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Cancer Cell Nov 2023Acute myeloid leukemia (AML) poses a singular challenge for chimeric antigen receptor (CAR) therapy owing to its phenotypic heterogeneity and similarity to normal...
Acute myeloid leukemia (AML) poses a singular challenge for chimeric antigen receptor (CAR) therapy owing to its phenotypic heterogeneity and similarity to normal hematopoietic stem/progenitor cells (HSPCs). Here we expound a CAR strategy intended to efficiently target AML while minimizing HSPC toxicity. Quantification of target expression in relapsed/refractory patient samples and normal HSPCs reveals a therapeutic window for gated co-targeting of ADGRE2 and CLEC12A: We combine an attenuated ADGRE2-CAR with a CLEC12A-chimeric costimulatory receptor (ADCLEC.syn1) to preferentially engage ADGRE2CLEC12A leukemic stem cells over ADGRE2CLEC12A normal HSPCs. ADCLEC.syn1 prevents antigen escape in AML xenograft models, outperforms the ADGRE2-CAR alone and eradicates AML despite proximate myelopoiesis in humanized mice. Off-target HSPC toxicity is similar to that of a CD19-CAR and can be mitigated by reducing CAR T cell-derived interferon-γ. Overall, we demonstrate the ability of target density-adapted cooperative CAR targeting to selectively eliminate AML and potentially obviate the need for hematopoietic rescue.
Topics: Humans; Animals; Mice; Cell Line, Tumor; T-Lymphocytes; Leukemia, Myeloid, Acute; Immunotherapy, Adoptive; Hematopoietic Stem Cells; Receptors, Mitogen; Lectins, C-Type
PubMed: 37802054
DOI: 10.1016/j.ccell.2023.09.010 -
Trends in Cancer Oct 2023Diffuse midline glioma (DMG) is a fatal pediatric cancer of the central nervous system (CNS). The location and infiltrative nature of DMG prevents surgical resection and... (Review)
Review
Diffuse midline glioma (DMG) is a fatal pediatric cancer of the central nervous system (CNS). The location and infiltrative nature of DMG prevents surgical resection and the benefits of palliative radiotherapy are temporary; median overall survival (OS) is 9-11 months. The tumor immune microenvironment (TIME) is 'cold', and has a dominant immunosuppressive myeloid compartment with low levels of infiltrating lymphocytes and proinflammatory molecules. Because survival statistics have been stagnant for many decades, and therapies targeting the unique biology of DMG are urgently needed, this has prompted the clinical assessment of chimeric antigen receptor (CAR) T cell therapies in this setting. We highlight the current landscape of CAR T cell therapy for DMG, the role the TIME may play in the response, and strategies to overcome treatment obstacles.
Topics: Child; Humans; Immunotherapy, Adoptive; Central Nervous System; Tumor Microenvironment; Glioma
PubMed: 37541803
DOI: 10.1016/j.trecan.2023.07.007 -
The Journal of Experimental Medicine Feb 2024Chimeric antigen receptor (CAR)-T cell therapies have demonstrated strong curative potential and become a critical component in the array of B-cell malignancy... (Review)
Review
Chimeric antigen receptor (CAR)-T cell therapies have demonstrated strong curative potential and become a critical component in the array of B-cell malignancy treatments. Successful deployment of CAR-T cell therapies to treat hematologic and solid cancers, as well as other indications such as autoimmune diseases, is dependent on effective CAR-T cell manufacturing that impacts not only product safety and efficacy but also overall accessibility to patients in need. In this review, we discuss the major process parameters of autologous CAR-T cell manufacturing, as well as regulatory considerations and ongoing developments that will enable the next generation of CAR-T cell therapies.
Topics: Humans; Autoimmune Diseases; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 38226974
DOI: 10.1084/jem.20230903 -
Cancer Discovery Sep 2023CAR T-cell product quality and stemness (Tstem) are major determinants of in vivo expansion, efficacy, and clinical response. Prolonged ex vivo culturing is known to...
UNLABELLED
CAR T-cell product quality and stemness (Tstem) are major determinants of in vivo expansion, efficacy, and clinical response. Prolonged ex vivo culturing is known to deplete Tstem, affecting clinical outcome. YTB323, a novel autologous CD19-directed CAR T-cell therapy expressing the same validated CAR as tisagenlecleucel, is manufactured using a next-generation platform in <2 days. Here, we report the preclinical development and preliminary clinical data of YTB323 in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL; NCT03960840). In preclinical mouse models, YTB323 exhibited enhanced in vivo expansion and antitumor activity at lower doses than traditionally manufactured CAR T cells. Clinically, at doses 25-fold lower than tisagenlecleucel, YTB323 showed (i) promising overall safety [cytokine release syndrome (any grade, 35%; grade ≥3, 6%), neurotoxicity (any grade, 25%; grade ≥3, 6%)]; (ii) overall response rates of 75% and 80% for DL1 and DL2, respectively; (iii) comparable CAR T-cell expansion; and (iv) preservation of T-cell phenotype. Current data support the continued development of YTB323 for r/r DLBCL.
