Since the 2011 FDA approval of the first checkpoint inhibitor, ipilimumab, immuno-oncology has gained momentum as a premier therapeutic strategy within precision medicine. Its promise is evident: the number of pipeline drugs rose from 399 to 1,875 between 2016 and 2019 (1).
To ensure the best experience and outcomes, sponsors of immuno-oncology clinical trials must partner with specialty central labs specifically experienced in immuno-oncology clinical trials. Their facilities must offer, at minimum, four core services: biomarker development and validation, flow cytometry, multiplex immunohistochemistry (mIHC) and next-generation sequencing (NGS). Each of these areas are crucial for immuno-oncology therapy development.
Biomarkers help predict the complex immune activation and response within the tumor microenvironment. Some therapeutics prove ineffective in as many as 75% of the patients they are expected to help (2,3). Sponsors must identify the remaining 25%. The right biomarkers can streamline immunotherapeutic and personalized medicine programs and enhance drug development success rates (4).
Biomarkers are increasing in importance and evolving quickly in immunotherapeutics to:
- Guide dose selection
- Characterize mode of action or resistance
- Stratify patients/determine inclusion-exclusion
- Predict drug efficacy and safety profiles
- Aid in prognosis
- Monitor disease
The right biomarker could be an off-the-shelf marker or a laboratory-developed test with clinical validation. The central lab works with the principal investigator to guide biomarker design and customization.
A single platform, however, will not suffice for immuno-oncology clinical trials. A complete program includes flow cytometry, IHC, and NGS.
Flow cytometry is a powerful tool capable of rapidly detecting and measuring thousands of cells with high sensitivity and specificity, providing a snapshot of the immune response. In addition to cell surface markers, flow cytometry can also detect intracellular antigens such as cytokines and phosphorylated signaling proteins. This methodology allows functional analysis and helps with therapeutic strategies and prediction of therapeutic response.
Immune profiling by flow cytometry produces a large amount of information from a single blood sample. The result is a very granular breakdown, for example, of lymphocytes and subtypes, down to T cell memory subsets and activated versus nonactivated markers.
Clinical researchers use flow cytometry to understand how patients respond to treatment and the therapies suitable for patient-specific treatment plans. Because of the skill involved, the lead time for assay development to validation must be considered. For global trials, consider a standardized approach that includes instrument standardization and assay process standardization (same SOP).
Multiplex Immunohistochemistry (mIHC) for Complex Phenotyping
For complex phenotyping, flow cytometry is a typical choice. However, it only provides a view of the circulating immune system status at the whole-body level. This may not reflect the populations at the tumor site.
NGS for Genetic Screening
Genetic screening measures changes in nucleic acid sequences associated with disease susceptibility or resistance. Next-generation sequencing (NGS) enables a wide range of new applications and investigations in genetics, including analysis of solid and hematologic tumor genomes as well as in-depth analysis of the patient’s immune repertoire pre- and post-treatment, including T cell receptor (TCR) analysis.
A central lab with high throughput and a large catalog of clinical and NGS genetic and genomic testing helps ensure timelines stay intact.
Applications of genetic insights to look for:
- Biomarker discovery, with comprehensive genomic profiling and customized assays that link mutation to disease
- Prospective patient stratification screening with NGS, PCR, and other assays
- Companion diagnostics development on NGS-based or CHIP-based multiplex qPCR platforms to assess therapeutic suitability
- Cyto- and molecular genetic diagnosis of constitutional and acquired disorders
The tumor mutational burden (TMB) is a genetic biomarker currently receiving some attention. Cancer is the result of a series of mutations, and cancer cell lines each have between 1 and 10,000 coding mutations, or .1 to 100 mutations per megabase. This is the tumor mutational burden.
TMB is associated with anti-tumor response and is a good predictor of response to cancer immunotherapy drugs in some cases, such as melanoma, cutaneous squamous cell carcinoma, and certain colorectal and non-colorectal GI cancers. The reason may be that tumor cells with high TMB have high neoantigen loads, leading to greater T cell reactivity and an enhanced anti-tumor T cell response. Although the gold standard TMB analysis has been whole exome sequencing, recent advances in NGS tumor panels have provided consistent results.
Immuno-oncology study execution hinges on the central lab’s expertise in biomarker development, flow cytometry, IHC, and NGS. Combined with skilled project managers, a global footprint, and expert data management, a central lab becomes a trusted partner for immuno-oncology developers.
1. “Cancer immunotherapy market to hit $115bn by 2023, says report,” European Pharmaceutical Review, January 8, 2020; retrieved August 7, 2020 from https://www.europeanpharmaceuticalreview.com/news/109714/cancer-immunotherapy-market-to-hit-115bn-by-2023-says-report/
2. Manpreet Sambi, Leila Bagheri, and Myron R. Szewczuk, U.S. National Library of Medicine National Institutes of Health, “Current Challenges in Cancer Immunotherapy: Multimodal Approaches to Improve Efficacy and Patient Response Rates,” February 28, 2019; retrieved August 7, 2020 from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420990/
3. C. Lee Ventola, U.S. National Library of Medicine National Institutes of Health, “Cancer Immunotherapy, Part 3: Challenges and Future Trends,” August 2019; retrieved August 7, 2020 from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521300/