MiniPDX® - an In Vivo 3D Organoid and Faster Alternative to PDX

Tech Snapshot® captures today’s cutting-edge tools and technologies that will help drive drug discovery tomorrow. This installment was written by LIDE Biotech, a company committed to the research, service and product development of individualized precision medicine for cancer.

It is well known that patient-derived xenografts (PDX) models represent the gold standard in functional diagnostics with their high predictive power for anticancer drug response. However, limitations such as engraftment failure and long lead times to establish and expand PDX models have limited their application to only the most promising targets. When considering the clinical setting and personalized cancer treatment, PDX does not enable the fast results needed to enable effective therapeutic selection. An alternative that has received much recent attention is leveraging 3D cell spheroids or organoids. Although lauded as a better representation of natural tumor environments vs. traditional 2D cell cultures, the still ex vivo 3D culture limits the ability to test systematic drug administration, hindering realistic results. LIDE has developed a new technology, MiniPDX® as an in-vivo version of a 3D organoid, and a faster alternative to PDX, without the lost in predictive power for drug response.

Methodology
MiniPDX® is a novel in-vivo drug sensitivity test with fast (7 days) turnaround time. It can be viewed as a faster PDX with well correlated results. The process can start with either fresh patient tumor samples or tissues from established PDX models. Cell suspensions are created and then implemented into a hollow fiber mini-capsule that can accommodate molecules up to 500kD, which could cover most small molecule drugs, big molecule drugs and bispecific antibodies. The capsules are inoculated in mice subcutaneously and then systematically treated with candidate and/or control drugs. Specific regimens are specified by the client and can be delivered orally or via injection. Post treatment, mini-capsules are removed and the cellular activity morphology and pharmacokinetics are systematically evaluated. This process can provide drug sensitivity results in as little as 7 days vs. the 4-6 months needed for traditional PDX results. Furthermore, each MiniPDX® model requires 70% less mice than the equivalent PDX study, saving resources both in number of mice used, and evaluation time needed.

Predictive Power
Given the time savings of MiniPDX® vs traditional PDX, it is natural to ask how results correlate between the two model types. In a published study, LIDE used 26 PDX models generated from patient tumor samples, including 14 gastric cancers, 10 lung cancers and 2 pancreatic cancers to demonstrate that drug responses in the PDX tumor graft assays correlated well with those in the corresponding MiniPDX assays. The positive predictive value of MiniPDX was 92% vs. PDX, and the negative predictive value was 81% with a sensitivity of 80% and a specificity of 93%.

PDX is well studied and shown to be 89% correlated with clinical result. Taken together with MiniPDX® results, this means MiniPDX® is 82% correlated with clinical results, by calculation. In China, LIDE has verified this in the clinical setting, with over 2400 treated cases at over 80% effectiveness.

Application in Drug R&D
The high correlation between drug responses of paired MiniPDX® and PDX tumor graft assay, as well as translational data suggest that MiniPDX® assay can be an effective pre-clinical testing tool in drug R&D. A straightforward application in a MiniPDX Mouse Trial allows for faster screening of candidate molecules before more resources are invested. Clinical indications can be validated, and new indications potentially discovered.

However, by combining MiniPDX® functional testing with proprietary LIDE OncoVee™ K-cell technology, only a small sample is needed to generate the appropriate base for transcription level analysis. RNA or DNA can be extracted from ~1,000’s of cells vs. 10-100s of thousands usually needed. This enables genomics, transcriptomics and even proteomics analysis that can reveal biomarkers to differentiate responders and non-responders. This is helpful in patient stratification when designing inclusive/exclusive criteria for clinical trials. LIDE calls this combined (MiniPDX® trial + omics analysis) approach “Functional Diagnosis,” and we believe it is the future of drug R&D.

Case Study
Pharma Company X had developed candidate “cpd” that had shown good efficacy against Cancer Type A in CDX models. Literature research also showed that the molecule could be effective against three other cancer types. LIDE designed a Functional Diagnosis study to isolate specific indication and identify any associated companion diagnosis.

In initial round of MiniPDX® testing, 31 samples across the four cancer types were treated with cpd. Overall ORR (overall response rate) in round one was 16.1%; only five cases were positive responses. Notably none were in Cancer Type A, the original candidate indication as identified by CDX. Cancer Type A was quickly abandoned while 10 additional samples of Cancer Type B were added for further testing.

In round two, testing was done only on Cancer Type B. Out of 20 cases, ORR was 35%, or 7 out of 20 positive responses. Although this was a MiniPDX® model, 35% ORR in PDX studies would’ve cleared benchmarks required for clinical trial approval.

LIDE then took both the negative and positive responders, leveraged our OncoVee™ K-cell technology and omics analysis, to reveal that positive responders were differentiated with downstream mutation E1/E2. This was a clear companion diagnostic that can be used to select patients and ensure success in clinical trials.

Application in Precision Medicine
MiniPDX® drug sensitivity tests have obvious application in the clinical setting. Using fresh tumor samples generated directly from patients, multiple drugs and regimens can be tested in mice first to determine best treatment for patients. This testing is not viable with traditional PDX, given the months needed for results. With its 7-day turnaround time, MiniPDX® diagnosis can guide clinician treatment plans. This was demonstrated in a study by Shanghai Ruijin Hospital. Patients with gall bladder carcinoma were treated with MiniPDX® guided therapies vs. a control group using conventional guidance-recommended therapies. MiniPDX® guided therapy had over 5-month improvement of OS (overall survival) and DFS (disease free survival). Similar results were recently shown by Nanjing First Hospital with gastric cancer (specifically GCLM) patients.

Conclusion and Future Perspective
In China, MiniPDX® is a proven technology with multiple supporting published papers. The benefits in clinic are clear enough that LIDE has received government authorization to partner with hospitals all over China to apply MiniPDX® testing to 10,000+ patients. After years of refinement and testing in China, we are now introducing this technology to the North American and European markets. LIDE looks forward to MiniPDX delivering precision medicine to oncology patients worldwide and impacting positive outcomes.

Although we are still in progress with regulatory approval for direct patient usage outside of China, the benefits of MiniPDX® can be realized today via partnerships with US and European companies. LIDE has amassed one of the largest tumor biobank in the world, many with rare mutations and/or drug resistance. We’ve also self-funded development of MiniPDX® and PDX models against that biobank. Leveraging the biobank and MiniPDX® enabled Functional Diagnosis will expedite development of oncology drugs and treatment.

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Visit www.lidebiotech.com/minipdx for more information.
Watch LIDE’s webinar on Translational Applications of MiniPDX on Scientist.com here.

For more information, contact Josh Caggiula, LIDE VP Client Service for North America & Europe.