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The Lancet. Oncology Aug 2023
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; Point-of-Care Systems; T-Lymphocytes; Immunotherapy, Adoptive
PubMed: 37414061
DOI: 10.1016/S1470-2045(23)00269-3 -
Current Hematologic Malignancy Reports Dec 2023The current review focuses on the preclinical development and clinical advances of natural killer (NK) cell therapeutics for hematologic malignancies and offers... (Review)
Review
PURPOSE OF REVIEW
The current review focuses on the preclinical development and clinical advances of natural killer (NK) cell therapeutics for hematologic malignancies and offers perspective on the unmet challenges that will direct future discovery in the field.
RECENT FINDINGS
Approaches to improve or re-direct NK cell anti-tumor functions against hematologic malignancies have included transgenic expression of chimeric antigen receptors (CARs), administration of NK cell engagers including BiKEs and TriKEs that enhance antibody-dependent cellular cytotoxicity (ADCC) by co-engaging NK cell CD16 and antigens on tumors, incorporation of a non-cleavable CD16 that results in enhanced ADCC, use of induced memory-like NK cells alone or in combination with CARs, and blockade of NK immune checkpoints to enhance NK cytotoxicity. Recently reported and ongoing clinical trials support the feasibility and safety of these approaches. NK cell-based therapeutic strategies hold great promise as cost-effective, off-the-shelf cell therapies for patients with relapsed and refractory hematologic diseases.
Topics: Humans; Immunotherapy, Adoptive; Killer Cells, Natural; Neoplasms; Receptors, Chimeric Antigen; Hematologic Neoplasms
PubMed: 37751103
DOI: 10.1007/s11899-023-00711-w -
Immunology and Cell Biology Sep 2023Breast cancer (BC) is the most common cause of cancer death in women. According to the American Cancer Society's yearly cancer statistics, BC constituted almost 15% of... (Review)
Review
Breast cancer (BC) is the most common cause of cancer death in women. According to the American Cancer Society's yearly cancer statistics, BC constituted almost 15% of all the newly diagnosed cancer cases in 2022 for both sexes. Metastatic disease occurs in 30% of patients with BC. The currently available treatments fail to cure metastatic BC, and the average survival time for patients with metastatic BC is approximately 2 years. Developing a treatment method that terminates cancer stem cells without harming healthy cells is the primary objective of novel therapeutics. Adoptive cell therapy is a branch of cancer immunotherapy that utilizes the immune cells to attack cancer cells. Natural killer (NK) cells are an essential component of innate immunity and are critical in destroying tumor cells without prior stimulation with antigens. With the advent of chimeric antigen receptors (CARs), the autologous or allogeneic use of NK/CAR-NK cell therapy has raised new hopes for treating patients with cancer. Here, we describe recent developments in NK and CAR-NK cell immunotherapy, including the biology and function of NK cells, clinical trials, different sources of NK cells and their future perspectives on BC.
Topics: Humans; Female; Immunotherapy, Adoptive; Breast Neoplasms; Killer Cells, Natural; Neoplasms; Receptors, Chimeric Antigen; Cell- and Tissue-Based Therapy
PubMed: 37282729
DOI: 10.1111/imcb.12658 -
Immunology Aug 2023Tumour immunotherapy has achieved good therapeutic effects in clinical practice and has received increased attention. Cytotoxic T cells undoubtedly play an important... (Review)
Review
Tumour immunotherapy has achieved good therapeutic effects in clinical practice and has received increased attention. Cytotoxic T cells undoubtedly play an important role in tumour immunotherapy. As a revolutionary tumour immunotherapy approach, chimeric antigen receptor T-cell (CAR-T-cell) therapy has made breakthroughs in the treatment of haematological cancers. However, T cells are easily exhausted in vivo, especially after they enter solid tumours. The exhaustion of T cells can lead to poor results of CAR-T-cell therapy in the treatment of solid tumours. Here, we review the reasons for T-cell exhaustion and how T-cell exhaustion develops. We also review and discuss ways to improve CAR-T-cell therapy effects by regulating T-cell exhaustion.
