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In question: the scientific value of preclinical safety pharmacology and toxicology studies with cell-based therapies.

Broichhausen C, Riquelme P, Ahrens N, Wege AK, Koehl GE, Schlitt HJ, Banas B, Fändrich F, Geissler EK, Hutchinson JA - Mol Ther Methods Clin Dev (2014)

Bottom Line: These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion.On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products.By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Surgery, Department of Surgery, University Hospital Regensburg , Regensburg, Germany.

ABSTRACT
A new cell-based medicinal product containing human regulatory macrophages, known as Mreg_UKR, has been developed and conforms to expectations of a therapeutic drug. Here, Mreg_UKR was subjected to pharmacokinetic, safety pharmacology, and toxicological testing, which identified no adverse reactions. These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion. This leads us to question whether there is adequate scientific justification for preclinical safety testing of similar novel cell-based medicinal products using animal models. In earlier work, two patients were treated with regulatory macrophages prior to kidney transplantation. In our opinion, the absence of acute or chronic adverse effects in these cases is the most convincing available evidence of the likely safety of Mreg_UKR in future recipients. On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products. By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.

No MeSH data available.


Related in: MedlinePlus

Weight gain in NMRI-nude mice was unaffected by human regulatory macrophages (Mreg_UKR) treatment. NMRI-nude mice were allocated to three groups of five animals. Mice received injections of either 106 or 107 viable human M regs resuspended in Ringer’s lactate solution plus 5% human serum albumin and 60 U heparin, or were given a vehicle-only injection. No significant difference in weight gain was observed over a 7-day observation period after Mreg_UKR administration. (Filled symbols indicate bodyweight on day 0; unfilled symbols indicate bodyweights on day 7.)
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fig2: Weight gain in NMRI-nude mice was unaffected by human regulatory macrophages (Mreg_UKR) treatment. NMRI-nude mice were allocated to three groups of five animals. Mice received injections of either 106 or 107 viable human M regs resuspended in Ringer’s lactate solution plus 5% human serum albumin and 60 U heparin, or were given a vehicle-only injection. No significant difference in weight gain was observed over a 7-day observation period after Mreg_UKR administration. (Filled symbols indicate bodyweight on day 0; unfilled symbols indicate bodyweights on day 7.)

Mentions: No acute adverse reaction to Mreg_UKR doses of 106 or 107 cells was detected. In particular, no deaths occurred following intravenous cell infusion, no change in respiratory rate or rhythm was detected, and no dyspnea, hemoptysis, or cyanosis was observed. This is perhaps a reassuring result because one theoretical concern with infusion of M regs, which have a diameter of 15–30 μm, is obstruction of pulmonary vessels by single cells or cell aggregates.18 Recipient mice in all groups recovered from general anesthesia within 30 minutes, and none showed signs of distress upon waking. At 3 hours postinfusion, mice from all treatment groups were normally active, and an abbreviated clinical examination revealed no respiratory or neurological abnormalities. No significant difference in weight gain between treatment groups was observed over the 7-day study (Figure 2). No delayed reactions, as assessed by changes in behavior or constitutional signs, were observed over the 7-day follow-up period, and no deaths occurred.


In question: the scientific value of preclinical safety pharmacology and toxicology studies with cell-based therapies.

Broichhausen C, Riquelme P, Ahrens N, Wege AK, Koehl GE, Schlitt HJ, Banas B, Fändrich F, Geissler EK, Hutchinson JA - Mol Ther Methods Clin Dev (2014)

Weight gain in NMRI-nude mice was unaffected by human regulatory macrophages (Mreg_UKR) treatment. NMRI-nude mice were allocated to three groups of five animals. Mice received injections of either 106 or 107 viable human M regs resuspended in Ringer’s lactate solution plus 5% human serum albumin and 60 U heparin, or were given a vehicle-only injection. No significant difference in weight gain was observed over a 7-day observation period after Mreg_UKR administration. (Filled symbols indicate bodyweight on day 0; unfilled symbols indicate bodyweights on day 7.)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362366&req=5

fig2: Weight gain in NMRI-nude mice was unaffected by human regulatory macrophages (Mreg_UKR) treatment. NMRI-nude mice were allocated to three groups of five animals. Mice received injections of either 106 or 107 viable human M regs resuspended in Ringer’s lactate solution plus 5% human serum albumin and 60 U heparin, or were given a vehicle-only injection. No significant difference in weight gain was observed over a 7-day observation period after Mreg_UKR administration. (Filled symbols indicate bodyweight on day 0; unfilled symbols indicate bodyweights on day 7.)
Mentions: No acute adverse reaction to Mreg_UKR doses of 106 or 107 cells was detected. In particular, no deaths occurred following intravenous cell infusion, no change in respiratory rate or rhythm was detected, and no dyspnea, hemoptysis, or cyanosis was observed. This is perhaps a reassuring result because one theoretical concern with infusion of M regs, which have a diameter of 15–30 μm, is obstruction of pulmonary vessels by single cells or cell aggregates.18 Recipient mice in all groups recovered from general anesthesia within 30 minutes, and none showed signs of distress upon waking. At 3 hours postinfusion, mice from all treatment groups were normally active, and an abbreviated clinical examination revealed no respiratory or neurological abnormalities. No significant difference in weight gain between treatment groups was observed over the 7-day study (Figure 2). No delayed reactions, as assessed by changes in behavior or constitutional signs, were observed over the 7-day follow-up period, and no deaths occurred.

Bottom Line: These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion.On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products.By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Surgery, Department of Surgery, University Hospital Regensburg , Regensburg, Germany.

ABSTRACT
A new cell-based medicinal product containing human regulatory macrophages, known as Mreg_UKR, has been developed and conforms to expectations of a therapeutic drug. Here, Mreg_UKR was subjected to pharmacokinetic, safety pharmacology, and toxicological testing, which identified no adverse reactions. These results would normally be interpreted as evidence of the probable clinical safety of Mreg_UKR; however, we contend that, owing to their uncertain biological relevance, our data do not fully support this conclusion. This leads us to question whether there is adequate scientific justification for preclinical safety testing of similar novel cell-based medicinal products using animal models. In earlier work, two patients were treated with regulatory macrophages prior to kidney transplantation. In our opinion, the absence of acute or chronic adverse effects in these cases is the most convincing available evidence of the likely safety of Mreg_UKR in future recipients. On this basis, we consider that safety information from previous clinical investigations of related cell products should carry greater weight than preclinical data when evaluating the safety profile of novel cell-based medicinal products. By extension, we argue that omitting extensive preclinical safety studies before conducting small-scale exploratory clinical investigations of novel cell-based medicinal products data may be justifiable in some instances.

No MeSH data available.


Related in: MedlinePlus