How was the first-in-human dose set for approved cell therapies?

“expression which represents the human equivalent dose (HED) of 2.05 x 108 CAR+ T cells for a 100-kg human.”

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

“The dose selection was based on a combination of animal studies conducted by TiGenix, published literature and experience in humans with ACI.”

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

“In both UIH-001 & UIH-002 studies a target islet dose of 10,000 EIN/kg was proposed based on the findings of previous experience with Edmonton Protocol for allogeneic islet transplantation.”

“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.”

“No formal pharmacokinetic, clinical dose finding, or dose regimen optimization studies have been performed during the development of RYONCIL for treatment of aGvHD in pediatrics.”

“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.”

“This omission is acceptable, as the applicant provided safety data from a Phase 1/2 clinical study with a similar clinical product to support initiation of the Phase 1b study”

“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”

“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.”

“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.”

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

“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.”

“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”

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

“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.”

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

“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.”

“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”