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Frontiers in Immunology 2021Chimeric antigen receptor (CAR) T-cell immunotherapy refers to an adoptive immunotherapy that has rapidly developed in recent years. It is a novel type of treatment that... (Review)
Review
Chimeric antigen receptor (CAR) T-cell immunotherapy refers to an adoptive immunotherapy that has rapidly developed in recent years. It is a novel type of treatment that enables T cells to express specific CARs on their surface, then returns these T cells to tumor patients to kill the corresponding tumor cells. Significant strides in CAR-T cell immunotherapy against hematologic malignancies have elicited research interest among scholars in the treatment of solid tumors. Nonetheless, in contrast with the efficacy of CAR-T cell immunotherapy in the treatment of hematologic malignancies, its general efficacy against solid tumors is insignificant. This has been attributed to the complex biological characteristics of solid tumors. CAR-T cells play a better role in solid tumors, for instance by addressing obstacles including the lack of specific targets, inhibition of tumor microenvironment (TME), homing barriers of CAR-T cells, differentiation and depletion of CAR-T cells, inhibition of immune checkpoints, trogocytosis of CAR-T cells, tumor antigen heterogeneity, etc. This paper reviews the obstacles influencing the efficacy of CAR-T cell immunotherapy in solid tumors, their mechanism, and coping strategies, as well as economic restriction of CAR-T cell immunotherapy and its solutions. It aims to provide some references for researchers to better overcome the obstacles that affect the efficacy of CAR-T cells in solid tumors.
Topics: Animals; Cost-Benefit Analysis; Cytotoxicity, Immunologic; Health Care Costs; Health Services Accessibility; Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Chimeric Antigen; T-Lymphocytes; Treatment Outcome; Tumor Microenvironment
PubMed: 34093592
DOI: 10.3389/fimmu.2021.687822 -
Current Oncology Reports Aug 2018This review will discuss the challenges facing adoptive cell techniques in the treatment of solid tumors and examine the therapies that are in development for... (Review)
Review
PURPOSE OF REVIEW
This review will discuss the challenges facing adoptive cell techniques in the treatment of solid tumors and examine the therapies that are in development for specifically pediatric solid tumors.
RECENT FINDINGS
Targeting solid tumors with adoptive cell therapy has been limited by the inhibitory tumor microenvironment and heterogeneous expression of targetable antigens. Many creative strategies to overcome these limitations are being developed but still need to be tested clinically. Early phase clinical trials in neuroblastoma with GD2 CAR T cells are promising but results need to be validated on a larger scale. Most research in other pediatric solid tumors is still in early stages. Adoptive cell therapy represents a useful tool to improve the outcomes of many pediatric solid tumors but significant study is still required. Several clinical trials are ongoing to test therapies that have shown promise in the lab.
Topics: Cell- and Tissue-Based Therapy; Child; Humans; Immunotherapy, Adoptive; Neoplasms
PubMed: 30069644
DOI: 10.1007/s11912-018-0715-9 -
Molecular Therapy : the Journal of the... Sep 2023Lymphodepleting pre-conditioning is a nearly universal component of T cell adoptive transfer protocols. The side effects of pre-conditioning regimens used in adoptive...
Lymphodepleting pre-conditioning is a nearly universal component of T cell adoptive transfer protocols. The side effects of pre-conditioning regimens used in adoptive cell therapy are clinically significant and include pan-cytopenia, immune suppression, and reactive myelopoiesis. We conducted studies to test the hypothesis that the mechanisms underlying effective engraftment are cell autonomous and not dependent on a lymphodepleted host immune status. These studies leveraged mouse models to examine the role of Stat5 signaling during T cell adoptive transfer. We observed that, by transiently expressing a constitutively active mutamer of Stat5b during the process of adoptive transfer, we could completely obviate the need for lymphodepletion prior to adoptive transfer. Using several functional assays, we benchmark the function of the engrafted T cells against T cells transferred after conventional lymphodepletion. These studies identify a cell-autonomous mechanism driven by transient Stat5b signaling with lasting effects on T cell phenotype and function. Furthermore, the results presented suggest that adoptive T cell therapy could be improved by removing lymphodepletion protocols entirely and replacing them with RNA transfection of T cells with transcripts encoding active Stat5.
Topics: Mice; Animals; T-Lymphocytes; Adoptive Transfer; Signal Transduction; Immunotherapy, Adoptive
PubMed: 37481703
DOI: 10.1016/j.ymthe.2023.07.015 -
Frontiers in Immunology 2022Chimeric antigen receptor (CAR) T-cell therapy has emerged recently as a standard of care treatment for patients with relapsed or refractory acute lymphoblastic leukemia...
