Cord Blood-derived HCT/Ps Remain ‘351 Category Products – Part One

Cord Blood Derived HCT

Back in mid-February, I was at the IOF Conference and was a part of a panel discussing various aspects of the questionable regulatory compliance by companies selling products that contain cord blood-derived components, including viable cells, among other issues. I was shocked to learn of the extent that the free-for-all in regenerative medicine involved donor cord blood, which spurred me after the conference to look into some of the offending companies and their cord blood-derived products. Needless to say, there are several issues I have with selling cord blood-derived products, especially if they contain viable cells, as follows:

  1. Cord blood is treated by the FDA as a biological drug.
  2. There are cells in cord blood that express HLA-antigens, meaning they are immunogenic.
  3. There are T-cells in cord blood that recently were found to attack maternal antigens.

The most perplexing aspect to me of the rise of donor-derived cord blood-based products is the fact that the FDA in no uncertain terms has classified donor-derived cord blood as a Section `351 category HCT/P. As I indicated in Item 1, cord blood’s status as a biological drug means that a facility/company must follow the process for an IND (Investigational New Drug) in order to sell cord blood or products derived from cord blood. In the case of cord blood, the first facility that went through the IND process and was approved to sell donor-derived cord blood was the New York Blood Center (Hemacord, HPC Cord is the product name).

The history of cord blood regulation by the FDA is well known, so I was really surprised when I reviewed the website of Invitrx, which shows the availability of a product they call “Invitra Cord Blood Stem Cells”. Naturally, I was drawn to the section they had on “Regulatory” as it relates to the Invitra Cord Blood product, which I have reproduced for your reading pleasure:

            “Regulatory

  • Umbilical Cord Blood is recognized as a HCT/P (human cells, tissues, and cellular and tissue-based products) by the FDA
  • HCT/P’s Regulated under 21 CFR 1271.3(d)(1) and Section 361 of the PHS Act
  • Invitrx Therapeutics is registered with the FDA and holds a CA tissue bank license allowing for the storage and distribution of Invitra CBSC Suspension”

And, just so there is no doubt as to what is in their donor cord blood-derived product, they offer the following:

“Contains cells extracted from umbilical cord blood containing a mixed cell population including hematopoietic (HSC) and mesenchymal stem cells (MSC).”

The product is cryo-preserved, so presumably the product vials contain a mixture of viable cells found in cord blood, including MSCs and HSCs.

I guess the impression you are supposed to get from reading the section on regulatory so helpfully provided by Invitrx is that they know what they are doing. They indicate that the FDA “recognizes” that cord blood is an HCT/P, and they contend that HCT/Ps are governed by 21 CFR 1271, from which they conclude that everything is happiness and light for the products Invitrx sells. The only problem with this curious syllogism is that it is false.

As I indicated above, the FDA has done more than just recognize that cord blood is an HCT/P, it has declared that it is a `351 category product. As a result of this designation, cord blood isn’t controlled by the provisions in 1271, and obviously can’t be a `361 category product if the FDA categorizes it as a `351. So, it would appear that Invitrx has misunderstood the regulatory framework for selling cord blood-derived products, which could lead to confusion among health care professions interested in using their products.

When I reviewed Invitrx’s website I could find no indication that the individual lots of Invitra Cord Blood Stem Cells are HLA-typed, so the products weren’t intended for use only in HLA-matched recipients. Not matching donor cord blood with the recipient’s HLA profile could be very problematic, due to the large number of negative outcomes that can occur when preparations containing immunologically-competent cells are provided to unrelated recipients. So, as indicated in Item 2 above, there is a very real chance of either the recipient’s cells attacking the cells in the implant, or the cells in the implant could attack the recipient’s tissues. This type of pathology is referred to as Graft-vs-Host disease or rejection by the host.

Beyond the regulatory issues associated with companies providing cord blood-derived products to all comers, and issues related to the potential immunological fire storm that might happen when un-matched cord blood or its components are implanted in a recipient (Item 2), there is an intriguing observation that suggests another negative outcome with using products containing cord blood-derived viable cell components—the presence of lymphocytes that are activated to attack maternal tissues/cells. In a recent report by Frascoli, et al. entitled, “Alloreactive fetal T cells promote uterine contractility in pre-term labor via IFN-γ and TNF-α”, the authors indicated that cord blood obtained from pre-term infants contained T-cells that “mount a robust proliferative, proinflammatory response to maternal antigens…”. They go on to state that the reactive responses of fetal T-cells were limited to the presence of maternal antigens, since so-called third-party antigens failed to trigger a similar response. Their conclusion is that there are maternal antigen-activated T-cells in the blood of pre-term infants.

The fact that there might be fetal T-cells activated against maternal antigens present in cord blood suggests to me that these activated T-cells could attack tissues and cells in recipients depending on just what maternal antigens were targeted. That this phenomenon very recently was recognized as a possible contributor to pre-term labor, suggests that maybe companies shouldn’t be selling cord blood-derived, viable cell-containing products willy-nilly. And more importantly, health care providers should think twice before buying into the hype of cord blood-derived products touted as being the most effective, since they contain younger stem cells. Clearly, these products could contain other cells that might not be so beneficial to the recipient.

I will deal in the next post with other cord blood-derived products offered by companies that in my opinion also are being marketing without following the appropriate regulatory pathway.

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