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T cells and NK cells expressing chimeric antigen receptors (CAR) have demonstrated potent clinical efficacy in patients with hematological malignancies. One of the issues to overcome in the treatment of solid tumors using CARs is the lack of a process that generates large amounts of CAR-T cells, reduces cell exhaustion and differentiation, and improves long term survival after infusion into patients. Previously, Torres Chavez et al. demonstrated in a series of in vitro and in vivo experiments, performed in both hematologic and solid tumor models, the profound qualitative impact on CAR-T cell performance after using human platelet lysate (hPL) as a cell growth supplement. T cells expanded with their hPL showed a good proliferative capacity and enhanced long-term in vivo persistence compared to Fetal Bovine Serum (FBS) or human AB Serum (ABS), resulting in superior anti-tumor effects. Additionally, this group demonstrated that the transduction of T cells to generate the CAR-T cells was significantly improved by the use of hPL. Mill Creek's human platelet lysate (hPL) is produced using expired human platelets obtained from accredited blood banks in the United States. These platelets were originally intended for use in patient transfusion. The safety of platelets used in transfusion is managed by the U.S. Food & Drug Administration (FDA), as well as the Association for the Advancement of Blood & Biotherapies (AABB). These organizations set standards, including testing for transmissible diseases. The United States record for blood safety is well established, with extremely low rates of disease transmission, making the platelet units used for hPL manufacture low risk. The Covid-19 pandemic has increased awareness of emerging infectious diseases, even though transmission of Covid-19 via blood transfusion has not been documented. For that reason, we developed gamma irradiated version of our products, which offer an additional safety measure in the clinic. Previously, we have shown that the use of our platelet lysates has the potential of significantly impacting T cell manufacture by improving the quality and potency of the end product. In this study, we compare the phenotypic profile of different subsets of peripheral blood lymphocytes cultured using our different hPL products versus serum derived products. Additionally we establish a protocol for large scale suspension culture, which could be used for expansion of allogeneic CAR cells. [ABSTRACT FROM AUTHOR]

Background: Pivotal trials of chimeric antigen receptor T-cell (CAR-T) have identified common toxicities but may have been underpowered to detect cardiovascular and pulmonary adverse events (CPAEs).Objectives: This study sought to investigate CPAEs associated with commercial CD19-directed CAR-T therapy.Methods: In this retrospective, pharmacovigilance study, the authors used the Food and Drug Administration adverse event reporting system to identify CPAEs associated with axicabtagene-ciloleucel and tisagenlecleucel. The authors evaluated disproportionate reporting by the reporting odds ratio (ROR) and the lower bound of the information component 95% credibility interval (IC025 >0 is deemed significant). Significant associations were further adjusted to age and sex (adj.ROR).Results: The authors identified CAR-T reports of 2,657 patients, including 546 CPAEs (20.5%). CPAEs overlapped with cytokine release syndrome in 68.3% (373 of 546) of the reports. Compared with the full database, CAR-T was associated with overreporting of tachyarrhythmias (n = 74 [2.8%], adj.ROR = 2.78 [95% CI: 2.21-3.51]), cardiomyopathy (n = 69 [2.6%], adj.ROR = 3.51 [2.42-5.09]), pleural disorders (n = 46 [1.7%], adj.ROR = 3.91 [2.92-5.23]), and pericardial diseases (n = 11 [0.4%], adj.ROR = 2.26 [1.25-4.09], all IC025 >0). Venous thromboembolic events (VTEs) were associated only with axicabtagene-ciloleucel therapy (n = 28 [1.6%], adj.ROR = 1.80 [1.24-2.62], IC025 >0). Atrial fibrillation (n = 55) was the leading tachyarrhythmia, followed by ventricular arrhythmias (n = 14). Tachyarrhythmias and VTEs were reported more often following axicabtagene-ciloleucel than tisagenlecleucel in an age- and sex-adjusted model (adj.ROR = 1.82 [1.04-3.18] and adj.ROR = 2.86 [1.18-6.93], respectively). Finally, the fatality rate of CPAEs was 30.9%.Conclusions: In this largest post-marketing study to date, the authors identified an association between CAR-T and various CPAEs, including tachyarrhythmias, cardiomyopathy, pericardial and pleural disorders, and VTEs. These findings should be considered in the multidisciplinary assessment for and monitoring of CAR-T therapy recipients. [ABSTRACT FROM AUTHOR]

Highlights • Cytokine release syndrome (CRS) and neurotoxicity are common after immune effector cell (IEC) therapy. • Neurotoxicity is now termed IEC-associated neurotoxicity syndrome (ICANS). • A consensus grading system for CRS and ICANS has been developed by experts in the field. • The grading system is designed for IEC therapies in clinical trials and commercial use. • Standardized reporting through the Center for International Blood and Marrow Transplant Research will meet commercial Risk Evaluation and Mitigation Strategies requirements. ABSTRACT Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting. [ABSTRACT FROM AUTHOR]

Abstract Cell and gene therapies have demonstrated excellent clinical results across a range of indications with chimeric antigen receptor (CAR)–T cell therapies among the first to reach market. Although these therapies are currently manufactured using patient-derived cells, therapies using healthy donor cells are in development, potentially offering avenues toward process improvement and patient access. An allogeneic model could significantly reduce aggregate cost of goods (COGs), potentially improving market penetration of these life-saving treatments. Furthermore, the shift toward offshore production may help reduce manufacturing costs. In this article, we examine production costs of an allogeneic CAR-T cell process and the potential differential manufacturing costs between regions. Two offshore locations are compared with regions within the United States. The critical findings of this article identify the COGs challenges facing manufacturing of allogeneic CAR-T immunotherapies, how these may evolve as production is sent offshore and the wider implication this trend could have. [ABSTRACT FROM AUTHOR]

• BCMA-targeted myeloma therapies include CAR-T cells and antibody-based constructs. • Neurotoxicity from BCMA-targeted therapies is generally considered to be off-target. • Unusual peripheral or Parkinsonian neurotoxicities have recently been characterized. • Given BCMA expression on neurons, on-target neurotoxicity may be possible. • Trials of BCMA-targeted therapies should monitor and document such toxicities. B-cell maturation antigen (BCMA) has become a key target for antibody-drug conjugates, bispecific antibodies, chimeric antigen receptor T-cell therapies, and other immunotherapies in multiple myeloma. Some of these agents such as belantamab mafodotin and idecabtagene vicleucel have already received regulatory approval in the United States. Although BCMA has generally been considered to be expressed almost exclusively in plasma cells with a low likelihood of on-target off-tumor toxicity, there has been a range of unusual neurotoxicity observed across the spectrum of BCMA immunotherapies. In certain cases, these unusual neurotoxicity presentations have led to patient death or withdrawal of agents from further development. Our review summarizes the literature in this field and highlights the possibility of on-target toxicities due to neural expression of BCMA. We draw attention to the need for further investigation of these toxicities. This risk becomes increasingly important as BCMA targeted therapies are brought to earlier lines of treatment. [ABSTRACT FROM AUTHOR]