Chimeric antigen receptor (CAR) T-cell therapy has emerged recently as a standard of care treatment for patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and several subtypes of B-cell non-Hodgkin lymphoma (NHL). However, its use remains limited to highly specialized centers, given the complexity of its administration and its associated toxicities. We previously reported our experience in using a novel Sleeping Beauty (SB) CD19-specific CAR T-cell therapy in the peri-transplant setting, where it exhibited an excellent safety profile with encouraging survival outcomes. We have since modified the SB CD19 CAR construct to improve its efficacy and shorten its manufacturing time. We report here the phase 1 clinical trial safety results. Fourteen heavily treated patients with relapsed/refractory ALL and NHL were infused. Overall, no serious adverse events were directly attributed to the study treatment. Three patients developed grades 1-2 cytokine release syndrome and none of the study patients experienced neurotoxicity. All dose levels were well tolerated and no dose-limiting toxicities were reported. For efficacy, 3 of 8 (38%) patients with ALL achieved CR/CRi (complete remission with incomplete count recovery) and 1 (13%) patient had sustained molecular disease positivity. Of the 4 patients with DLBCL, 2 (50%) achieved CR. The SB-based CAR constructs allow manufacturing of targeted CAR T-cell therapies that are safe, cost-effective and with encouraging antitumor activity.
Topics: Humans; Adaptor Proteins, Signal Transducing; Antigens, CD19; B-Lymphocytes; Hematologic Neoplasms; Immunotherapy, Adoptive; Neoplasms; Receptors, Antigen, T-Cell
PubMed: 36439104
DOI: 10.3389/fimmu.2022.1032397 -
Blood Advances Nov 2023CD19 chimeric antigen receptor (CAR) T cells can induce prolonged remissions and potentially cure a significant proportion of patients with relapsed/refractory large...
CD19 chimeric antigen receptor (CAR) T cells can induce prolonged remissions and potentially cure a significant proportion of patients with relapsed/refractory large B-cell lymphomas. However, some patients may die of causes unrelated to lymphoma after CAR T-cell therapy. To date, little is known about the nonrelapse mortality (NRM) after CAR T-cell therapy. Using the French DESCAR-T registry, we analyzed the incidence and causes of NRM and identified risk factors of NRM. We report on 957 patients who received standard-of-care axicabtagene ciloleucel (n = 598) or tisagenlecleucel (n = 359) between July 2018 and April 2022, in 27 French centers. With a median follow-up of 12.4 months, overall NRM occurred in 48 patients (5.0% of all patients): early (before day 28 after infusion) in 9 patients (0.9% of all patients and 19% of overall NRM), and late (on/after day 28 after infusion) in 39 patients (4.1% of all patients and 81% of overall NRM). Causes of overall NRM were distributed as follows: 56% infections (29% with non-COVID-19 and 27% with COVID-19), 10% cytokine release syndromes, 6% stroke, 6% cerebral hemorrhage, 6% second malignancies, 4% immune effector cell associated neurotoxicities, and 10% deaths from other causes. We report risk factors of early NRM and overall NRM. In multivariate analysis, both diabetes and elevated ferritin level at lymphodepletion were associated with an increased risk of overall NRM. Our results may help physicians in patient selection and management in order to reduce the NRM after CAR T-cell therapy.
Topics: Humans; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Risk Factors; Antigens, CD19
PubMed: 37672383
DOI: 10.1182/bloodadvances.2023010624 -
Pharmacology 2022Adoptive therapy with genetically modified T cells achieves spectacular remissions in advanced hematologic malignancies. In contrast to conventional drugs, this kind of... (Review)
Review
BACKGROUND
Adoptive therapy with genetically modified T cells achieves spectacular remissions in advanced hematologic malignancies. In contrast to conventional drugs, this kind of therapy applies viable autologous T cells that are ex vivo genetically engineered with a chimeric antigen receptor (CAR) and are classified as advanced therapy medicinal products.
SUMMARY
As "living drugs," CAR T cells differ from classical pharmaceutical drugs as they provide a panel of cellular capacities upon CAR signaling, including the release of effector molecules and cytokines, redirected cytotoxicity, CAR T cell amplification, active migration, and long-term persistence and immunological memory. Here, we discuss pharmaceutical aspects, the regulatory requirements for CAR T cell manufacturing, and how CAR T cell pharmacokinetics are connected with the clinical outcome.
KEY MESSAGES
From the pharmacological perspective, the development of CAR T cells with high translational potential needs to address pharmacodynamic markers to balance safety and efficacy of CAR T cells and to address pharmacokinetics with respect to trafficking, homing, infiltration, and persistence of CAR T cells.
