneously detecting >50 protein biomarkers in a single tissue section using DNA-barcoded antibodies. Using a similar approach, a method was demonstrated that enabled the simultaneous 10-color immunostaining of FFPE-tissues without staining iteration and spectral unmixing.
“Multiplex immunofluorescence is the most effective, efficient way to identify specific immune cell types, their location, and their state of activation, as well as the presence of immunoactive molecular expression, all at the same time.”
At the AACR-meeting information was shared regarding a novel digital spatial profiling technology allowing for simultaneous interrogation of around 1.000 protein targets. The method allowing for the highest level of multiplexing IHC is undoubtedly in situ imaging mass spectrometry presented by Dr. Berndt Bodenmiller at the University of Zurich. The platform takes advantage of metal-labeled antibodies, mass spectrometry which, due to spectral no-overlap, permits analysis of cancer tissue phenotypic heterogeneity at 30-100-plex complexity at down to 50 nm subcellular resolution.
Related cells are often morphologically indistinguishable and sometimes also disguise their true identity (and pharmaceutical “targetability”) even with the use of established biomarker sets. By single-cell isolation and single-cell RNA sequencing (scRNASeq) unbiased molecular profiling has developed at an unprecedented pace and has provided significant insights into in vivo cellular diversity, identification of novel cell types and rich phenotypic plasticity.
Several examples of this were presented at the AACR-meeting. One interesting case was described by Dr. Chris Vakoc at Cold Spring Harbor, NY, USA, reporting on, POU2F3, the master regulator of the tuft cell lineage in a number of normal tissues appeared as the chief marker and elite target for cancer therapy of the 20-25% non-neuroendocrine cell populations of the small cell lung carcinoma (SCLC), known to have an exceedingly poor clinical prognosis.
4. Non-Invasive Liquid Biopsies
The non-Invasive sampling of body fluids like blood, plasma, urine, cerebrospinal fluid together with high-throughput microfluidics with single-cell or single molecule resolution, collectively categorized as liquid biopsies, was a major theme at the AACR meeting.
“Liquid biopsy is done on samples of blood, plasma, urine or CSF, to look for circulating cancer cells or for circulating pieces of DNA from tumor cells. A liquid biopsy may be used to help find cancer at an early stage.”
The limited availability of solid tumor biopsies puts a restraint to the ability to diagnose and monitor cancer progression during the course of therapy. Critical parameters like drug resistance may, therefore, remain undiscovered for therapeutic intervention. Longitudinal use of liquid biopsies allows non-invasive sampling during the course of a treatment permitting the analysis of the “evolution” of drug resistance and hence therapy resilience.
The interrogation of rare circulating populations of shed tumor cells, cell-free DNA (cfDNA) and RNA (cfRNA), as well as exosomes and microvesicles seeded into the blood, constitute the sources for these analyses. Furthermore, a clinically important “protein fingerprinting” method for non-invasive assessment of tumor stroma status-a measure of malignancy was presented. Microfluidic enrichment and RNA-based digital PCR scoring of RNA of circulating tumor cells CTCs may be used to predict therapeutic response in metastatic cancer and early dissemination.
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