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Human Vaccines & Immunotherapeutics Dec 2023Chimeric antigen receptor T cell (CAR-T) therapy is an innovative immunotherapeutic approach that utilizes genetically modified T-cells to eliminate cancer cells using... (Review)
Review
Chimeric antigen receptor T cell (CAR-T) therapy is an innovative immunotherapeutic approach that utilizes genetically modified T-cells to eliminate cancer cells using the specificity of a monoclonal antibody (mAb) coupled to the potent cytotoxicity of the T-lymphocyte. CAR-T therapy has yielded significant improvements in relapsed/refractory B-cell malignancies. Given these successes, CAR-T has quickly spread to other hematologic malignancies and is being increasingly explored in solid tumors. From early clinical applications to present day, CAR-T cell therapy has been accompanied by significant toxicities, namely cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and on-target off-tumor (OTOT) effects. While medical management has improved for CRS and ICANS, the ongoing threat of refractory symptoms and unanticipated idiosyncratic toxicities highlights the need for more powerful safety measures. This is particularly poignant as CAR T-cell therapy continues to expand into the solid tumor space, where the risk of unpredictable toxicities remains high. We will review CAR-T as an immunotherapeutic approach including emergence of unique toxicities throughout development. We will discuss known and novel strategies to mitigate these toxicities; additional safety challenges in the treatment of solid tumors, and how the inducible Caspase 9 "safety switch" provides an ideal platform for continued exploration.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Antibodies, Monoclonal; Cytokine Release Syndrome; Neoplasms
PubMed: 37968136
DOI: 10.1080/21645515.2023.2275457 -
Medicina Clinica May 2024Patients with multiple myeloma who present with refractory disease or relapse after receiving the main classes of available drugs -immunomodulators, proteasome... (Review)
Review
Patients with multiple myeloma who present with refractory disease or relapse after receiving the main classes of available drugs -immunomodulators, proteasome inhibitors and antibodies against CD38- do not have satisfactory therapeutic alternatives. New treatments based on the redirection of T lymphocytes to act directly against tumor cells, such as bispecific antibodies and T cells with chimeric antigen receptors, are changing this scenario. The published information confirms unprecedented antitumor activity of these agents in patients with refractory myeloma and they will certainly represent the backbone of the treatment of these patients in the immediate future. However, these therapies also present specific characteristics and medium or long-term toxicities that pose new healthcare challenges. In this review, we address the current results and future challenges of the administration of these treatments in patients with relapsed or refractory multiple myeloma.
Topics: Humans; Multiple Myeloma; Antibodies, Bispecific; Immunotherapy; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Antineoplastic Agents, Immunological
PubMed: 38218655
DOI: 10.1016/j.medcli.2023.11.019 -
International Journal of Molecular... Jan 2024Sarcomas are a group of malignancies of mesenchymal origin with a plethora of subtypes. Given the sheer heterogeneity of various subtypes and the rarity of the disease,... (Review)
Review
Sarcomas are a group of malignancies of mesenchymal origin with a plethora of subtypes. Given the sheer heterogeneity of various subtypes and the rarity of the disease, the management of sarcomas has been challenging, with poor patient outcomes. Surgery, radiation therapy and chemotherapy have remained the backbone of treatment in patients with sarcoma. The introduction of immunotherapy has revolutionized the treatment of various solid and hematological malignancies. In this review, we discuss the basics of immunotherapy and the immune microenvironment in sarcomas; various modalities of immunotherapy, like immune checkpoint blockade, oncolytic viruses, cancer-targeted antibodies, vaccine therapy; and adoptive cell therapies like CAR T-cell therapy, T-cell therapy, and TCR therapy.
