Over the past year we have seen unprecedented demand for IHC assay development services with the goal of creating a prototype CDx assay. These requests are mostly centered on therapeutics in the immuno-oncology space: CAR T-cells, TCR therapeutics, bi-specific T-cell engagers (BiTEs) and engineered cellular therapeutics. It’s not just new applications of well-established markers such as PDL1 and HER2 (although we still get our share of those). Most of what we have in our portfolio are novel biomarkers we were not working on 5 years ago.
This trend is evidenced by reviewing a multitude of targets listed on the CRI iAtlas (see below). The diversity of targets here is extensive. I admittedly had to cut off the list at n=2 in order to fit it within this blog post.
The vast majority of these IO therapeutics have a protein target (or multiple proteins for engager-based therapeutics). Based on my experience with requests for clinical trial support in this space, a significant number of therapeutics in this class (30-40% to be conservative) employ a biomarker clinical trial strategy utilizing an assay that is very likely to become a CDx. And given the mechanism of action for this class of drugs, that CDx is likely to be IHC based (with some instances where ISH, FISH, or CNV by NGS may also be useful). At this point, the diversity of IHC biomarkers in our “CDx-track” portfolio now vastly outnumbers what we have historically provided for molecular testing (e.g., KRAS, BRAF, EGFR, et. al.).
This brings me to my main point:
- We can expect to see many more approvals for IHC companion diagnostics in the coming year
- The number of IHC markers is expected to be very broad
- Histology and comprehensive genomic profiling already require a good deal of tissue
- Do we have enough left over to run a panel of 7-10 single-plex IHC assays for therapy choice?
We encountered this effect with molecular testing several years ago – the need for KRAS, BRAF, EGFR, etc. testing for NSCLC. NGS panels was the solution. Unfortunately, NGS proteomics solutions are as yet no match for IHC in terms of predicting expression levels (not to mention cost, turnaround time, or broad acceptance by reference laboratories, and familiarity to the regulators and loss of spatial and co-expression insights).
For this reason, development of therapeutic-specific panels using multiplex immunofluorescence (mIF) is going to be needed sooner rather than later. In anticipation NeoGenomics has invested in a few different spatial multiplexed technologies. A proprietary MultiOmyx system (up to 60 plex), Nanostring Digital Spatial Profiling (DSP), and Akoya’s PhenoImager (up to 7 plex). We are now starting to see requests for CDx development in this field, but it is mostly limited to examples where multiple protein targets must be evaluated for a single investigational product, rather than creation of a panel for general therapeutic selection. Because of the high regulatory and commercialization thresholds of gaining approval and deploying mIF as an IVD, regulated development is reserved for when there is a need for multiple protein co-expression and/or spatial information. Additionally, a fit arises if protein biomarkers must be assessed in a precise quantitative manner, which is known to pose challenges to reproducible pathology interpretation. Use of image analysis (IA) software can solve for reproducibility issues, and furthermore, IA is native in the mIF ecosystem.
Commercialization strategy raises many additional questions – as regulatory strategy may not necessarily align with an ideal commercial launch and adoption. This will be covered in a future blog.