Topics: Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 35696994
DOI: 10.1159/000525052 -
Clinical Pharmacology and Therapeutics Nov 2022Adoptive cell therapies (ACTs) have shown transformative efficacy in oncology with five US Food and Drug Administration (FDA) approvals for chimeric antigen receptor... (Review)
Review
Adoptive cell therapies (ACTs) have shown transformative efficacy in oncology with five US Food and Drug Administration (FDA) approvals for chimeric antigen receptor (CAR) T-cell therapies in hematological malignancies, and promising activity for T cell receptor T-cell therapies in both liquid and solid tumors. Clinical pharmacology can play a pivotal role in optimizing ACTs, aided by modeling and simulation toolboxes and deep understanding of the underlying biological and immunological processes. Close collaboration and multilevel data integration across functions, including chemistry, manufacturing, and control, biomarkers, bioanalytical, and clinical science and safety teams will be critical to ACT development. As ACT is comprised of alive, polyfunctional, and heterogeneous immune cells, its overall physicochemical and pharmacological property is vastly different from other platforms/modalities, such as small molecule and protein therapeutics. In this review, we first describe the unique kinetics of T cells and the appropriate bioanalytical strategies to characterize cellular kinetics. We then assess the distinct aspects of clinical pharmacology for ACTs in comparison to traditional small molecule and protein therapeutics. Additionally, we provide a review for the five FDA-approved CAR T-cell therapies and summarize their properties, cellular kinetic characteristics, dose-exposure-response relationship, and potential baseline factors/variables in product, patient, and regimen that may affect the safety and efficacy. Finally, we probe into existing empirical and mechanistic quantitative techniques to understand how various modeling and simulation approaches can support clinical pharmacology strategy and propose key considerations to be incorporated and explored in future models.
Topics: Humans; Receptors, Chimeric Antigen; Pharmacology, Clinical; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; T-Lymphocytes; Neoplasms
PubMed: 34888856
DOI: 10.1002/cpt.2509 -
Cancer Journal (Sudbury, Mass.) 2019Refractory and relapsed acute myeloid leukemia (AML) and T-lineage leukemia have poor prognosis and limited therapeutic options. Adoptive cellular immunotherapies are... (Review)
Review
Refractory and relapsed acute myeloid leukemia (AML) and T-lineage leukemia have poor prognosis and limited therapeutic options. Adoptive cellular immunotherapies are emerging as an effective treatment for patients with chemotherapy refractory hematological malignancies. Indeed, the use of unselected donor lymphocyte infusions has demonstrated successes in treating patients with AML and T-lineage leukemia post-allogeneic transplantation. The development of ex vivo manipulation techniques such as genetic modification or selection and expansion of individual cellular components has permitted the clinical translation of a wide range of promising cellular therapies for AML and T-cell acute lymphoblastic leukemia. Here, we will review clinical studies to date using adoptive cell therapy approaches and outline the major challenges limiting the development of safe and effective cell therapies for both types of acute leukemia.
Topics: Combined Modality Therapy; Humans; Immunotherapy, Adoptive; Leukemia, Myeloid, Acute; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome
PubMed: 31135527
DOI: 10.1097/PPO.0000000000000376 -
Genes and Immunity Jan 2020
Topics: Colorectal Neoplasms; Humans; Immunotherapy, Adoptive; Organoids
PubMed: 31105265
DOI: 10.1038/s41435-019-0079-7 -
Journal of Hematology & Oncology Sep 2018Genetically modified T cells that express a chimeric antigen receptor (CAR) are opening a new frontier in cancer immunotherapy. CAR T cells currently are in clinical... (Review)
Review
Genetically modified T cells that express a chimeric antigen receptor (CAR) are opening a new frontier in cancer immunotherapy. CAR T cells currently are in clinical trials for many cancer types. Cytokine release syndrome (CRS) and neurotoxicities (CAR-related encephalopathy syndrome, CRES) are major adverse events limiting wide deployment of the CAR T cell treatment. Major efforts are ongoing to characterize the pathogenesis and etiology of CRS and CRES. Mouse models have been established to facilitate the study of pathogenesis of the major toxicities of CAR T cells. Myeloid cells including macrophages and monocytes, not the CAR T cells, were found to be the major cells mediating CRS and CRES by releasing IL-1 and IL-6 among other cytokines. Blocking IL-1 or depletion of monocytes abolished both CRS and CRES, whereas IL-6 blocker can ameliorate CRS but not CRES. Therefore, both IL-1 and IL-6 are major cytokines for CRS, though IL-1 is responsible for CRES. It was also demonstrated in the mouse models that blocking CRS does not interfere with the CAR T cell antitumor functions. We summarized new developments in the grading, modeling, and possible new therapeutic approaches for CRS and CRES in this review.
Topics: Animals; Cytokines; Humans; Immune System Diseases; Immunotherapy, Adoptive; Neoplasm Grading; Neoplasms; Syndrome
PubMed: 30249264
DOI: 10.1186/s13045-018-0653-x