Topics: Humans; Sarcoma; Immunotherapy; Immunotherapy, Adoptive; Soft Tissue Neoplasms; Hematologic Neoplasms; Tumor Microenvironment
PubMed: 38279265
DOI: 10.3390/ijms25021266 -
Molecular Diagnosis & Therapy Nov 2023Chimeric antigen receptor T-cell therapies have transformed the management of hematologic malignancies but have not yet demonstrated consistent efficacy in solid tumors.... (Review)
Review
Chimeric antigen receptor T-cell therapies have transformed the management of hematologic malignancies but have not yet demonstrated consistent efficacy in solid tumors. Glioblastoma is the most common primary malignant brain tumor in adults and remains a major unmet medical need. Attempts at harnessing the potential of chimeric antigen receptor T-cell therapy for glioblastoma have resulted in glimpses of promise but have been met with substantial challenges. In this focused review, we discuss current and future strategies being developed to optimize chimeric antigen receptor T cells for efficacy in patients with glioblastoma, including the identification and characterization of new target antigens, reversal of T-cell dysfunction with novel chimeric antigen receptor constructs, regulatable platforms, and gene knockout strategies, and the use of combination therapies to overcome the immune-hostile microenvironment.
Topics: Humans; Receptors, Chimeric Antigen; Glioblastoma; T-Lymphocytes; Immunotherapy, Adoptive; Hematologic Neoplasms; Tumor Microenvironment
PubMed: 37700186
DOI: 10.1007/s40291-023-00671-0 -
Molecular Therapy : the Journal of the... Aug 2023Multiple clinical studies have treated mesothelin (MSLN)-positive solid tumors by administering MSLN-directed chimeric antigen receptor (CAR) T cells. Although these...
Multiple clinical studies have treated mesothelin (MSLN)-positive solid tumors by administering MSLN-directed chimeric antigen receptor (CAR) T cells. Although these products are generally safe, efficacy is limited. Therefore, we generated and characterized a potent, fully human anti-MSLN CAR. In a phase 1 dose-escalation study of patients with solid tumors, we observed two cases of severe pulmonary toxicity following intravenous infusion of this product in the high-dose cohort (1-3 × 10 T cells per m). Both patients demonstrated progressive hypoxemia within 48 h of infusion with clinical and laboratory findings consistent with cytokine release syndrome. One patient ultimately progressed to grade 5 respiratory failure. An autopsy revealed acute lung injury, extensive T cell infiltration, and accumulation of CAR T cells in the lungs. RNA and protein detection techniques confirmed low levels of MSLN expression by benign pulmonary epithelial cells in affected lung and lung samples obtained from other inflammatory or fibrotic conditions, indicating that pulmonary pneumocyte and not pleural expression of mesothelin may lead to dose-limiting toxicity. We suggest patient enrollment criteria and dosing regimens of MSLN-directed therapies consider the possibility of dynamic expression of mesothelin in benign lung with a special concern for patients with underlying inflammatory or fibrotic conditions.
Topics: Humans; Mesothelin; GPI-Linked Proteins; Immunotherapy, Adoptive; Neoplasms; T-Lymphocytes
PubMed: 37312454
DOI: 10.1016/j.ymthe.2023.06.006 -
Viruses Aug 2023The HIV-1 latent reservoir is considered the major barrier to achieve the eradication, although some evidences indicate that curing HIV-1 is a feasible goal [...].
The HIV-1 latent reservoir is considered the major barrier to achieve the eradication, although some evidences indicate that curing HIV-1 is a feasible goal [...].
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; HIV Seropositivity; HIV-1; Cell- and Tissue-Based Therapy
PubMed: 37766199
DOI: 10.3390/v15091793 -
Nature Dec 2023
Topics: Humans; Autoimmune Diseases; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Treatment Outcome
PubMed: 38087105
DOI: 10.1038/d41586-023-03968-6 -
Cancer Immunology, Immunotherapy : CII Oct 2023Adoptive cell transfer of tumor-infiltrating lymphocytes (TIL) can mediate durable complete responses in some patients with common epithelial cancers but does so...
