Clinical lot or not: what material did approved cell therapies test?

“*Lot Nos. were not assigned for CAR T cells assessed in nonclinical studies #1-8; they were manufactured under Experiment Nos.”

“Idecabtagene vicleucel (ide-cel, bb2121) consists of autologous CD3+ T cells that are transduced using a lentiviral vector to express a BCMA-directed chimeric antigen receptor (CAR).”

“In most studies, cell preparations were expanded with the method of manufacture and to the same population doubling level of the product for clinical use.”

“assess efficacy and safety of expanded allogeneic adipose-derived stem cells (eASC) for the”

“No nonclinical studies were conducted with AMTAGVI. Instead, the applicant cited published nonclinical data evaluating similar murine and human tumor-derived T lymphocytes to provide support for AMTAGVI.”

“AMTAGVI is a cellular suspension containing live autologous T lymphocytes isolated from a patient’s resected tumor.”

“The main difference is that the starting material for the nonclinical product was healthy donor PBMCs, while for the clinical product it was non-stimulated leukapheresate from patients.”

“AUCATZYL™ (obecabtagene autoleucel; obe-cel; AUTO1; CAT19 CAR T cells) is a cell suspension consisting of autologous human CD4+ and CD8+ T cells transduced with a lentiviral vector encoding a CAR consisting of an anti-CD19 scFv linked to 4-1BB and CD3ζ T cell activating domains.”

“The objective of this in vivo study was to evaluate the anti-tumor activity of cryopreserved preclinical lots of JCAR017 produced from several preclinical production runs (page 3 in the study report). The cells were thawed and expanded according to a protocol that mimics the post-transduction manipulation process for BREYANZI®.”

“BREYANZI® (lisocabtagene maraleucel; JCAR017) is a cell suspension consisting of autologous human CD4+ and CD8+ T cells that are engineered with a lentiviral vector encoding a chimeric antigen receptor (CAR) consisting of an anti-CD19 single-chain variable fragment (scFv)”

“In the non-clinical package, CAR T cells from different LV manufacturing developmental stages have been used (refer to Section 2.4.2. ). In all cases, the CAR expressed by the CAR-T cells is identical.”

“CARVYKTI™ (ciltacabtagene autoleucel; cilta-cel; JNJ-68284528; or LCAR-B38M CAR-T cells) is a cell suspension consisting of autologous T cells that are genetically modified ex vivo with a lentiviral vector (LV) encoding a chimeric antigen receptor (CAR) targeting the B cell maturation antigen (BCMA).”

“In goats either autologous cells or human articular chondrocytes, expanded according to the ChondroCelect culture process were implancted via an ACI procedure.”

“ChondroCelect is composed of non-modified human autologous cells.”

“In process ATA129 product was received on Day 27 of ongoing culture and was separated into CD4 and CD8 enriched fractions.”

“Tabelecleucel is a cell based therapeutic product that is not genetically modified.”

“The device used in this study is an early prototype that is 11 mm in length (the proposed clinical device is 6.5 mm). Thus, this study is preliminary regarding assessing the overall pharmacology of the product, NT-501.”

“The ENCELTO dose of rhCNTF derives from an implant containing 200,000-440,000 allogeneic retinal pigment epithelial (RPE) cells expressing rhCNTF (NTC-201-6A cell line).”

“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.”

“In vitro analysis of the cellular components of Apligraf®, allogeneic keratinocytes and dermal fibroblasts, did not show induction of an alloimmune response”

“The karyotype analysis included chromosomal counts and the frequency of hyperploidy, hypoploidy, polyploidy, breaks and structural abnormalities in 50 metaphasic cells in six batches cultured from the drug product.”

“The non-clinical development programme of Holoclar, a transparent sheet of autologous human corneal epithelial cells including stem cells, comprised an evaluation of published studies from the scientific literature”

“the pharmacology studies were conducted with cells transduced with lentiviral vector made at the University of Pennsylvania, or at a further facility in the US, whereas clinical studies were done with cells transduced with vector made by Oxford Biomedica”

“Tisagenlecleucel (KYMRIAH™, CTL019) gene transfer is accomplished via ex vivo transduction with a replication-deficient human lentiviral vector (LV) encoding the transgene.”

“No nonclinical studies were conducted with LANTIDRA. 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”

“LANTIDRA (donislecel-jujn) is a cellular therapy comprised of islets of Langerhans obtained from the pancreas of deceased adult human donors.”

“The preparation of the rabbit analog cells used in this study did not duplicate the procedure that is used for IT preparation; for example, the rabbit cells were separated from the skin biopsy by mincing and treating with dispase; however, only digestive enzymes are used to prepare IT.”

“Autologous fibroblasts (Human, dermal, Isolagen Technologies, Inc.) expanded ex vivo, administered intradermally.”

