Animal model or human cells: efficacy evidence for approved cell therapies

“In mice bearing subcutaneous BCMA+ human MM xenografts, intravenous administration of bb2121 demonstrated dose-dependent anti-tumor activity and improved survival compared to control mice.”

“No single or repeat-dose toxicity studies were conducted with ide-cel as traditional animal studies employing common toxicology study designs are not appropriate for ide-cel since autologous human T cells do not graft in immunocompetent animals.”

“Dose dependent, statistically significant improvements in overall survival and body weight loss were associated with eASC treatment relative to TNBS control treatment.”

“In vivo, no model for anal fistulas was used to provide proof-of-concept data. This was agreed by the CHMP during the 2011 scientific advice.”

“In vivo pharmacology studies demonstrated that a single intravenous administration of obe-cel at a dose level of 2.5 × 106 CAT19 CAR T cells/animal in a systemic human tumor xenograft mouse model resulted in significant reduction in tumor burden on Day 12 post administration.”

“Aucatzyl, a patient-specific product, is not appropriate for administration to immunocompetent animals, as the T cells will not engraft.”

“The lack of conventional in vivo studies and the use of immune-deficient Raji Burkitt’s lymphoma-bearing NOD/SCID IL-2Rγnull mice model are justified and appropriate to investigate autologous cell-based products.”

“The results support that JCAR017 is specific for human CD-19 binding and lacks species cross-reactivity, in particular towards mouse and non-human primate.”

“In vivo pharmacology studies showed significant dose-dependent anti-tumor activity and increased survival following administration of LCAR-B38M CAR-T cells in immune-deficient mice engrafted with human MM cells.”

“In vitro data indicate that does not significantly bind to recombinant mouse or NHP BCMA expressed on cells. Therefore, animal studies evaluating the safety profile of CARVYKTI™ were limited due to lack of a pharmacologically relevant animal species.”

“The in vivo experiments demonstrated a pronounced therapeutic effect/increased survival of SCID mice suffering from intraperitoneal EBV-induced lymphoblastic B cell lymphomas (EBV-BLCL) that were treated with autologous (with respect to EBV-BLCL) tabelecleucel.”

“Because SCID mice are unable to generate functional lymphocytes, engraftment and growth of human lymphocytes and several human tumours are possible.”

“An early pharmacology study showed that the outer nuclear layer (ONL) in dogs with retinitis pigmentosa caused by rod-cone dysplasia type 1 (rcd1) was protected from photoreceptor loss following implantation of NT-501.”

“Rcd1 dogs are a well-established animal model for retinitis pigmentosa.”

“The purpose of this study was to characterize the in vivo tissue maturation, remodeling, and cellular persistence of Apligraf in a full-thickness wound in athymic mice.”

“Apligraf®, which is identical to Apligraf® (oral), is approved under a PMA filing (reviewed by CDRH) for the treatment of venous leg and diabetic foot ulcers; therefore, limited additional preclinical studies were conducted in support of this BLA.”

“A series of studies in mice bearing human primary pre-B ALL conducted to evaluate anti-tumor activity of CTL019 derived from different healthy human donors showed significantly improved survival in the tumor-bearing mice receiving intravenous (i.v.) injection of CTL019 at 2x106 cells/mouse as compared to the mock T cell administered animals.”

“The lack of single-dose toxicity studies is acceptable, since tisagenlecleucel is a patient specific product, which is not appropriate to administer to immune competent animals.”

“Studies evaluating cells cultured with NAM and cytokines in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice at 1.2 x 106 to 1 x 107 cells/mouse (approximately 4.8 x 107 to 4 x 108 cells/kg) showed an increased overall engraftment”

“Results showed that NOD/SCID mice were preferable over mice based on cell engraftment levels.”

“Studies were conducted in nude rats to to identify potentially optimal culture conditions of allogeneic neonatal thymus that result in engraftment and development of an endogenous T cell population (i.e., thymogenesis) following transplantation.”

“Per the applicant, based on the acceptable clinical safety profile of RVT-802 and the lack of relevant animal models, no nonclinical toxicology studies with RVT-802 were conducted.”

“Murine in vivo xenograft studies demonstrated dose-dependent TECELRA-mediated tumor control.”

“In the applicant’s POC studies using xenogeneic models, co-administration of human donor Tregs with Tcons demonstrated dose-dependent GVHD inhibition in sub-lethally irradiated immunodeficient mice.”

