More on standards in cell therapy – meeting at NIST

by Alexey Bersenev on February 5, 2016 · 2 comments

in cell product, consensus

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Last week, National Institute of Standards and Technology (NIST)/ IBBR hosted a meeting – CAR-T Biomanufacturing Symposium. Despite “CAR-T cell” in the title, many discussions, which took place during the meeting, were widely applicable to the whole field of cell therapy. As far as I know, it was the second conference, organized by NIST for cell therapy field. The first meeting – Strategies to Achieve Measurement Assurance for Cell Therapy Products took place last year.

You may ask – why NIST? Well, NIST is highly involved in development of standards and measurements for biomanufacturing industry. Cell therapy is relatively new, very fluid and rapidly evolving field, which currently is lacking standards in many aspects. In the last few years, NIST in collaboration with other organizations has started such cell therapy-related projects as cell counting, pluripotent stem cells and 3D tissue scaffolds. There are very new initiatives, supported by NIST, such as recently proposed Advancing Standards in Regenerative Medicine Act.

It seem to me that cell therapy developers are in agreement about potential benefits of collaboration in developing standards by NIST and other organizations. The most important reason for such collaboration was articulated by David Stroncek (NIH): “I do a lot daily in-process testing and product release testing with no controls – this is very bad practice!” (not because he is a bad, but because controls are not available). Talking of specifics, NIST is developing and would like to be involved in the following areas of cell therapy:
– enabling tools (devices calibration against standards)
– developing and publishing of protocols
reference materials
– analyticals (cell counting, cell characterization)
– bioprocessing (ancillary and raw materials, cell transportation and logistics)
– bioinformatics and modeling.

It is important to understand that NIST does not impose standards, they are discussed and accepted by consensus. The biggest impact for cell therapy could be standards in cell product characterization. Availability of reference material and ability to measure will help developers to understand how to characterize the cellular products.

Sadik Kassim (Novartis) presented very interesting data on variability in characterization of CAR T-cells by flow cytometry. He said: “Flow cytometry assays are the most variable assays in both – in-process and cell product release testing. Therefore, standardization of cell product analytics is usually related to flow cytometry standardization”. He thinks that automation of flow cytometry in clinical cell product characterization can provide potential cost-effective solution. Kassim, then discussed a problem with potency assays. All published CAR T-cell clinical studies cite only 2 types of potency assays – (1) level of interferon-gamma and (2) cytotoxicity by 51Cr release. Both potency assays are not very accurate and poorly differentiate responders versus non-responders. He said, that CAR T-cell products potency could not be captured in one dimension analytical readout. It is possible, that there may not be “one size fits all” potency assay for CAR T-cell products – it could be indication-specific or process-specific or effector cell-specific.

As expected, the potency assays was one of the hottest topics of this meeting. Somebody from NIST asked if they can develop and recommend few potency assays for the field. Victor Lu (FDA) responded that it will be very difficult to apply, because every cell product is usually unique. I think, it is still a good idea, because developer can look at the list of these potency assays, pick 1-2 and try to apply to specific product. It is better then nothing.

FDA was heavily present at the meeting and actively discussed hot topics. FDA has a great interest to standards development in cell therapy, because it will make their work easier – they will have something to compare with and something to reference. One important message from FDA folks was that they recognize variability between patients and challenges related to it. They would listen developers about all variables and advice. On the one hand, FDA wants to see potency assay with great correlation to clinical response, but, on the other hand, they understand how difficult it is to come up with such assay, considering specifics of alive cells as a medicine. So, try to do your best in developing potency to measure precisely biologic activity of your cells, but don’t kill yourself if it does not always correlate with clinical response. Another interesting remark from FDA was about potential collaboration between cell product developers. Each developer has their own dataset of assays (which FDA also has), but it is pretty much never shared. Seem like FDA encourages such sharing, since it could advance the field.

Throughout the meeting I felt like NIST folks are really really interested in cell therapy field. NIST people were very much engaged into all kinds of discussions and asked very good questions. It seem to me, they were trying to understand what is the best fit for them and what is the best area to get involved to help cell therapy developers. One good advice came from the panel – breaking up the whole field into small pieces and getting involved in some areas little-by-little will be more attractive approach. And the reason for this is a huge competition (CAR T-cell field is the best example) between companies, which are rushing to market and may see any sort of collaboration or consortia as distraction.

I was really enjoying the meeting and would highly recommend any other cell therapy meetings at NIST. Frank Gayle (NIST) said that currently in US there is a huge gap between innovation (R&D) and commercialization (mass manufacturing) and NIST sees its role in bridging this gap. I think, this is a great mission, because development of local manufacturing should be a national priority for every country.

{ 2 comments… read them below or add one }

Kelley Rogers February 5, 2016 at 9:18 am

Thanks for the shout-out, Alexey. NIST welcomes the guidance from the cell-therapy community as we develop our program priorities.

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Alicia Henn February 10, 2016 at 11:58 am

Great summary, Alexey. I was at the meeting as well. The discussion I found the most fascinating was of “Patient 10” by Bruce Levine. This patient had a delayed response which was later attributed to a single clone growing out of the mix. Out of the billions of cells infused, it only took one clone to achieve that response.
Since the only factor correlating so far with efficacy is in vivo expansion and persistence of the CAR T cells, the critical potency measure is still elusive. Until we can connect the only part under our direct control, the ex vivo cell treatment, with the in vivo expansion through cell or patient characteristic(s), the critical potency measure will continue to elude us.

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