Adoptive cell transfer of tumor-infiltrating lymphocytes (TIL) can mediate durable complete responses in some patients with common epithelial cancers but does so infrequently. A better understanding of T-cell responses to neoantigens and tumor-related immune evasion mechanisms requires having the autologous tumor as a reagent. We investigated the ability of patient-derived tumor organoids (PDTO) to fulfill this need and evaluated their utility as a tool for selecting T-cells for adoptive cell therapy. PDTO established from metastases from patients with colorectal, breast, pancreatic, bile duct, esophageal, lung, and kidney cancers underwent whole exomic sequencing (WES), to define mutations. Organoids were then evaluated for recognition by autologous TIL or T-cells transduced with cloned T-cell receptors recognizing defined neoantigens. PDTO were also used to identify and clone TCRs from TIL targeting private neoantigens and define those tumor-specific targets. PDTO were successfully established in 38/47 attempts. 75% were available within 2 months, a timeframe compatible with screening TIL for clinical administration. These lines exhibited good genetic fidelity with their parental tumors, especially for mutations with higher clonality. Immunologic recognition assays demonstrated instances of HLA allelic loss not found by pan-HLA immunohistochemistry and in some cases WES of fresh tumor. PDTO could also be used to show differences between TCRs recognizing the same antigen and to find and clone TCRs recognizing private neoantigens. PDTO can detect tumor-specific defects blocking T-cell recognition and may have a role as a selection tool for TCRs and TIL used in adoptive cell therapy.
Topics: Humans; T-Lymphocytes; Antigens, Neoplasm; Neoplasms; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Lymphocytes, Tumor-Infiltrating
PubMed: 37368077
DOI: 10.1007/s00262-023-03476-6 -
Cell Reports Oct 2023Understanding of cellular evolution and molecular programs of chimeric antigen receptor-engineered (CAR)-T cells post-infusion is pivotal for developing better treatment...
Understanding of cellular evolution and molecular programs of chimeric antigen receptor-engineered (CAR)-T cells post-infusion is pivotal for developing better treatment strategies. Here, we construct a longitudinal high-precision single-cell transcriptomic landscape of 7,578 CAR-T cells from 26 patients with B cell acute lymphoblastic leukemia (B-ALL) post-infusion. We molecularly identify eight CAR-T cell subtypes, including three cytotoxic subtypes with distinct kinetics and three dual-identity subtypes with non-T cell characteristics. Remarkably, long-term remission is coincident with the dominance of cytotoxic subtypes, while leukemia progression is correlated with the emergence of subtypes with B cell transcriptional profiles, which have dysfunctional features and might predict relapse. We further validate in vitro that the generation of B-featured CAR-T cells is induced by excessive tumor antigen stimulation or suppressed TCR signaling, while it is relieved by exogenous IL-12. Moreover, we define transcriptional hallmarks of CAR-T cell subtypes and reveal their molecular changes along computationally inferred cellular evolution in vivo. Collectively, these results decipher functional diversification and dynamics of peripheral CAR-T cells post-infusion.
Topics: Humans; Immunotherapy, Adoptive; Antigens, CD19; Receptors, Chimeric Antigen; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes
PubMed: 37851569
DOI: 10.1016/j.celrep.2023.113263 -
Clinical Pharmacology and Therapeutics Dec 2023The emergence of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, including multiple myeloma (MM). Two... (Review)
Review
The emergence of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, including multiple myeloma (MM). Two BCMA-directed CAR T-cell products - idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) - have received US Food and Drug Administration (FDA) approval for patients with relapsed/refractory MM who underwent four or more prior lines of therapy (including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody). Despite producing unprecedented response rates in an otherwise difficult to treat patient population, CAR T-cell therapies are commonly associated with immune-related adverse events (e.g., cytokine release syndrome and neurotoxicity), cytopenias, and infections. Moreover, many patients continue to exhibit relapse post-treatment, with resistance mechanisms yet to be fully understood. Ongoing basic, translational, and clinical research efforts are poised to generate deeper insights into the optimal utilization of these therapies, improve their efficacy, minimize associated toxicity, and identify new target antigens in patients with MM.
Topics: Humans; Multiple Myeloma; Immunotherapy, Adoptive; Neoplasm Recurrence, Local; Hematologic Neoplasms; Antiviral Agents
PubMed: 37750399
DOI: 10.1002/cpt.3057