“Two studies in two different GvHD animal models both based on the NOD/SCID system were performed to evaluate the PK and primary PD of MM-TK.”

“The DLI engraftment is dependent on the availability of human cytokines IL7, IL15 and IL2, and promoted by the TCR of HLA-expressing antigen presenting cells, which are not present in the animal model.”

“In vivo engraftment studies were conducted to show primary and secondary engraftment of UM171-cultured human CD34+ cord blood cells, thereby also evaluating the impact of changes in culture conditions.”

“The human cell product has been used in these immunocompromised animals, because the applicant explained that UM171 had no activity on mouse HSCs (i.e. homologous murine product not possible).”

“anti-tumor activity of tumor-derived lymphocytes, in combination with Cy and IL-2, in murine models of colon adenocarcinoma and sarcoma with lung and liver metastases.”

“Primary pharmacodynamic studies were performed in two animal models, an ectopic model in nu/nu mice and an orthotopic model in goats.”

“In another study in goats comparing passage 1 versus passage 5 expanded human articular chondrocytes according to ChondroCelect culture process all animals showed poor repair, possibly due to an immunological reaction to the human cells.”

“Instead, the applicant referenced multiple publications and one manuscript in the BLA submission that evaluated biological activity, local (liver) distribution, and the local (liver) safety of transplanted allogeneic or syngeneic islets in combination with various immunosuppressive agents in diabetic rodent (mice, rats) and nonhuman primate (NHP) models.”

“The fibroblasts were administered to immune competent animals (animal analog cells) and to immunodeficient mice (human cells).”

“The BLA states that due to this previous commercial experience in humans, and due to the lack of a ‘suitable’ preclinical animal model for rhytids, no preclinical studies using IT were performed.”

“Collectively, the rabbit and equine studies indicate that implantation of MACI secured with a commercially available fibrin sealant resulted in improved repair of critical-sized defects in the knee/stifle, compared to implanted membrane alone or empty defect.”

“ability of rat APCs loaded with rPAP•rGM-CSF fusion protein to stimulate prostate specific inflammation, and the ability of antigen loaded APCs to protect against tumour challenge in mice.”

“It was acknowledged that the use of appropriate (prostate) tumour models was difficult if not impossible since such models were not available at the time of performing the non-clinical studies.”

“of-concept studies were conducted in immunodeficient mice and in two large animal models: a pilot study in minipig and a pivotal 6-month study in Merino sheep. In these studies human Spheroxs or autologous spheroids produced in an analogous way were used.”

“Comparative analyses of chondrocytes from different species showed that only a limited number of animals including Göttinger mini-pig and Merino sheep were capable of producing stable spheroids. These species were then selected for proof-of-concept studies.”

“Additionally, an in vivo study conducted using an analogous murine CAR construct recognizing the murine CD19 molecule demonstrated anti-tumor activity and increased survival in a lymphodepleted syngeneic adoptive transfer mouse model of CD19+ B cell lymphoma.”

“Since the anti-CD19 scFv utilised for KTE-X19 does only recognise human CD19, a murine surrogate model was engineered for non-clinical proof-of-concept studies in immune competent mice.”

“To evaluate CD19-specific anti-tumor activity in vivo, an analogous murine CAR construct recognizing the murine CD19 molecule was evaluated in a lymphodepleted syngeneic mouse model of CD19+ B cell lymphoma.”

“The scFv construct used to manufacture KTE-C19 recognizes human, but not murine CD19. Therefore, the NCI investigators developed an anti-murine CD19 CAR construct to administer in a syngeneic mouse model of B cell lymphoma in proof-of-concept experiments that also evaluated general safety.”

“In vitro studies characterizing the effects of bone marrow-derived ceMSC in co-culture with allogeneic immune cells demonstrated that ceMSC suppressed alloreactive T cell proliferation and can modify the cytokine secretion profile of various immune cells in culture.”

“support for the proof of principle was available from published non-clinical studies in rats which showed that ex vivo expanded limbal cells cultured on a fibrin support can be used to replace and regenerate corneal epithelium lost due to LSCD”

“the lack of relevant animal models due to differences in the ocular structure of most other mammals. Furthermore, complications may arise from the xenograft setting of such studies and due to ethical concerns with primate models.”

“However, no nonclinical pharmacology studies were conducted; please refer to the clinical review memo for confirmation of these claims.”