Microtube Array Membrane Hollow Fiber Assay (MTAM-HFA)—An Accurate and Rapid Potential Companion Diagnostic and Pharmacological Interrogation Solution for Cancer Immunotherapy (PD-1/PD-L1)

Abstract

Immunotherapy is one of the most promising forms of cancer treatment. In particular, immune checkpoint blockers (ICBs) represent some of the leading candidates which many drug developers have heavily invested in. During pre-clinical development and prior to human clinical trials, animal tests are a critical component for determining the safety and efficacy of newly developed ICBs for cancer treatment. In this study, we strive to demonstrate the feasibility of using hollow fiber assay microtube array membrane (MTAM-HFA) in the screening of anti-cancer ICBs. The MTAM-HFA process was carried out by encapsulating peripheral blood mononuclear cells (PBMCs) and the target cancer cells (cell lines or primary cells) and subcutaneously implanting them into Balb/C mice. At predetermined time points combination regimens of PD-1/PD-L1+ were administered accordingly and at a predetermined time point, the MTAMs were retrieved, and cell viability assays were carried out. The outcomes of the MTAM-HFA were compared against the clinical outcome of patients. Clinical comparison demonstrated excellent correlation between the screening outcome of MTAM-HFA of PD-1/PD-L1+ combination therapy and the clinical outcome of the lung cancer patients. Basic cell studies revealed that the utilization of MTAM-HFA in PD-1/PD-L1+ combination therapy revealed enhanced T-cell activity upon the administration of the PD-1/PD-L1 drug; thereby resulting in the reduction of tumor cell viability by up to 70%, and the cytotoxic effects by 82%. The outcome was echoed in the in vivo cell studies. This suggested that the MTAM-HFA system is suitable for use in PD-1/PD-L1+ screening and the accuracy, rapidity and cost effectiveness made it extremely suitable for application as a companion diagnostic system in both personalized medicine for cancer treatment and could potentially be applied to screen for candidate compounds in the development of next generation PD-1/PD-L1+ combination therapies.

Microtube Array Membrane Encapsulated Cell Therapy: A Novel Platform Technology Solution for Treatment of Alzheimer’s Disease

“…PSF MTAMs were successfully electrospun with the desired microstructures as reported in previous works [ 23 , 29 , 33 ]. The porous structure was observed in the morphology of MTAMs ( Figure 1 A–H).…”

Review of electrospun microtube array membrane (MTAM)‐a novel new class of hollow fiber for encapsulated cell therapy (ECT) in clinical applications

“…15,20,22 At this thickness, permeation of nutrients and biological compounds were unhindered as demonstrated in several previous works. 13,14,18,21 Interestingly, the hybridoma cells that were encapsulated within the PSF MTAMs registered 50% improvement in terms of quantity of anti-CEACAM 6 antibody, despite registering lower viability when compared to the hybridoma cells cultured on standard TCPs. Evidence suggested that the significantly greater functional viability can be attributed to the excellent 3D configuration in which the hybridoma cells encountered when encapsulated within the respective lumens of the PSF MTAMs, which was highly aligned with the findings of several other research groups.…”

“…12,16,17 The permeation of biological compounds across the top and bottom lumen walls were successfully demonstrated in multiple works ranging from encapsulated cell therapy, fermentation, tissue regeneration, drug diffusion and and so forth. 13,14,[18][19][20][21][22] Despite being an unique hollow fiber (HF) member, MTAMs often have a surface that is 20-50 times greater than that of normal HFs. This is partly because the MTAMs are made using much smaller dimensions than standard HFs, and this directly translates to a significantly greater packing density.…”

“…38,39 The unique one-to-one linked structure that creates the macroscale membrane makes it possible for everyone to manage and handle it without the need for expensive, specialist equipment. 13,16 Additionally, this permits a significant improvement in terms of patient biosafety as the entire membrane along with all implanted cells that are encapsulated can be removed right away in the event of a negative outcome-a special characteristic that current micron scale encapsulation technology do not afford. [40][41][42] With this special and extremely advantageous value proposition of MTAMs as an encapsulated cell treatment platform, we have proven the novel application in the disciplines of cancer therapy, Alzheimer's disease, Cardio Patch and Human Dermal Fibroblast (HDF) will be covered in subsequent parts.…”

“…However, we discovered that by gathering the fibers that were guided by unique set of voltage as previously described, allowed for the collection of the individual fibers before entering the instability area and using a rotating drum, we could produce highly aligned, one-to-one connected fibers (Figure 1). [12][13][14] This led to the successful production of MTAMs with a superior surface area of up to 2.3-2.5 times that of conventional Hollow Fibers. The MTAMs have a greater diffusion and absorption surface area due to their formation of ultra-thin, individually connected hollow fibers arranged in an array.…”