: How has research in cancer immunotherapy changed in the past decade and how have technological developments contributed to this evolution?
JS: What we have seen in the past decade is a paradigm shift from tumor directed treatments toward treatments of or employing the immune system. This shift has become possible because of the drastic evolution of cancer genome and cancer immunosurveillance analysis techniques. We now understand better how T cells specifically recognize tumor cells; we can analyze genomic intra-tumor heterogeneity with higher precision thanks to single-cell sequencing; we can “take the brakes off” immune cells by using checkpoint inhibitors; and we have plenty of tools available for enrichment and functional analysis of tumor-specific T cells, such as cytokine secretion assays, cytokine capture assays, and others.
: What are some of the biggest hurdles/challenges facing researchers in this field and do you think they are being adequately addressed?
JS: CAR T cell technology created an entirely new treatment option for cancer. With two CAR T cell therapies currently approved, Kymriah® and Yescarta®, we have gained powerful treatment options for relapsed or refractory B cell precursor acute lymphoblastic leukemia (B-ALL) and large B cell lymphomas. However, these personalized cellular therapies still come with some limitations. They are extremely expensive, and obtaining adequate reimbursement by insurance or government payers has proven challenging. Furthermore, the "vein-to-vein time" is still too long: typically this process, which consists of cell collection, CAR T cell manufacturing, and infusion back into the patient, takes 3-4 weeks—a time frame that renders the therapy unsuitable for patients whose cases are rapidly progressing. Current centralized manufacturing models require about 14 days to generate enough CAR T cells, and subsequently ship this frozen product over long distances. Reducing the vein-to-vein time will make this treatment a viable option for more patients, helping to save more lives.
: Which technological solutions currently under development are you most excited about?
JS: Our CliniMACS Prodigy® platform tries to address some of the challenges CAR T cell therapies face by fully automating their generation. Our goal is to shorten both the manufacturing process and the shipping times involved in CAR T cell therapy by placing CliniMACS Prodigy systems close to the point of care, either directly in hospitals or else in local manufacturing units. Doing so would neatly avoid the current freeze and thaw cycles samples endure, and would minimize shipping time. We’re also developing procedures that reduce the production time of CAR T cells from where they currently stand at 12–14 days to just eight days—or even less in the future.
: What are some of the new trends that you are seeing in this field? Will existing technology keep up with those trends?
JS: Despite the success of CAR T cell therapies for B cell malignancies, applying this technology to solid tumors remains a major challenge due to higher levels of tumor heterogeneity and the nature of the microenvironment that surrounds them. This makes it very likely that we will need to combine different treatments: the traditional, such as surgery, chemotherapy, and radiotherapy, and the new modalities, including targeted cancer therapies, CAR T cells, immune checkpoint inhibitors, and neoantigen vaccines. This is definitely a trend that we are seeing right now.
But also on the discovery side, we are seeing new and sophisticated technologies that will help us get a much better picture of the immune landscape of cancer, which will in turn dramatically improve tumor response assessment. For example, our new ultra-high content imaging platform, MACSima®, allows us to analyze several hundred markers in parallel on a tumor tissue section by making use of cyclic immunofluorescence. This affords a much clearer picture of all cells present, as well as their functional state.
Another particularly useful imaging technology is the Ultramicroscope II light sheet microscope, which allows us, for instance, to detect CAR T cells within an entire tumor tissue, and thus provide insights into the location and functional status of CAR T cells within the tissue.
: 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?
JS: Just as a tumor can become resistant to chemotherapy via dozens of mechanisms, they can also escape immunotherapies, such as CAR T cell therapies or neoantigen-directed therapies. Patients with B cell malignancies become resistant to CAR T cell therapies by loss, downregulation, or modification of the target antigen. We try to mitigate antigen escape in CAR T cell therapy with the use of bispecific CAR T cells on the basis of tandem CAR exodomains.
Additionally, tumor response assessment and analysis of therapy resistance has many limitations. While imaging modalities, such as bioluminescence imaging, fluorescence imaging, near-infrared imaging, 2-photon laser scanning microscopy, and magnetic particle imaging, allow longitudinal studies of what is going on in the tumor in animal models, we still lack powerful, noninvasive imaging technologies with single-cell resolution in the clinic. MRI, SPECT, PET, and CT are all very limited in this regard. However, we want to know as early as possible if a treatment is failing or succeeding in order to explore other treatment options for the patient. We also still lack appropriate in vivo and in vitro models to predict the safety and efficacy of new immunotherapies.
: As a technology/service provider, how are you impacting progress in this field? What can you do more/better, and what will help to make this happen?
JS: We developed the CliniMACS Prodigy platform to generate CAR T cells in a simple and fully automated fashion. It consists of the CliniMACS Prodigy instrument, a single-use, biocompatible tubing set, and all the reagents, media, and buffers required for sample preparation, T cell enrichment, stimulation, viral transduction, expansion, and final formulation. The platform is currently being used in numerous CAR T cell trials around the world, as well as in our own trials. Beyond these tools for automated manufacturing, we also provide everything bar the sample that is necessary for automated flow cytometric in-process control and release testing. Our aim is to develop this into a complete blueprint for a CAR T cell manufacturing facility, including SOPs and data management.
By providing off-the-shelf and automated solutions, cell manufacturing becomes much more robust, making it better able to meet the demands of safe and efficient, personalized cell therapies.
: If you could change one thing to drive progress in this field what would that be?
JS: With cancer, every patient is an individual medical case with very individual genetic alterations and tumor escape mechanisms. Thus, every patient essentially requires personalized treatment. This is difficult to achieve under the current regulatory framework’s requirements for clinical study design. A randomized clinical trial, for example, is difficult to run with a personalized approach, e.g., in terms of selection of the control and treatment groups. We need to move forward and adequately address the challenges of personalized treatments. This also includes a careful risk-benefit evaluation when treating a single patient with his or her specific cancer in a personalized way.