What safety margins were accepted for approved cell therapies?

“Except for one study in the minipig, in which up to 3.2 fold the maximum clinical dose was applied, all studies used doses similar to the intended clinical dose.”

“There were no indications of treatment related adverse effects and the implant was well tolerated.”

“As shown in the above table, MOEs are above 100, indicating adequate protection of human health and a low risk of adverse reproductive and developmental effects.”

“ITV implantation of NT-501 did not cause any effects on systemic clinical signs, gross pathology, or histopathology of non-ocular organs.”

“Intravenous administration at doses 8,000-20,000 times higher than the estimated human exposure to UM171 demonstrated no toxicity in rats (single-dose study) or cynomolgus monkeys”

“Intravenous administration at doses 8,000-20,000 times higher than the estimated human exposure to UM171 demonstrated no toxicity in rats (single-dose study) or cynomolgus monkeys”

“No bb2121-related adverse findings were reported in these studies.”

“Taken together, two administrations of eASC two weeks apart at doses up to 2.5 x 106 cells were well tolerated in athymic nude rats when administered via the perianal route.”

“No toxicology studies were conducted for AMTAGVI. Given the characteristics and biological activity of AMTAGVI, this omission is acceptable.”

“The data indicate that human tissue cross reactivity with the CAT19 CAR binding domain was consistent with the expected profile of CD19 expression on B lymphocytes.”

“Animal studies to assess the long-term safety of JCAR017 were limited because the JCAR017 does not survive in immunocompetent rodents and induces graft-versus-host disease in immunocompromised mice.”

“There were no test article-related adverse effects on survival, clinical signs, body weights or body temperatures.”

“No effects on body systems or systemic toxicity was seen in the mice, sheep or goats”

“Studies conducted in immunodeficient animal models for EBV+ PTLD revealed no overt signs of toxicity (e.g. loss of activity or weight loss) associated with a single dose of tabelecleucel.”

“This biocompatibility testing paradigm did not reveal any findings of significant biological concern.”

“No evidence of chromosomal aberrations or minor chromosomal damage was detected”

“There was no histologic evidence of systemic toxicity associated with CTL019 versus mock T cells. No abnormal cell growth was detected by clinical pathology or by PCR at any time point in any animal.”

“These findings were observed on Day 1, progressed to necrotic regions surrounded by multifocal leucocyte infiltrates by Day 3, with progressive mononuclear leukocyte infiltration of the colonized islets (from peri-islet to intra-islet), leading to islet destruction by Days 9-14.”

“There were no significant safety signals identified in the animals.”

“No test article-related adverse effects were observed in body weights, food consumption, clinical pathology, or histopathology assessments.”

“It was agreed that the cell dose is apparently not limited by toxicity.”

“The recommended dose range is to 22,000 mm2”

“Dose levels of 15x106 cells/kg and higher resulted in increased mortality shortly after dosing, associated with shallowed breathing, impaired righting reflex, and pale discolored skin.”

“No test article-related findings were observed in the examined tissues.”

“Notably, this complete and prolonged absence of B cells was not accompanied by any evidence of overt toxicity.”

“An alloreactivity screen against a panel of cells expressing a range of HLA alleles indicated in vitro alloreactivity against HLA-A*02:05. Therefore, afamitresgene autoleucel is contraindicated for adults who are heterozygous or homozygous for HLA-A*02:05P.”

“Histopathological examination revealed dose-dependent T cell infiltration in hepatic periportal regions and parenchyma, thickening of intestinal lamina propria, and atrophy of subcutaneous fat and hair follicles”

“B cell aplasia was observed, but no overt toxicity was exhibited (Experiment E).”

“In preliminary studies a dose dependent GvHD-induced mortality was observed with a 100% incidence at the dose of 20x106 cells/mouse, which was chosen as the target dose. Of note, the chosen target dose is around two log higher than the proposed clinical dose, thus providing large safety margins.”

“Non clinical safety data obtained in two different immunedeficient animal models for Graft Versus Host disease did not indicate special hazards for humans, but allowed only a very limited safety assessment.”