Which risks did regulators probe for approved cell therapies?

“It is also expected that ide-cel will deplete healthy plasma cells that express BCMA.”

“A biphasic peak expansion of bb2121 cells was observed on Days 2 and 11 in the peripheral blood and Days 8 and 15 in analyzed tissues in tumor-bearing mice.”

“Data generated in other toxicity studies show low potential for T-cell mediated eASC recognition, in vitro and delayed NK cell mediated elimination.”

“In conclusion, when administered locally human eASC is only persistent for a short period of time in rats.”

“Compared to TILs expanded in 1000 U/ml of IL-2 alone, TILs activated with anti-CD3 + 50 U/ml of IL-2 demonstrated higher cytotoxicity against autologous tumor cells but not against Daudi, K562, or histologically matched heterologous tumor cells.”

“No nonclinical studies were conducted to evaluate distribution of AMTAGVI. Based on the available information on the in vivo distribution of intravenously administered T cell products, this omission is acceptable.”

“Known risks of CAR T cell therapies (e.g., CRS or neurotoxicity) can be clinically monitored and managed.”

“Traditional non-clinical pharmacokinetic studies (absorption, distribution, metabolism, excretion and in vitro drug-drug interaction) have not been conducted because obe-cel is an autologous gene therapy product and there is no pharmacologically relevant species.”

“These data provide support for administration of commercially available antibodies targeting the truncated EGFR domain on the surface of JCAR017 to reduce/eliminate the CAR T cells in vivo, if necessary.”

“No biodistribution studies with JCAR017 were conducted.”

“These toxic effects have not been investigated in non-clinical studies which is acceptable considering that these effects are general effects of CAR T cells”

“No biodistribution studies with JNJ-68284528 were conducted.”

“implantation of human or allogeneic chondrocytes causes an immune response to the CBMP, resulting in poor repair.”

“implanted cells become a structural part of newly formed cartilage.”

“Ebvallo is tested for specificity of lysis of EBV+ targets, T-cell HLA restriction of specific lysis, and verification of low alloreactivity.”

“Migration and infiltration occurred into fully HLA-matched tumours and was absent from mismatched tumours.”

“Two preclinical studies in minipigs or pigs implanted with NT-501-6A.02 device for up to 6 months showed no immune response to rhCNTF or cell producing the protein.”

“In rabbits, NT-501 implants established CNTF levels averaging about 7-9 ng/day for up to 9 months.”

“The potential for Apligraf® to induce an alloimmune response by indirect allorecognition was not evaluated.”

“The grafted keratinocytes and fibroblasts persisted for at least 1 year after grafting.”

“no significant adaptive immune response was observed after repeated transplantation in the clinical setting”

“classical absorption, distribution, metabolism and excretion studies were not considered relevant for a human CBMP”

“Protein array assessment for binding of murine and humanized CD19-CAR scFV to human membrane proteins showed that CD19 was identified by both biotinylated scFv fragments of human and murine, while no other human membrane protein binders were detected on the array.”

“On day 56 post-injection, CART-19 cell signals were detected in these same tissues plus the liver, heart, blood and bone marrow in Groups 1 through 3 with more frequency in Group 1 as compared to Groups 2 and 3.”

“These data suggest that an immunosuppression regimen is necessary for islet survival post-transplant and provide overall support for use of the (revised) Edmonton Protocol with intraportal transplantation of LANTIDRA in the target patient population.”

“The distribution of the 18F-FDG-labeled islet cells in the liver was found to be heterogeneous. No accumulation of radioactivity was detected in non-hepatic tissues.”

“Inflammation was present in all knees, likely due to defect creation and possible immune response to the porcine membrane.”

“There was no indication of systemic adverse reactions or systemic distribution of MACI, ACI-Maix, or the seeded chondrocytes.”

“The dose-safety relationship is essentially flat suggesting that an increase in dose did not result in an increase in adverse events of interest such as aGvHD and cGvHD.”

“At Week 12, relatively high quantities of human DNA were found in femur, spleen, lung, liver, and kidney in the high dose group.”

“Mild to severe interstitial inflammation was observed in Groups 4-6 rats.”

“No conventional ADME studies were submitted by the applicant”

“there was a time-dependent decrease in donor-derived T cells in the peripheral blood as the endogenous T cell population developed.”

“No cell distribution studies were conducted.”

“Low level alloantibody formation in ceMSC-administered animals was observed.”

“Cells were initially detected in the lung within the first hour following cell administration, followed by distribution to the liver, kidney and spleen within the first 24 hours”

“It should be noted that poplietal lymph nodes (lymph nodes draining the knee joint) of two of the animals were enlarged.”

“There were no indications of significant systemic distribution of the cells, or were there any indications of tumour or ectopic tissue formation after 6 months in the tumourigenicity part of this study.”

“STRATAGRAFT® is composed of human cells, thus the potential for elicitation of a xenogeneic response following administration in immune competent animals exists.”

“A total of 85 subjects in the Phase 1 and Phase 3 clinical trials were evaluated at 3 months for persistence of allogeneic STRATAGRAFT DNA at the treatment site.”

“These toxic effects have also not been investigated in non-clinical studies which is fully acceptable considering that these effects are general effects of CAR T cells”

“Anti-murine CD19 CAR T cells were not detected in the spleens of treated mice at Day 63 after injection of CAR T cells; longer follow-up for anti-murine CD19 CAR T cells was not examined.”

“No immunogenicity studies have been performed on afamitresgene autoleucel, as there are no suitable animal models for assessment of the immunogenicity of human TCRs.”

“Afamitresgene autoleucel, cell suspension for infusion is an autologous T-cell product. Therefore, traditional pharmacokinetic and ADME studies are not considered relevant to this product.”

“No safety/toxicology studies were conducted to assess additional safety endpoints, such as immunotoxicity and local tolerance, for TREGZI.”

“No nonclinical studies were conducted to evaluate cell distribution of TREGZI.”

“These toxic effects cannot be investigated in non-clinical studies as they are general effects of CAR T cells and the extent of expected toxicities are largely based on patient-specific parameters such as the individual tumour load.”

“No biodistribution studies with KTE-C19 were conducted.”

“Studies on antigenicity or immunotoxicity, dependence, metabolites, impurities were not submitted”

“No formal biodistribution studies have been performed for MM-TK.”

“in vivo transplantation cannot be performed with DP2 due to an expected GvHD reaction in the NSG mice caused by mature immune cells in this fraction.”

“The distribution of the UM171-treated cells is not evaluated.”

“the autologous cultured fibroblasts could survive in vivo for more than 5 months”