SIGNIFICANCE
Traditional CAR T-cell manufacturing requires extended ex vivo cell culture, reducing naive and stem cell memory T-cell populations and diminishing antitumor activity. YTB323, which expresses the same validated CAR as tisagenlecleucel, can be manufactured in <2 days while retaining T-cell stemness and enhancing clinical activity at a 25-fold lower dose. See related commentary by Wang, p. 1961. This article is featured in Selected Articles from This Issue, p. 1949.
Topics: Mice; Animals; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Lymphoma, Non-Hodgkin; Lymphoma, Large B-Cell, Diffuse; Cell Culture Techniques; Antigens, CD19
PubMed: 37249512
DOI: 10.1158/2159-8290.CD-22-1276 -
Journal of Hematology & Oncology Sep 2023Pancreatic cancer lacks effective therapy. Here, we reported two metastatic pancreatic cancer patients administrated with Claudin 18.2 (CLDN 18.2) CART therapy after the...
Pancreatic cancer lacks effective therapy. Here, we reported two metastatic pancreatic cancer patients administrated with Claudin 18.2 (CLDN 18.2) CART therapy after the failure of standard therapy (NCT04581473 and NCT03874897). In case 1, with CLDN 18.2 expression of 2+, 70%, 250 × 10 cells were infused after lymphodepletion. Grade 1 cytokine release syndrome (CRS) occurred on d1 which was later controlled by tocilizumab. Partial response (PR) was achieved according to RECIST v1.1, with great shrinkage of lung metastasis. An increasing CD8+ T cell and Treg cells and declining CD4+ T cell and B cell were observed. In case 2, IHC result of ClDN18.2 showed 3+, 60%. 250 × 10 CLDN18.2 CART cells were subsequently administered. Patient experienced grade 2 CRS, which was controlled with tocilizumab. Target lesions of lung metastasis further achieved complete response. Similar increasing CD8+ T cell and Treg cell was detected from peripheral blood. Elevating IL-8 and declining TGF-β1 were also observed. The tumor is still under well control until the last follow-up on July 18, 2023.
Topics: Humans; Immunotherapy, Adoptive; Pancreatic Neoplasms; B-Lymphocytes; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokine Release Syndrome; Claudins
PubMed: 37689733
DOI: 10.1186/s13045-023-01491-9 -
International Journal of Molecular... Aug 2023As an emerging treatment strategy for malignant tumors, chimeric antigen receptor T (CAR-T) cell therapy has been widely used in clinical practice, and its efficacy has... (Review)
Review
As an emerging treatment strategy for malignant tumors, chimeric antigen receptor T (CAR-T) cell therapy has been widely used in clinical practice, and its efficacy has been markedly improved in the past decade. However, the clinical effect of CAR-T therapy is not so satisfying, especially in solid tumors. Even in hematologic malignancies, a proportion of patients eventually relapse after receiving CAR-T cell infusions, owing to the poor expansion and persistence of CAR-T cells. Recently, CRISPR/Cas9 technology has provided an effective approach to promoting the proliferation and persistence of CAR-T cells in the body. This technology has been utilized in CAR-T cells to generate a memory phenotype, reduce exhaustion, and screen new targets to improve the anti-tumor potential. In this review, we aim to describe the major causes limiting the persistence of CAR-T cells in patients and discuss the application of CRISPR/Cas9 in promoting CAR-T cell persistence and its anti-tumor function. Finally, we investigate clinical trials for CRISPR/Cas9-engineered CAR-T cells for the treatment of cancer.
Topics: Humans; Receptors, Chimeric Antigen; T-Lymphocytes; CRISPR-Cas Systems; Gene Editing; Neoplasm Recurrence, Local; Immunotherapy, Adoptive; Neoplasms
PubMed: 37569693
DOI: 10.3390/ijms241512317 -
Transplant Infectious Disease : An... Nov 2023Revaccination after receipt of a hematopoietic cell transplant (HCT) or cellular therapies is a pillar of patient supportive care, with the potential to reduce morbidity... (Review)
Review
Revaccination after receipt of a hematopoietic cell transplant (HCT) or cellular therapies is a pillar of patient supportive care, with the potential to reduce morbidity and mortality linked to vaccine-preventable infections. This review synthesizes national, international, and expert consensus vaccination schedules post-HCT and presents evidence regarding the efficacy of newer vaccine formulations for pneumococcus, recombinant zoster vaccine, and coronavirus disease 2019 in patients with hematological malignancy. Revaccination post-cellular therapies are less well defined. This review highlights important considerations around poor vaccine response, seroprevalence preservation after cellular therapies, and the optimal timing of revaccination. Future research should assess the immunogenicity and real-world effectiveness of new vaccine formulations and/or vaccine schedules in patients post-HCT and cellular therapy, including analysis of vaccine response that relates to the target of cellular therapies.
