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Synthetic immunity to cancer has been pioneered by the application of chimeric antigen receptor (CAR) engineering into autologous T cells. CAR T cell therapy is highly amenable to molecular engineering to bypass barriers of the cancer immunity cycle, such as endogenous antigen presentation, immune priming, and natural checkpoints that constrain immune responses. Here, we review CAR T cell design and the mechanisms that drive sustained CAR T cell effector activity and anti-tumor function. We discuss engineering approaches aimed at improving anti-tumor function through a variety of mechanistic interventions for both hematologic and solid tumors. The ability to engineer T cells in such a variety of ways, including by modifying their trafficking, antigen recognition, costimulation, and addition of synthetic genes, circuits, knockouts and base edits to finely tune complex functions, is arguably the most powerful way to manipulate the cancer immunity cycle in patients. Chimeric antigen receptor (CAR) T cells have demonstrated impressive success in the treatment of some cancers. Singh and Maus review the fundamentals of function of these receptors; recent advances in gene, genome and protein editing that have propelled advanced engineering of CAR T cells; and look toward the next decade of progress in synthetic immunity. [ABSTRACT FROM AUTHOR]

While chimeric antigen receptor (CAR) T cells targeting CD19 can cure a subset of patients with B cell malignancies, most patients treated will not achieve durable remission. Identification of the mechanisms leading to failure is essential to broadening the efficacy of this promising platform. Several studies have demonstrated that disruption of CD19 genes and transcripts can lead to disease relapse after initial response; however, few other tumor-intrinsic drivers of CAR T cell failure have been reported. Here we identify expression of the Golgi-resident intramembrane protease Signal peptide peptidase-like 3 (SPPL3) in malignant B cells as a potent regulator of resistance to CAR therapy. Loss of SPPL3 results in hyperglycosylation of CD19, an alteration that directly inhibits CAR T cell effector function and suppresses anti-tumor cytotoxicity. Alternatively, over-expression of SPPL3 drives loss of CD19 protein, also enabling resistance. In this pre-clinical model these findings identify post-translational modification of CD19 as a mechanism of antigen escape from CAR T cell therapy. Loss of surface CD19 expression by leukemic cells leads to resistance and relapse to CD19-targeted CAR-T therapies. Here the authors show that loss of SPPL3 in malignant B cells results in hyperglycosylation of CD19. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-engineered T cells have demonstrated remarkable success in the treatment of B cell malignancies. FDA approval of these therapies represents a watershed moment in the development of therapies for cancer. Despite the successes of the last decade, many patients will unfortunately not experience durable responses to CAR therapy. Emerging research has shed light on the biology responsible for these failures, and further highlighted the hurdles to broader success. Here, we review the recent research identifying how interactions between cancer cells and engineered immune cells result in resistance to CAR therapies. [ABSTRACT FROM AUTHOR]

Background aims. Chimeric antigen receptor (CAR) T-cell therapy targeting CD 19 has demonstrated remarkable success in targeting B-cell malignancies but is often complicated by serious systemic toxicity in the form of cytokine release syndrome (CRS). CRS symptoms are primarily mediated by interleukin 6 (IL-6), and clinical management has focused on inhibition of IL-6 signaling. The cellular source and function of IL-6 in CRS remain unknown. Methods. Using co-culture assays and data from patients on our clinical CAR T-cell trials, we investigated the cellular source of IL-6, as well as other CRS-associated cytokines, during CAR T-cell activation. We also explored the effect that IL-6 has on T-cell function. Results. We demonstrated that IL-6 is secreted by monocyte-lineage cells in response to CAR T-cell activation in a contactindependent mechanism upon T-cell engagement of target leukemia. We observed that the presence of antigen-presenting cell-derived IL-6 has no impact on CAR T-cell transcriptional profiles or cytotoxicity. Finally, we confirm that CART cells do not secrete IL-6 in vivo during clinical CRS. Discussion. These findings suggest that IL-6 blockade will not affect CD 19 CAR T-cell-driven anti-leukemic cytotoxicity, permitting enhanced control of CRS while maintaining CAR T-cell efficacy. [ABSTRACT FROM AUTHOR]

Opinion Statement: Adoptive transfer of autologous T cells engineered to express a chimeric antigen receptor (CAR) represents a powerful targeted immunotherapy that has shown great promise in some of the most refractory leukemias. CAR-modified T cells directed against CD19 have led the way, setting a high standard with remission rates as high as 90 % in clinical trials for relapsed/refractory acute lymphoblastic leukemia (ALL). Yet, the first demonstration of efficacy was in another disease, chronic lymphocytic leukemia (CLL), in which CD19-targeted CAR T cells eradicated bulky, highly refractory disease. Despite early encouraging results, clinical trials in CLL have yielded lower response rates, revealing disease-specific differences in response in this form of immunotherapy. Ongoing research focused on identifying and overcoming these limitations, promises to improve response rates. Beyond the induction of remission, the transformative impact of engineered T cell therapy lies in its potential for long-term disease control. With longer follow-up and durable T cell persistence now reported, we are closer to answering the question of whether sustained remissions are possible with CAR T cell monotherapy. As might be expected with a highly effective therapy using a single mechanism of action, escape pathways have emerged. Combinatorial approaches are needed to anticipate and prevent this mode of relapse. Lastly, toxicity management is vital to ensure the safety of this exciting cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The article presents a study that determines the role of T cell expansion potential and memory phenotype during chemotherapy in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). It offers details of the study, which also demonstrates that patients with T cell population for early lineage cells has expanded better in vitro. It also explains the result which indicates that early lineage cells are essential to T cell fitness for expansion and enrichment.

The article discusses the use of engineered T cells in the treatment of cancer and a study by Ma et al. which discusses a vaccine-boosting strategy to improve the efficacy of Chimeric antigen receptor (CAR)-T cells to target solid tumors.

The cancer-testis antigen NY-ESO-1 is expressed by many solid tumors and has limited expression by mature somatic tissues, making it a highly attractive target for tumor immunotherapy. Targeting NY-ESO-1 using engineered T cells has demonstrated clinical efficacy in the treatment of some adult tumors. Neuroblastoma is a significant cause of cancer mortality in children, and is a tumor type shown to be responsive to immunotherapies. We evaluated a large panel of primarily resected neuroblastoma samples and demonstrated that 23% express NY-ESO-1. After confirming antigen-specific activity of T cells genetically engineered to express an NY-ESO-1 directed high-affinity transgenic T cell receptorin vitro, we performed xenograft mouse studies assessing the efficacy of NY-ESO-1-targeted T cells in both localized and disseminated models of neuroblastoma. Disease responses were monitored by tumor volume measurement andin vivobioluminescence. After delivery of NY-ESO-1 transgenic TCR T cells, we observed significant delay of tumor progression in mice bearing localized and disseminated neuroblastoma, as well as enhanced animal survival. These data demonstrate that NY-ESO-1 is an antigen target in neuroblastoma and that targeted T cells represent a potential therapeutic option for patients with neuroblastoma. [ABSTRACT FROM PUBLISHER]