: How has research in cancer immunotherapy changed in the past decade and how have the technological developments contributed to this evolution?
CM: One of main areas that has changed has been the decrease in the cost of sequencing, including whole-genome, next-gen and RNA-seq, and the impact of this on big data, with groups like TCGA and CPTAC performing broad molecular profiling across multiple tumor types and specimen types to identify new targets and biomarkers with as much associated data as possible and sharing that information publicly allowing researchers to mine the data.
The understanding of biology around the immune cells within the tumor microenvironment, specifically regarding checkpoint inhibitors, is another area of growth. Especially with the ability to disrupt the ability of the tumor cells to evade the immune system itself. A key technology in this area is the development of multiplex immunohistochemistry (IHC), allowing up to 6 targets to be examined in a single tissue section. Because it is IHC, you can see the spatial analysis of where within the tumor in relation to other cells and targets the immune effector cells are versus only whether they are present within the tumor.
Finally, the development and growth of the adoptive cell therapy space, for example CAR-T, has greatly changed the immunotherapy field. These researchers need large quantities of PBMCs through provision of fresh leukopaks for development of protocols, which we provide through our donor centers in both the U.S. and EU. Researchers are also exploring models for safety testing of these cellular therapies.
: What are some of the biggest hurdles/challenges facing researchers in this field and do you think they are being adequately addressed?
CM: Having access to the right research samples that are regulatory compliant. High-quality, ethically procured, well-characterized and annotated specimens that cover the breadth of subtypes in cancer that are in the right formats to suit the specific application needs and are collected to a standard that allows for downstream workflows are essential. Working with partners with a thorough understanding of and who are compliant with the regulatory oversight needs of the pharmaceutical and diagnostic industries is a must, otherwise these researchers jeopardize their research. Access to these types of samples procured with the proper documentation in a clinical research setting is going to be critical for success and very difficult to manage with multiple clinical sites participating in these research trials.
BioIVT has a large clinical site network from which we procure our samples and our sites are trained to collect to our standards. They are audited on a yearly basis and retrained on an ongoing basis to ensure sample procurement in line with our SOPs, providing us control over the sample quality, associated clinical data, and regulatory documentation.
: Are there technological solutions that are currently being developed that you are excited about?
CM: The expansion of multiplex capabilities is continuing to grow in demand enabling further understanding of the complexities of cancer biology. There are multiple mechanisms that play a role in each individual patient’s disease and it is necessary to combine different therapeutic solutions based on these differences for a personalized solution. Thus, the more complex the biology the more markers one may need to figure out optimum combination of therapies. This complexity and therapeutic approach will continue to drive the need for multiplex technologies. Understanding the microenvironment in terms of tumor cells and different immune cell subsets, the interplay between these cell populations within the tumor milieu will expand the scope of the multiplex technology.
: What are some of the new trends that you are seeing in this field? Will existing technology keep up with those trends?
CM: The needs of the CAR-T therapy development space include high-quality, high-volume and well-characterized immune cells for process validation and development, and eventually one day for supporting allogenic T-cell therapy development. BioIVT has an interesting role in this area as a niche specialty research organization and has developed a portfolio of centers for sourcing leukopaks, including mobilized leukopaks with enhanced protocols to maximize CD34+ cell yield, for research & development—a strategy that is driven by our clients approaching us to aid in developing these new expansion areas. We’re confident that technology will continue to innovate and that researchers involved in cancer immunotherapy and other fields will strive for solutions to enable the best therapeutic developments for patients.
: 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?
CM: In terms of the development of therapeutic antibodies, and many of the related immuno-oncology approaches such as antibody-like molecules, one of the regulatory requirements is an assessment of the potential for tissue cross-reactivity—i.e. the potential for those biological therapeutics to bind to normal human tissue. This is a test that is on the critical path as an IND-enabling assay that is required by FDA, EMA, MHRA regulatory authorities to support safety assessment of novel biologics. Importantly, not all the immuno-oncology therapeutic drugs are traditional monoclonal antibodies but include many antibody-like molecules and other modalities that are being developed. Multi-specific molecules, such as bi-specific and tri-specific molecules, and modified antibody fragments, are being generated to try and overcome some of the pharmacokinetic issues around traditional therapeutic monoclonal antibodies, making them more drug-like with better distribution and good pharmacokinetics, etc. However, one of the challenges is that from a safety point of view, it is required to have a robust and reliable binding assay as the desired end-result is a negative result in these tissue cross-reactivity studies, as having off-target binding of this therapeutic agent here and there would not be safe. This is one of the strengths of BIoIVT as we have a strong 20-year history of developing robust immunohistochemistry assays utilizing human tissues and difficult therapeutic molecules and performing these tissue cross reactivity studies to GLP standards.
: 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?
CM: It’s very hard to look in a crystal ball and predict what cancer immunotherapy researchers will ask for in a year or two years’ time. Thus, our goal is to keep abreast of the current state of play as much as possible and look to make investments, be it in a specific technology or to bring on clinical sites able to source a specific cancer that is in need, etc. What we do see is that there is often a focus on a specific target or set of targets or specific tumor type(s) and then there will be a paper published where a novel target / tumor relationship has been identified and suddenly from a tissue supply and research support point of view there is a gap—or certainly a new need. Thus, we need to be fairly flexible and respond to those changes in the market, which are not easy to predict.
: If you could change one thing to drive progress in this field what would that be?
CM: A better balance between efficacy vs. toxicity in terms of balancing autoimmunity/autoimmune responses that arise from the immuno-oncology therapies and understanding/mitigating the risk to healthy organs. To aid these, preclinical toxicity models are needed. For example, technologies for the non-systemic delivery of immunotherapies such targeted delivery of ADC-like molecules to tumors, where side effects are seen from the Fc receptors binding of these ADCs. Solutions include inhalation and microinjection for delivery to the lung, which would mitigate systemic side effects and allow a concentrated and targeted dose delivery.