Topics: Humans; Communicable Diseases; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Immunotherapy, Adoptive; Seroepidemiologic Studies; Vaccines
PubMed: 37515788
DOI: 10.1111/tid.14109 -
The Journal of Experimental Medicine Nov 2023Recent studies suggest that training of innate immune cells such as tissue-resident macrophages by repeated noxious stimuli can heighten host defense responses. However,...
Recent studies suggest that training of innate immune cells such as tissue-resident macrophages by repeated noxious stimuli can heighten host defense responses. However, it remains unclear whether trained immunity of tissue-resident macrophages also enhances injury resolution to counterbalance the heightened inflammatory responses. Here, we studied lung-resident alveolar macrophages (AMs) prechallenged with either the bacterial endotoxin or with Pseudomonas aeruginosa and observed that these trained AMs showed greater resilience to pathogen-induced cell death. Transcriptomic analysis and functional assays showed greater capacity of trained AMs for efferocytosis of cellular debris and injury resolution. Single-cell high-dimensional mass cytometry analysis and lineage tracing demonstrated that training induces an expansion of a MERTKhiMarcohiCD163+F4/80low lung-resident AM subset with a proresolving phenotype. Reprogrammed AMs upregulated expression of the efferocytosis receptor MERTK mediated by the transcription factor KLF4. Adoptive transfer of these trained AMs restricted inflammatory lung injury in recipient mice exposed to lethal P. aeruginosa. Thus, our study has identified a subset of tissue-resident trained macrophages that prevent hyperinflammation and restore tissue homeostasis following repeated pathogen challenges.
Topics: Animals; Mice; Adoptive Transfer; c-Mer Tyrosine Kinase; Macrophages, Alveolar; Phagocytosis; Trained Immunity
PubMed: 37615937
DOI: 10.1084/jem.20221388 -
Frontiers in Immunology 2023Gene-engineered immune cell therapies have partially transformed cancer treatment, as exemplified by the use of chimeric antigen receptor (CAR)-T cells in certain... (Review)
Review
Gene-engineered immune cell therapies have partially transformed cancer treatment, as exemplified by the use of chimeric antigen receptor (CAR)-T cells in certain hematologic malignancies. However, there are several limitations that need to be addressed to target more cancer types. Natural killer (NK) cells are a type of innate immune cells that represent a unique biology in cancer immune surveillance. In particular, NK cells obtained from heathy donors can serve as a source for genetically engineered immune cell therapies. Therefore, NK-based therapies, including NK cells, CAR-NK cells, and antibodies that induce antibody-dependent cellular cytotoxicity of NK cells, have emerged. With recent advances in genetic engineering and cell biology techniques, NK cell-based therapies have become promising approaches for a wide range of cancers, viral infections, and senescence. This review provides a brief overview of NK cell characteristics and summarizes diseases that could benefit from NK-based therapies. In addition, we discuss recent preclinical and clinical investigations on the use of adoptive NK cell transfer and agents that can modulate NK cell activity.
Topics: Humans; Killer Cells, Natural; Immunotherapy, Adoptive; Neoplasms; Immunotherapy; Genetic Therapy
PubMed: 37539051
DOI: 10.3389/fimmu.2023.1192907 -
Ageing Research Reviews Feb 2024Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by cognitive impairment with few therapeutic options. Despite many failures in... (Review)
Review
Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by cognitive impairment with few therapeutic options. Despite many failures in developing AD treatment during the past 20 years, significant advances have been achieved in passive immunotherapy of AD very recently. Here, we review characteristics, clinical trial data, and mechanisms of action for monoclonal antibodies (mAbs) targeting key players in AD pathogenesis, including amyloid-β (Aβ), tau and neuroinflammation modulators. We emphasized the efficacy of lecanemab and donanemab on cognition and amyloid clearance in AD patients in phase III clinical trials and discussed factors that may contribute to the efficacy and side effects of anti-Aβ mAbs. In addition, we provided important information on mAbs targeting tau or inflammatory regulators in clinical trials, and indicated that mAbs against the mid-region of tau or pathogenic tau have therapeutic potential for AD. In conclusion, passive immunotherapy targeting key players in AD pathogenesis offers a promising strategy for effective AD treatment.
Topics: Humans; Alzheimer Disease; Neurodegenerative Diseases; Amyloid beta-Peptides; Antibodies, Monoclonal; Immunization, Passive; Immunotherapy; tau Proteins; Antibodies, Monoclonal, Humanized
PubMed: 38219962
DOI: 10.1016/j.arr.2024.102192