: How has research in cancer immunotherapy changed in the past decade and how have the technological developments contributed to this evolution?
MSL: Cancer immunotherapy has experienced a renaissance in the past decade. Patients with late-stage disease are now achieving durable survival, but we are still at the early stages of realizing the full potential of cancer immunotherapies. Many unanswered questions remain about extending durable responses and survival. Deciphering the complex interactions between the highly regulated immune system and cancer, which is adaptive, dynamic, and heterogeneous, requires advanced tools. Single cell and spatial sequencing approaches are unlocking insights to maximize the efficacy of immunotherapies by deconstructing the interplay between the immune system and cancer cells.
: What are some of the biggest hurdles/challenges facing researchers in this field and do you think they are being adequately addressed?
MSL:
- The biggest challenge in the field is fully understanding why most patients don’t respond to immunotherapies. For example, for metastatic melanoma, checkpoint inhibitors (like anti-PD-1 or anti-CTLA-4) have a response rate of about 20% and many patients who initially respond develop resistance later on. Technologies like single cell and spatial sequencing enable researchers to look at response and resistance as a complex system—articulating the cell types and states that contribute to an anti-tumor response over time. These cell states can then potentially be used as biomarkers to better track and predict patient response to immunotherapies.
- Current bulk methods, such as IHC (immunohistochemistry) and bulk next-generation sequencing, are insufficient to deconvolute the complexity of the tumor and immune microenvironments and their responses to therapy. For example, it was widely believed that checkpoint inhibitors, like anti-PD1, worked by reinvigorating T cells in the tumor microenvironment. Recent publications using multiomic single cell sequencing of the tumor, adjacent normal tissue, and blood discovered that checkpoint inhibitors may actually elicit replenishment of new T cells from the periphery—challenging a long-held dogma in the field.
: Are there technological solutions that are currently being developed that you are excited about?
MSL:
- For cellular immunotherapies, we are seeing great progress in scaling target identification and functional screens to develop the next generation of engineered T-cell therapies. For example, there is still a long way to go to deepen the efficacy of T-cell therapies in solid tumors, given the highly immunosuppressive microenvironment. One exciting area of research is the development of new therapies that are “armored” to resist exhaustion and suppression in the microenvironment.
- Two single cell approaches, scRNA-seq (single cell RNA sequencing) and scATAC-seq (single cell Assay for Transposase Accessible Chromatin using sequencing), are being used to identify intrinsic regulators of T-cell dysfunction, as well as extrinsic activators and suppressors in the microenvironment. Next, massively parallelized single cell CRISPR screens allow the functional testing of re-engineered T-cell therapies. Using these tools, researchers can test multiple different combinations of engineered constructs in a scalable and systematic way within a significantly reduced timeframe.
: What are some of the new trends that you are seeing in this field? Will existing technology keep up with those trends?
MSL:
- One emerging trend in the field is the use of combination therapy strategies to deepen and expand response by targeting multiple biological steps in immunity simultaneously. A major challenge in the field is the rational design of combination strategies and identification of biomarkers to aid in patient stratification. Single cell and spatial sequencing are capable of delineating synergistic, additive, neutral, or antagonistic effects on cellular and molecular targets of combination therapies. Further, the technology can be used to map the second order therapeutic effects on other cell populations in the microenvironment that may be indirectly targeted.
- Another emerging trend is the complexity of antibody-based therapeutics, such as bispecific or even trispecific antibodies. Having the right mix of targets, and the high-throughput capability to identify antibodies with the right specificity and avidity for their targets, will have a great impact on these drug development programs and, one hopes, future therapeutic success in patients. Single cell immune profiling by multiomic cytometry, particularly in combination with technology that enables the rapid identification of diverse B-cell antigens through DNA barcoding, has recently emerged as a key method for high-throughput screening of novel antigen-specific antibody sequences. This method will radically alter antibody discovery programs by dramatically reducing overall costs, increasing target specificity and avidity, and shortening discovery program time, from months or even years down to just weeks.
: Are there gaps in current technology offerings for cancer immunotherapy? How do they relate to lack of instrumentation, technical know-how, data deluge, translational issues?
MSL:
- One of the greatest challenges of current technology is understanding the diversity and spatial relationships of malignant clones, including actionable mutations or other biomolecules that could be therapeutic targets, within any particular tumor microenvironment. Concepts like minor allele frequencies, tumor mutational burden, and microsatellite instability have all been developed on PCR-based or bulk next-generation sequencing platforms as a proxy for elucidating the molecular genetic basis for disease, prognosis, and rational therapy decisions.
- However, these approaches have fundamentally lacked the capability to discern such critical characteristics at single cell resolution, and effectively average out gene expression and other metrics across all cells within a sample prior to analysis. With single cell and spatial sequencing, it will be possible to convert an equivalent amount of data into a more actionable set of recommendations for clinical care. This will require advancements in data analysis in particular, as well as ensuring that single cell and spatial methods can be applied to the widest possible range of sample input types. Similarly, while tools for discovery of tumor or neo-antigens have become more widely adopted, translating these into targets for cellular immunotherapy will benefit from continuing to develop and scale therapeutic discovery technologies for antigen presentation, single cell immune profiling, and immune mapping.
: As a technology/service provider how are you impacting the progress in this field? What can you do more/better and what will help to make this happen?
MSL:
- The 10x Genomics mission is to master biology to advance human health. We firmly believe that once we understand biology we can prevent deadly diseases like cancer, as well as auto-immune and neurodegenerative diseases.
- 10x Genomics has demonstrated a commitment to innovation and continuously seeks opportunities to push the boundaries of discovery and clinical translation with our technology. We are making progress on many fronts, including the acquisition and further development of our spatial transcriptomics platform, Visium, which we are planning to augment with additional multiomic data types, such as proteins; other methodological improvements, such as immunofluorescence; and support for FFPE samples. For our single cell genomics solutions, we are investing in ongoing efforts to improve sample inputs for diverse and challenging sample types; we are also developing software tools to make interpretation of single cell data faster, more accessible, and more collaborative across disciplines and disparate research teams.
: If you could change one thing to drive progress in this field what would that be?
MSL:
- I would say increased awareness that if we don’t understand biology, we cannot improve human health outcomes. Today, due to COVID-19, the world has a greater appreciation for science and biology, but we should not have to experience a pandemic for us to recognize that. We need to get ready to battle the next, and we need to have a very detailed understanding of our biology to drive faster outcomes in control, prevention, and cures.
- More specifically, I would say we need to drive the awareness and adoption of single cell and spatial genomics technologies generally. The more people, globally, we have working on the challenges and solutions to community problems, the better. With the right scale of effort, we’ll continue to see even more rapid development of tools, publications, and other resources that the global community needs to be able to solve the greatest number of outstanding challenges.