Adoptive T cell therapy: Addressing challenges in cancer immunotherapy.
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ABSTRACT:
SUBMITTER: Yee C
PROVIDER: S-EPMC1131930 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cancer immunotherapy has gained attention as the supreme therapeutic modality for the treatment of various malignancies. Adoptive T-cell therapy (ACT) is one of the most distinctive modalities of this therapeutic approach, which seeks to harness the potential of combating cancer cells by using autologous or allogenic tumor-specific T-cells. However, a plethora of circumstances must be optimized to produce functional, durable, and efficient T-cells. Recently, the potential of ACT has been further realized by the introduction of novel gene-editing platforms such as the CRISPR/Cas9 system; this technique has been utilized to create T-cells furnished with recombinant T-cell receptor (TCR) or chimeric antigen receptor (CAR) that have precise tumor antigen recognition, minimal side effects and treatment-related toxicities, robust proliferation and cytotoxicity, and nominal exhaustion. Here, we aim to review and categorize the recent breakthroughs of genetically modified TCR/CAR T-cells through CRISPR/Cas9 technology and address the pearls and pitfalls of each method. In addition, we investigate the latest ongoing clinical trials that are applying CRISPR-associated TCR/CAR T-cells for the treatment of cancers.
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Project description:Immunotherapy is an emerging method for the treatment of cervical cancer and is more effective than surgery and radiotherapy, especially for recurrent cervical cancer. However, immunotherapy is limited by adverse effects in clinical practice. In recent years, nanotechnology has been widely used for tumor diagnosis, drug delivery, and targeted therapy. In the setting of cervical cancer, nanotechnology can be used to actively or passively target immunotherapeutic agents to tumor sites, thereby enhancing local drug delivery, reducing drug adverse effects, achieving immunomodulation, improving the tumor immune microenvironment, and optimizing treatment efficacy. In this review, we highlight the current status of therapeutic vaccines and adoptive cell therapy in cervical cancer immunotherapy, as well as the application of lipid carriers, polymeric nanoparticles, inorganic nanoparticles, and exosomes in this context.
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Project description:Adoptive cell therapies (ACTs) have existed for decades. From the initial infusion of tumor-infiltrating lymphocytes to the subsequent specific enhanced T cell receptor (TCR)-T and chimeric antigen receptor (CAR)-T cell therapies, many novel strategies for cancer treatment have been developed. Owing to its promising outcomes, CAR-T cell therapy has revolutionized the field of ACTs, particularly for hematologic malignancies. Despite these advances, CAR-T cell therapy still has limitations in both autologous and allogeneic settings, including practicality and toxicity issues. To overcome these challenges, researchers have focused on the application of CAR engineering technology to other types of immune cell engineering. Consequently, several new cell therapies based on CAR technology have been developed, including CAR-NK, CAR-macrophage, CAR-γδT, and CAR-NKT. In this review, we describe the development, advantages, and possible challenges of the aforementioned ACTs and discuss current strategies aimed at maximizing the therapeutic potential of ACTs. We also provide an overview of the various gene transduction strategies employed in immunotherapy given their importance in immune cell engineering. Furthermore, we discuss the possibility that strategies capable of creating a positive feedback immune circuit, as healthy immune systems do, could address the flaw of a single type of ACT, and thus serve as key players in future cancer immunotherapy.
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Project description:We previously described adoptive immunotherapy (AIT) with cytotoxic T lymphocytes (CTLs) stimulated by the mucin 1 (MUC1)-expressing human pancreatic cancer cell line YPK-1 (MUC1-CTLs) and demonstrated that MUC1-CTLs might prevent liver metastasis. In the present study, we combined gemcitabine (GEM) and AIT for the treatment of pancreatic cancer.A total of 43 patients who underwent radical pancreatectomy received treatment with MUC1-CTLs and GEM. After surgery, MUC1-CTLs were induced and administered intravenously 3 times, and GEM administered according to the standard regimen for 6 months. The patients whose relative dose intensity of GEM was 50% or more and who received 2 or more MUC1-CTL treatments were used as the adequate treatment group (n = 21).In the adequate treatment group, disease-free survival was 15.8 months, and overall survival was 24.7 months. Liver metastasis was found only in 7 patients (33%), and local recurrence occurred in 4 patients (19%). The independent prognostic factor of long-term disease-free survival on multivariate analysis was the average number of CTLs administered (P = 0.0133).The combination therapy with AIT and GEM prevented liver metastasis and local recurrence. Moreover, the disease free-survival was improved in patients who received sufficient CTLs.