“Studies conducted in horses and rabbits compared ACI-Maix or empty defects to analogous products consisting of ACI-Maix seeded with rabbit or horse cells.”

“The product, MACI™, is an implant which consists of characterized autologous cultured chondrocytes (ACI) seeded on a resorbable porcine-derived collagen membrane (ACI-Maix)”

“The nonclinical studies were conducted with products from different stages of development before the final manufacturing process of omidubicel-onlv was implemented.”

“OMISIRGE is a cryopreserved, allogeneic hematopoietic cellular therapy consisting of two cell fractions; a CF and NF, which are both derived from the same subject-specific CBU.”

“However, splenic rat cells were loaded with PAP antigens instead of peripheral blood mononuclear cells and the manufacturing processes for the cellular products differed from the sipuleucel-T process.”

“Provenge (sipuleucel-T) consists of autologous peripheral blood mononuclear cells (PBMCs), including antigen presenting cells (APCs) that have been activated ex vivo with a recombinant fusion protein, PA2024, composed of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF).”

“Animal studies were conducted in nude rats 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.”

“RVT-802 is an allogeneic, processed postnatal thymus tissue product that is administered via surgical implantation.”

“Nonclinical studies were conducted using human bone marrow-derived culture-expanded MSC (ceMSC) and surrogate animal-derived ceMSC produced using an early manufacturing process. As a result, the completed nonclinical studies provide limited support for RYONCIL.”

“Remestemcel-L is comprised of expanded allogeneic human bone marrow-derived mesenchymal stromal cells.”

“In these studies human Spheroxs or autologous spheroids produced in an analogous way were used.”

“The active substance, spheroids of human autologous matrix-associated chondrocytes, is formulated in 0.9% sodium chloride solution”

“Per the applicant, the STRATAGRAFT® manufacturing process was being refined as the product development program progressed. The applicant cited the following differences between the manufacturing process of STRATAGRAFT® for Studies #1 and #14 and the commercial process.”

“The construct is composed of an epidermal layer of fully-stratified allogeneic immortalized near-diploid human keratinocytes (NIKS® keratinocytes) grown on a dermal equivalent (DE) consisting of allogeneic normal human dermal fibroblasts (NHDFs) in a rat tail collagen-rich matrix.”

“Some of the presented non-clinical in vitro pharmacology studies were conducted with CD19 CAR T cells that were generated at the NCI with a manufacturing process similar, but not fully equivalent to the KTE-X19 process. In order to complete the pharmacology data package, additional non-clinical in vitro pharmacology studies were conducted with CD19 CAR T cells manufactured using the KTE-X19 process.”

“KTE-X19 (also referred to as axicabtagene ciloleucel) is an autologous chimeric antigen receptor (CAR) T-cell product engineered with a retroviral vector”

“Although the human Tregs and Tcons administered in the nonclinical studies were manufactured similarly to the intended clinical DP lots, this lack of clarity limits the ability to determine whether nonclinical dose levels (cells/mouse) reflect comparable biological activity to clinical Treg DP and Tcon DP dose levels in TREGZI.”

“TREGZI (Orca-T) is an allogeneic hematopoietic stem and progenitor cell (HSPC), and T-cell immunotherapy designed to improve survival free of cGVHD in adult patients with hematologic malignancies undergoing a myeloablative preparative regimen.”

“Non-clinical in vitro pharmacology studies were performed with CD19 CAR T cells that were generated using two previous manufacturing processes established at the NCI (CLP-1.0 and CLP-2.0); neither of them represents the current process (CLP-2.2).”

“KTE-C19 comprises human autologous cells transduced with a retroviral vector containing an anti-CD19 CAR.”

“Preclinical in vitro and in vivo studies in immune deficient mice were performed using for cell preparation both the SFCMM-3 #35 retroviral vector and an optimized version of the vector, encoding a mutated form of the HSV-TK gene (HSV-TK Mut2 #48), as well as and an optimized process manufacture developed before launching the phase III clinical study.”

“The finished medicinal product of Zalmoxis is defined as frozen donor T lymphocytes genetically modified with the SFCMM-3 Mut2 #48 retroviral vector and encoding for the HSV-TK and the ΔLNGFR genes”

“Except for study ECT/2018-12-001, none of the submitted non-clinical studies have been conducted with the clinical/commercial manufacturing process using 35 mM UM171, 4F and no LDLs in a 7-day culture. No thorough non-clinical study has been conducted to evaluate the final clinical process culture conditions all together.”

“The CD34+ cell fraction consists of cord blood-derived CD34+ cells that are expanded in vitro in the presence of the small molecule UM171 and hematopoietic growth factors.”

“TECELRA consists of autologous T cells that are genetically modified with the lentiviral vector (LVV) MAGE-A4-c1032 to constitutively express an affinity-enhanced T cell receptor (TCR) specific for human MAGE-A4.”