Topics: Humans; Receptors, Chimeric Antigen; T-Cell Exhaustion; Immunotherapy, Adoptive; Neoplasms; Cell- and Tissue-Based Therapy; Receptors, Antigen, T-Cell
PubMed: 36942414
DOI: 10.1111/imm.13642 -
Frontiers in Immunology 2023
Topics: Humans; Immunotherapy, Adoptive; Expert Testimony; Neoplasms; Receptors, Chimeric Antigen
PubMed: 37545532
DOI: 10.3389/fimmu.2023.1257016 -
European Journal of Cancer (Oxford,... Nov 2023Immunotherapy has ignited hope to cure paediatric solid tumours that resist traditional therapies. Among the most promising methods is adoptive cell therapy (ACT).... (Review)
Review
Immunotherapy has ignited hope to cure paediatric solid tumours that resist traditional therapies. Among the most promising methods is adoptive cell therapy (ACT). Particularly, ACT using T cells equipped with chimeric antigen receptors (CARs) has moved into the spotlight in clinical studies. However, the efficacy of ACT is challenged by ACT-intrinsic factors, like lack of activation or T cell exhaustion, as well as immune evasion strategies of paediatric solid tumours, such as their highly immunosuppressive microenvironment. Novel strategies, including ACT using innate-like lymphocytes, innovative cell engineering techniques, and ACT combination therapies, are being developed and will be crucial to overcome these challenges. Here, we discuss the main classes of ACT for the treatment of paediatric extracranial solid tumours, reflect on the available preclinical and clinical evidence supporting promising strategies, and address the challenges that ACT is still facing. Ultimately, we highlight state-of-the-art developments and opportunities for new therapeutic options, which hold great potential for improving outcomes in this challenging patient population.
Topics: Humans; Child; Immunotherapy, Adoptive; Neoplasms; T-Lymphocytes; Receptors, Chimeric Antigen; Immunotherapy; Tumor Microenvironment
PubMed: 37832507
DOI: 10.1016/j.ejca.2023.113347 -
Journal of Immunology (Baltimore, Md. :... Jul 2023Immunotherapy development for solid tumors remains challenging, partially due to a lack of reproducible, cost-effective in vitro three-dimensional (3D) models to mimic...
Immunotherapy development for solid tumors remains challenging, partially due to a lack of reproducible, cost-effective in vitro three-dimensional (3D) models to mimic the heterogeneous and complex tumor microenvironment. Here, we investigate the cellular anti-tumor reactivity of αβ T cells engineered to express a defined γδ TCR (TEG A3). For that purpose, we developed a 3D cytotoxicity assay targeting cell line-derived spheroids or patient-derived tumor organoids formed in serum-free media. Tumor cell lysis by TEG A3 was monitored using the Incucyte S3 live-cell imaging system with the apoptosis marker caspase 3/7 green and endpoint readouts of IFN-γ secretion in the supernatant. The 3D cytotoxicity assay model system was able to adequately demonstrate TEG A3 reactivity toward targets expressing an isoform of CD277 (CD277J). To obtain a more complex heterogeneous tumor microenvironment, patient-derived organoids were mixed with unmatched patient-derived fibroblasts or matched cancer-associated fibroblasts. In all assays, we demonstrated the tumor target specificity of TEG A3, lysing tumor cells within 48 h. Our study demonstrates the utility of complex 3D cytotoxicity assay model systems incorporating the tumor microenvironment in the functional evaluation of T cell-based adoptive immunotherapy, providing a useful platform for early-stage preclinical development of immunotherapies.
Topics: Humans; Neoplasms; T-Lymphocytes; Immunotherapy, Adoptive; Immunotherapy; Cell- and Tissue-Based Therapy; Tumor Microenvironment
PubMed: 37294309
DOI: 10.4049/jimmunol.2200573 -
Nature Medicine Aug 2023Despite advances, few therapeutics have shown efficacy in severe coronavirus disease 2019 (COVID-19). In a different context, virus-specific T cells have proven safe and... (Randomized Controlled Trial)
Randomized Controlled Trial
Despite advances, few therapeutics have shown efficacy in severe coronavirus disease 2019 (COVID-19). In a different context, virus-specific T cells have proven safe and effective. We conducted a randomized (2:1), open-label, phase 1/2 trial to evaluate the safety and efficacy of off-the-shelf, partially human leukocyte antigen (HLA)-matched, convalescent donor-derived severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells (CoV-2-STs) in combination with standard of care (SoC) in patients with severe COVID-19 compared to SoC during Delta variant predominance. After a dose-escalated phase 1 safety study, 90 participants were randomized to receive CoV-2-ST+SoC (n = 60) or SoC only (n = 30). The co-primary objectives of the study were the composite of time to recovery and 30-d recovery rate and the in vivo expansion of CoV-2-STs in patients receiving CoV-2-ST+SoC over SoC. The key secondary objective was survival on day 60. CoV-2-ST+SoC treatment was safe and well tolerated. The study met the primary composite endpoint (CoV-2-ST+SoC versus SoC: recovery rate 65% versus 38%, P = 0.017; median recovery time 11 d versus not reached, P = 0.052, respectively; rate ratio for recovery 1.71 (95% confidence interval 1.03-2.83, P = 0.036)) and the co-primary objective of significant CoV-2-ST expansion compared to SοC (CoV-2-ST+SoC versus SoC, P = 0.047). Overall, in hospitalized patients with severe COVID-19, adoptive immunotherapy with CoV-2-STs was feasible and safe. Larger trials are needed to strengthen the preliminary evidence of clinical benefit in severe COVID-19. EudraCT identifier: 2021-001022-22 .
