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Nature Reviews. Drug Discovery Oct 2023
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell
PubMed: 37673977
DOI: 10.1038/d41573-023-00140-7 -
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 -
Clinical Pharmacology and Therapeutics Sep 2023With the promise of a potentially "single dose curative" paradigm, CAR-T cell therapies have brought a paradigm shift in the treatment and management of hematological... (Review)
Review
With the promise of a potentially "single dose curative" paradigm, CAR-T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies. Both CAR-T and TCR-T cell therapies have also made great progress toward the successful treatment of solid tumor indications. The field is rapidly evolving with recent advancements including the clinical development of "off-the-shelf" allogeneic CAR-T therapies that can overcome the long and difficult "vein-to-vein" wait time seen with autologous CAR-T therapies. There are unique clinical pharmacology, pharmacometric, bioanalytical, and immunogenicity considerations and challenges in the development of these CAR-T and TCR-T cell therapies. Hence, to help accelerate the development of these life-saving therapies for the patients with cancer, experts in this field came together under the umbrella of International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) to form a joint working group between the Clinical Pharmacology Leadership Group (CPLG) and the Translational and ADME Sciences Leadership Group (TALG). In this white paper, we present the IQ consortium perspective on the best practices and considerations for clinical pharmacology and pharmacometric aspects toward the optimal development of CAR-T and TCR-T cell therapies.
Topics: Humans; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Pharmacology, Clinical; Neoplasms; Immunotherapy, Adoptive
PubMed: 37393588
DOI: 10.1002/cpt.2986 -
Nature Biotechnology Nov 2023Identification of optimal target antigens that distinguish cancer cells from normal surrounding tissue cells remains a key challenge in chimeric antigen receptor (CAR)...
Identification of optimal target antigens that distinguish cancer cells from normal surrounding tissue cells remains a key challenge in chimeric antigen receptor (CAR) cell therapy for tumors with intratumoral heterogeneity. In this study, we dissected tissue complexity to the level of individual cells through the construction of a single-cell expression atlas that integrates ~1.4 million tumor, tumor-infiltrating normal and reference normal cells from 412 tumors and 12 normal organs. We used a two-step screening method using random forest and convolutional neural networks to select gene pairs that contribute most to discrimination between individual malignant and normal cells. Tumor coverage and specificity are evaluated for the AND, OR and NOT logic gates based on the combinatorial expression pattern of the pairing genes across individual single cells. Single-cell transcriptome-coupled epitope profiling validates the AND, OR and NOT switch targets identified in ovarian cancer and colorectal cancer.
Topics: Female; Humans; T-Lymphocytes; Immunotherapy, Adoptive; Antigens, Neoplasm; Ovarian Neoplasms
PubMed: 36797491
DOI: 10.1038/s41587-023-01686-y -
Blood Reviews Jul 2023Natural Killer (NK) cells yield promise in therapy of hematologic malignancies. The clinical experience with adoptively transferred allogeneic NK cells over past two... (Review)
Review
Natural Killer (NK) cells yield promise in therapy of hematologic malignancies. The clinical experience with adoptively transferred allogeneic NK cells over past two decades has revealed safety and minimal risk of CRS or ICANS. Unlike T cells which have to be genetically altered to avoid graft vs host disease (GVHD), HLA mismatched NK cells can be infused without GVHD risk. This makes them ideal for the development of off-the-shelf products. In this review we focus on NK biology relevant to the cancer therapy, the trajectory of NK therapeutics for leukemia, lymphoma, and myeloma; and advantages of the NK cell platform. We will also discuss novel methods to enhance NK cell targeting, persistence, and function in the tumor microenvironment. The future of NK cell therapy depends on novel strategies to realize these qualities.
Topics: Humans; Hematologic Neoplasms; Killer Cells, Natural; Immunotherapy, Adoptive; Graft vs Host Disease; Cell- and Tissue-Based Therapy; Tumor Microenvironment
PubMed: 36959057
DOI: 10.1016/j.blre.2023.101073 -
The New England Journal of Medicine Feb 2024
Topics: Humans; Cell- and Tissue-Based Therapy; Immunotherapy, Adoptive; Neoplasms, Second Primary; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 38265704
DOI: 10.1056/NEJMp2400209 -
Cancer Cell Jan 2024Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors, but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963)...
Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors, but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963) of GD2 CAR-Ts (GD2-CAR.OX40.28.z.iC9), demonstrating feasibility and safety of administration in children and young adults with osteosarcoma and neuroblastoma. Since CAR-T efficacy requires adequate CAR-T expansion, patients were grouped into good or poor expanders across dose levels. Patient samples were evaluated by multi-dimensional proteomic, transcriptomic, and epigenetic analyses. T cell assessments identified naive T cells in pre-treatment apheresis associated with good expansion, and exhausted T cells in CAR-T products with poor expansion. Myeloid cell assessment identified CXCR3 monocytes in pre-treatment apheresis associated with good expansion. Longitudinal analysis of post-treatment samples identified increased CXCR3 classical monocytes in all groups as CAR-T numbers waned. Together, our data uncover mediators of CAR-T biology and correlates of expansion that could be utilized to advance immunotherapies for solid tumor patients.
Topics: Child; Young Adult; Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Proteomics; Immunotherapy, Adoptive; T-Lymphocytes; Neuroblastoma; Cell- and Tissue-Based Therapy
PubMed: 38134936
DOI: 10.1016/j.ccell.2023.11.011 -
British Journal of Haematology May 2024Chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of multiple myeloma (MM) has fundamentally changed the relapsed and refractory therapeutic landscape,...
Chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of multiple myeloma (MM) has fundamentally changed the relapsed and refractory therapeutic landscape, but the disease remains incurable. Two CAR-T products, idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel, Carvykti), have been FDA- and EMA-approved for the treatment of relapsed/refractory MM (RRMM); both target B-cell maturation antigen (BCMA), a surface glycoprotein highly expressed on MM cells. Despite deep and durable responses following CAR-T therapy, most patients will need subsequent treatment, and the optimal next-line therapy is presently unclear. Commentary on: Liu et al. Outcomes in patients with multiple myeloma receiving salvage treatment after BCMA-specific CAR-T therapy: A retrospective analysis of LEGEND-2. Br J Haematol 2024;204:1780-1789.
Topics: Humans; Multiple Myeloma; Immunotherapy, Adoptive; Salvage Therapy; B-Cell Maturation Antigen; Receptors, Chimeric Antigen
PubMed: 38563345
DOI: 10.1111/bjh.19439 -
Neuro-oncology Nov 2023Glioblastoma (GB) is incurable at present without established treatment options for recurrent disease. In this phase I first-in-human clinical trial we investigated...
BACKGROUND
Glioblastoma (GB) is incurable at present without established treatment options for recurrent disease. In this phase I first-in-human clinical trial we investigated safety and feasibility of adoptive transfer of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2, which is expressed at elevated levels by a subset of glioblastomas.
METHODS
Nine patients with recurrent HER2-positive GB were treated with single doses of 1 × 107, 3 × 107, or 1 × 108 irradiated CAR-NK cells injected into the margins of the surgical cavity during relapse surgery. Imaging at baseline and follow-up, peripheral blood lymphocyte phenotyping and analyses of the immune architecture by multiplex immunohistochemistry and spatial digital profiling were performed.
RESULTS
There were no dose-limiting toxicities, and none of the patients developed a cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Five patients showed stable disease after relapse surgery and CAR-NK injection that lasted 7 to 37 weeks. Four patients had progressive disease. Pseudoprogression was found at injection sites in 2 patients, suggestive of a treatment-induced immune response. For all patients, median progression-free survival was 7 weeks, and median overall survival was 31 weeks. Furthermore, the level of CD8+ T-cell infiltration in recurrent tumor tissue prior to CAR-NK cell injection positively correlated with time to progression.
CONCLUSIONS
Intracranial injection of HER2-targeted CAR-NK cells is feasible and safe in patients with recurrent GB. 1 × 108 NK-92/5.28.z cells was determined as the maximum feasible dose for a subsequent expansion cohort with repetitive local injections of CAR-NK cells.
Topics: Humans; Receptors, Chimeric Antigen; Glioblastoma; Neoplasm Recurrence, Local; Killer Cells, Natural; Recurrence; Immunotherapy, Adoptive
PubMed: 37148198
DOI: 10.1093/neuonc/noad087 -
Blood Oct 2023
Topics: Humans; B-Cell Maturation Antigen; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; T-Lymphocytes; Parkinsonian Disorders; Antineoplastic Agents
PubMed: 37796518
DOI: 10.1182/blood.2023021860