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Project description:Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with very poor prognosis and few advances in its treatment. Recently, fast-growing cancer immunotherapy provides a glimmer of hope for GBM treatment. Adoptive cell therapy (ACT) aims at infusing immune cells with direct anti-tumor activity, including tumor-infiltrating lymphocyte (TIL) transfer and genetically engineered T cells transfer. For example, complete regressions in patients with melanoma and refractory lymphoma have been shown by using naturally tumor-reactive T cells and genetically engineered T cells expressing the chimeric anti-CD19 receptor, respectively. Recently, the administration of ACT showed therapeutic potentials for GBM treatment as well. In this review, we summarize the success of ACT in the treatment of cancer and provide approaches to overcome some challenges of ACT to allow its adoption for GBM treatment.
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Project description:PURPOSE OF REVIEW:In the rapidly developing field of adoptive cell immunotherapy, there is urgent need for discoveries that would improve outcomes, extend the applicability, and reduce the costs. Induced pluripotent stem cells (iPSC) can be a source of broadly applicable cellular immunotherapeutics, which have been manufactured, validated, and banked in advance, and can be applied across HLA barriers. Here, we discuss the recent advances and challenges in the generation of iPSC-derived cellular products for cancer therapy. RECENT FINDINGS:iPSCs can be differentiated to functional tumor-specific T and NK cells in vitro with demonstrable in vitro and in vivo anti-tumor activity. Genetic modifications employed at the iPSC level can deliver desirable immunotherapeutic attributes to the generated immune effectors. iPSC-NK cells are currently evaluated in a clinical setting and pre-clinical testing of iPSC-T cells shows promising results but their production seems more challenging. The use of iPSCs for the generation of tumor-targeting T/NK cells constitutes a feasible strategy to overcome limitations in manufacturing, efficacy, and applicability of cellular therapeutics.
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Project description:With the establishment of the immune surveillance mechanism since the 1950s, attempts have been made to activate the immune system for cancer treatment through the discovery of various cytokines or the development of antibodies up to now. The fruits of these efforts have contributed to the recognition of the 3rd generation of anticancer immunotherapy as the mainstream of cancer treatment. However, the limitations of cancer immunotherapy are also being recognized through the conceptual establishment of cold tumors recently, and colorectal cancer (CRC) has become a major issue from this therapeutic point of view. Here, it is emphasized that non-clinical strategies to overcome the immunosuppressive environment and clinical trials based on these basic investigations are being made on the journey to achieve better treatment outcomes for the treatment of cold CRC.
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Project description:Adoptive cell therapy (ACT) is a rapidly growing anti-cancer strategy that has shown promise in treating various cancer types. The concept of ACT involves activating patients' own immune cells ex vivo and then transferring them back to the patients to recognize and eliminate cancer cells. Currently, the commonly used ACT includes tumor-infiltrating lymphocytes (TILs), genetically engineered immune cells, and dendritic cells (DCs) vaccines. With the advancement of cell culture and genetic engineering techniques, ACT has been used in clinics to treat malignant hematological diseases and many new ACT-based regimens are in different stages of clinical trials. Here, representative ACT approaches are introduced and the opportunities and challenges for clinical translation of ACT are discussed.
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Project description:AimThe aim of this study was to systemically evaluate the therapeutic efficacy of cytokine-induced killer (CIK) cells for the treatment of non-small cell lung cancer.Materials and methodsA computerized search of randomized controlled trials for CIK cell-based therapy was performed. The overall survival, clinical response rate, immunological assessment and side effects were evaluated.ResultsOverall, 17 randomized controlled trials of non-small cell lung cancer (NSCLC) with a total of 1172 patients were included in the present analysis. Our study showed that the CIK cell therapy significantly improved the objective response rate and overall survival compared to the non-CIK cell-treated group. After CIK combined therapy, we observed substantially increased percentages of CD3+, CD4+, CD4+CD8+, CD3+CD56+ and NK cells, whereas significant decreases were noted in the percentage of CD8+ and regulatory T cell (Treg) subgroups. A significant increase in Ag-NORs was observed in the CIK-treated patient group (p = 0.00001), whereas carcinoembryonic antigen (CEA) was more likely to be reduced to a normal level after CIK treatment (p = 0.0008). Of the possible major side effects, only the incidence of fever in the CIK group was significantly higher compared to the group that received chemotherapy alone.ConclusionThe CIK cell combined therapy demonstrated significant superiority in the overall survival, clinical response rate, and T lymphocytes responses and did not present any evidence of major adverse events in patients with NSCLC.
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