Topics: Humans; COVID-19; SARS-CoV-2; Immunotherapy, Adoptive; Cell- and Tissue-Based Therapy; Treatment Outcome
PubMed: 37460756
DOI: 10.1038/s41591-023-02480-8 -
International Journal of Oncology Dec 2023Cancer is the primary and one of the most prominent causes of the rising global mortality rate, accounting for nearly 10 million deaths annually. Specific methods have... (Review)
Review
Cancer is the primary and one of the most prominent causes of the rising global mortality rate, accounting for nearly 10 million deaths annually. Specific methods have been devised to cure cancerous tumours. Effective therapeutic approaches must be developed, both at the cellular and genetic level. Immunotherapy offers promising results by providing sustained remission to patients with refractory malignancies. Genetically modified T‑lymphocytic cells have emerged as a novel therapeutic approach for the treatment of solid tumours, haematological malignancies, and relapsed/refractory B‑lymphocyte malignancies as a result of recent clinical trial findings; the treatment is referred to as chimeric antigen receptor T‑cell therapy (CAR T‑cell therapy). Leukapheresis is used to remove T‑lymphocytes from the leukocytes, and CARs are created through genetic engineering. Without the aid of a major histocompatibility complex, these genetically modified receptors lyse malignant tissues by interacting directly with the carcinogen. Additionally, the outcomes of preclinical and clinical studies reveal that CAR T‑cell therapy has proven to be a potential therapeutic contender against metastatic breast cancer (BCa), triple‑negative, and HER 2+ve BCa. Nevertheless, unique toxicities, including (cytokine release syndrome, on/off‑target tumour recognition, neurotoxicities, anaphylaxis, antigen escape in BCa, and the immunosuppressive tumour microenvironment in solid tumours, negatively impact the mechanism of action of these receptors. In this review, the potential of CAR T‑cell immunotherapy and its method of destroying tumour cells is explored using data from preclinical and clinical trials, as well as providing an update on the approaches used to reduce toxicities, which may improve or broaden the effectiveness of the therapies used in BCa.
Topics: Humans; Female; Breast Neoplasms; Immunotherapy, Adoptive; T-Lymphocytes; Immunotherapy; Hematologic Neoplasms; Receptors, Antigen, T-Cell; Tumor Microenvironment
PubMed: 37830150
DOI: 10.3892/ijo.2023.5578 -
Physiological Research Oct 2023Our knowledge of tumor-infiltrating lymphocytes (TILs) is dramatically expanding. These cells have proven prognostic and therapeutic value for many cancer outcomes and... (Review)
Review
Our knowledge of tumor-infiltrating lymphocytes (TILs) is dramatically expanding. These cells have proven prognostic and therapeutic value for many cancer outcomes and potential to treat also disseminated breast, colorectal, or lung cancer. However, the therapeutical outcome of TILs is negatively affected by tumor mutational burden and neoantigens. On the other hand, it can be improved in combination with checkpoint blockade therapy. This knowledge and rapid detection techniques alongside gene editing allow us to classify and modify T cells in many ways. Hence, to tailor them precisely to the patient´s needs as to program T cell receptors to recognize specific tumor-associated neoantigens and to insert them into lymphocytes or to select tumor neoantigen-specific T cells, for the development of vaccines that recognize tumor-specific antigens in tumors or metastases. Further studies and clinical trials in the field are needed for an even better-detailed understanding of TILs interactions and aiming in the fight against multiple cancers.
Topics: Humans; Lymphocytes, Tumor-Infiltrating; Immunotherapy, Adoptive; Lung Neoplasms; T-Lymphocytes; Antigens, Neoplasm; Colorectal Neoplasms
PubMed: 37888965
DOI: 10.33549/physiolres.935155