Every year, the IO360° conference unites experts from the Immuno-Oncology (IO) field to discuss the most recent advancements in the fight against cancer. The Genedata Profiler team attended the virtual conference in February 2021, and we would like to share our key takeaways.
Takeaway 1: Cell Therapies Are Here to Stay
The conference began with a full day dedicated to cell and gene therapy (CGT), two rapidly evolving fields that recently saw the approval of the first anti-BCMA CAR-T Cell Therapy of Bristol Myers Squibb for relapsed or refractory multiple myeloma. With the immense increase in total financing, cell therapy companies can be expected to make further significant progress in 2021. Even as the market has historically favored smaller start-up biotech companies specializing in CGT technologies, increasing interest and resource deployment has occurred in top multi-national companies.
Throughout the first day of IO360°, talks often centered on the pros and cons of autologous (manipulated apheresis cells returned to the same patient) and allogeneic (manipulated apheresis cells from multiple donors administered to un-related patients) cell therapies, and on technological advances that expand the repertoire of cell therapy products with the drive to increase process and product efficacy and safety. Autologous therapies have proven successful in gaining FDA approval for hematological cancers but face challenges in being universally available to patients due, in part, to the prohibitively high costs of the personalized culturing processes. Companies specialized in allogeneic therapies aim to “industrialize cell manufacturing” and make cell therapies available at a lower cost yet struggle to establish prolonged therapeutic effects and minimize patient immunological rejection, a primary concern when utilizing non-self-donor cells to produce a shelf-ready product. The panel session entitled “Deep Dive into Key Issues of CGT” emphasized the importance of a “bedside-to-bench” approach, also referred to as “reverse-translation,” to improve product engineering and ensure the progressive quality of cell products as response (efficacy) data is gathered. This is especially crucial as the field transitions towards tackling solid tumors that have been particularly challenging for both autologous and allogeneic cell therapies because they require infiltration of the tumor microenvironment (TME). In Takeaway 3, we provide more detail.
Takeaway 2: Circulating Tumor DNA (ctDNA) as an Early Predictive Biomarker of IO Resistance
The use of ctDNA as an early predictive biomarker for IO therapy resistance also generated significant buzz among IO360° participants and continues to become more clinically relevant in the field. Not long after the conference, the FDA approved two additional breakthrough device designations for the Signatera molecular residual disease (MRD) test as a companion diagnostic through phase III clinical trials for two cancer treatments. These approvals highlight the value of ctDNA for patient selection and bode well for its use long-term.
Angel Rodriguez, Oncology Medical Director at Natera, discussed using ctDNA as an early biomarker for assessing tumor burden in patients before and after curative treatment. The ctDNA assay is both highly specific and sensitive for an individual’s tumor and has a 98% predictive value for identifying colon cancer patients susceptible to relapse. With the hope that ctDNA can specifically function as a predictive biomarker in the clinic for other cancers, several studies are now investigating how ctDNA can be used as a clinical endpoint. A notable mention is the ABACUS study presented by David Shames, Executive Director and Staff Scientist Oncology Biomarker Development at Genentech, in which ctDNA was used as a surrogate prognostic biomarker tracked before and after surgery for patients with muscle-invasive urothelial cancer. Monitoring indicated that levels of ctDNA correlated with patient response and could differentiate what type of treatment a patient was receiving. Identifying patient subgroups with ctDNA who may not need intervention or are at high risk of relapse allows for agile patient intervention and ultimately improved patient outcomes. Using ctDNA as an early predictive biomarker has the promise to advance precision medicine treatment.
Takeaway 3: Single Cell Approaches in Combination with Other Data Modalities for Interrogating the TME
Another rapidly emerging topic in the field of IO highlighted throughout the conference is the race to understand the complexity of the TME and the interactions between cancer cells. There is a major knowledge gap concerning how the TME is altered during treatment, especially in understanding how distinct cell populations and individual cell phenotypes contribute to treatment resistance. In pursuit of characterizing the TME, single-cell RNA sequencing (scRNA-seq) approaches have emerged as a powerful way to conduct high-resolution analysis of gene expression signatures at the level of individual cells, permitting the definition of profiles specific to cell types and the characterization of their changing transcriptomic milieu. The use of scRNA-seq can assist in the identification of small, previously underappreciated cell populations of clinical relevance and provide insight into the molecular details of why some people respond or have more severe toxicities, while others do not.
As an example, Shannon Turley, Senior Director, Cancer Immunotherapy at Genentech, described a high-resolution, integrated multi-omics approach to define the therapeutic impact of anti-PLD1 and anti-TGFb combination therapy on immune excluded tumors in mice. In immune-excluded tumors, T-cells are unable to infiltrate the tumor and are excluded in the stroma. The combination strategy allowed infiltration of T-cells, but how these therapies promoted this change within the TME was further dissected using scRNA-seq and additional omics approaches. A high-definition atlas of the tumor ecosystem found that all cell compartments of tumor cells were affected by the combination treatment. These studies and others presented throughout the conference show that coupling scRNAseq with integrative multi-omics data analysis will enable researchers to better understand how therapies must be tailored to the TME in order to improve tissue targeting and efficacy by inducting local immune responses.
Takeaway 4: The Unique Challenges of IO Biomarker Identification
The mission to identify the “right drug for the right patient at the right time”, underpins all IO precision medicine initiatives and was invoked regularly throughout IO360°. Biomarker-driven strategies in targeted oncology clinical trials aim to identify patient subpopulations that will benefit from a specific therapy. These strategies are fine-tuned to predict and prevent future relapse or complications from therapies. Scientists are increasingly using integrative approaches, such as multi-omics data analysis, for the identification of precision biomarkers. As new technologies are further developed and better understood, the applications for therapy development will continue to expand.
During an insightful IO360° panel, led by Theresa LaVallee, Vice President of Translational Medicine and Regulatory Affairs at the Parker Institute for Immunotherapy, the participants discussed one of the major challenges of increasing biomarker-enabled trials: the need to prove that biomarker subgroups are indicative of patient need and response. Clinical validation of biomarkers in clinical trials is challenging as small single-arm trials are typically used for cutoff selection, generating constrained datasets that are difficult to translate to wider randomized trials due to low sample size and heterogeneity of participants. Shortfalls in the amount and quality of the data limit the adoption of biomarkers and are reflected by the low number of clinically validated biomarkers to date. As such, the panelists emphasized the importance of collecting sufficient data to enable statistical power and the need to standardize and harmonize multi-omics approaches to advance the confidence in clinical biomarkers.
Technological Solutions for Integrative Approaches in Immuno-Oncology
The IO360 conference highlighted the major advancements and challenges of the field today. As IO moves towards tumor agnostic therapies, understanding tumor heterogeneity, as well as disease mechanism, and teasing apart the complexity of the TME will be a major goal for years to come. Increasing the validation of clinical biomarkers will require a push for standardization, harmonization, and reproducibility in data acquisition and analytics. These initiatives require a secure infrastructure to manage clinical and translational data that will enable collaboration among scientists.
Genedata Profiler provides the digital architecture to address the complexities of clinical and high-dimensional molecular data by automating data processing, harmonization, and integration. Genedata Profiler also consists of a high-performance analytical package for data visualization and analysis enabling scientists to draw conclusions that accelerate the development of precision medicine.
Mention of companies or research organizations in this article does not indicate their endorsement of Genedata or its products. Presentations mentioned here have been selected based on our opinion of their scientific and technological interest.