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Nature Immunology Dec 2023The advent of chimeric antigen receptor (CAR) T cell therapy has resulted in unprecedented long-term clearance of relapse/refractory hematological malignancies in both... (Review)
Review
The advent of chimeric antigen receptor (CAR) T cell therapy has resulted in unprecedented long-term clearance of relapse/refractory hematological malignancies in both pediatric and adult patients. However, severe toxicities, such as cytokine release syndrome and neurotoxicity, associated with CAR T cells affect therapeutic utility; and treatment efficacies for solid tumors are still not impressive. As a result, engineering strategies that modify other immune cell types, especially natural killer (NK) cells have arisen. Owing to both CAR-dependent and CAR-independent (innate immune-mediated) antitumor killing capacity, major histocompatibility complex-independent cytotoxicity, reduced risk of alloreactivity and lack of major CAR T cell toxicities, CAR NK cells constitute one of the promising next-generation CAR immune cells that are also amenable as 'off-the-shelf' therapeutics. In this Review, we compare CAR T and CAR NK cell therapies, with particular focus on immunological synapses, engineering strategies and challenges.
Topics: Humans; Child; Receptors, Chimeric Antigen; Killer Cells, Natural; Immunotherapy, Adoptive; Neoplasms; Cell- and Tissue-Based Therapy
PubMed: 38012406
DOI: 10.1038/s41590-023-01659-y -
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 Clinical Oncology : Official... Sep 2023Historically, the outcomes for individuals with triple-class refractory and penta-drug refractory multiple myeloma (MM) have been poor because of a dearth of effective... (Review)
Review
Historically, the outcomes for individuals with triple-class refractory and penta-drug refractory multiple myeloma (MM) have been poor because of a dearth of effective treatment options. However, the advent of chimeric antigen receptor (CAR) T-cell and T-cell redirecting bispecific antibody (BsAb) therapies has led to unprecedented response rates and durations of response in heavily relapsed/refractory (R/R) populations. Currently, two B-cell maturation antigen (BCMA)-directed CAR T-cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) as well as one BCMA/CD3 BsAb (teclistamab) have been approved for late-line (greater than four previous lines) R/R MM in the United States. The purpose of this review is to analyze the recent data for these approved therapies as well as provide an overview of other related CAR T-cell and BsAb therapies under development, including non-BCMA-targeting agents. We review efficacy and safety considerations, with particular focus on cytokine release syndrome, neurotoxicity, and infection risk. The relative merits and limitations of each class of therapy are discussed, as well as the areas of unmet need with respect to optimal sequencing and supportive care measures. We examine the factors that challenge equitable access to these novel therapies across minoritized racial, ethnic, and socioeconomic populations. Although it is evident that CAR T-cell and BsAb therapies will transform treatment paradigms in MM for years to come, significant work remains to identify the optimal utilization of these novel therapies and ensure equitable access.
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; T-Lymphocytes; Immunotherapy, Adoptive; Treatment Outcome; Antibodies, Bispecific
PubMed: 37471687
DOI: 10.1200/JCO.23.00512 -
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 -
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 -
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 -
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 -
Annual Review of Medicine Jan 2024The treatment for COVID-19 has evolved rapidly since the start of the pandemic and now consists mainly of antiviral and immunomodulatory agents. Antivirals, such as... (Review)
Review
The treatment for COVID-19 has evolved rapidly since the start of the pandemic and now consists mainly of antiviral and immunomodulatory agents. Antivirals, such as remdesivir and nirmatrelvir-ritonavir, have proved to be most useful earlier in illness (e.g., as outpatient therapy) and for less severe disease. Immunomodulatory therapies, such as dexamethasone and interleukin-6 or Janus kinase inhibitors, are most useful in severe disease or critical illness. The role of anti-SARS-CoV-2 monoclonal antibodies has diminished because of the emergence of viral variants that are not anticipated to be susceptible to these treatments, and there still is not a consensus on the use of convalescent plasma. COVID-19 has been associated with increased rates of venous thromboembolism, but the role of antithrombotic therapy is limited. Multiple investigational agents continue to be studied, which will alter current treatment paradigms as new data are released.
Topics: Humans; COVID-19; COVID-19 Serotherapy; Immunomodulation; Interleukin-6; Janus Kinase Inhibitors
PubMed: 37722709
DOI: 10.1146/annurev-med-052422-020316