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Med (New York, N.Y.) Jun 2024Med discusses the future of CAR T cell therapy for autoimmune diseases with Dr. Fabian Müller, Senior Attending Physician and Head of the CAR T Cell Unit, Department...
Med discusses the future of CAR T cell therapy for autoimmune diseases with Dr. Fabian Müller, Senior Attending Physician and Head of the CAR T Cell Unit, Department of Medicine 5 (Hematology and Oncology), University Hospital Erlangen, Germany.
Topics: Humans; Autoimmune Diseases; Immunotherapy, Adoptive; Germany; Receptors, Chimeric Antigen
PubMed: 38878762
DOI: 10.1016/j.medj.2024.04.004 -
Cell Reports. Medicine Feb 2024Chimeric antigen receptor (CAR)-T therapy has shown superior efficacy against hematopoietic malignancies. However, many patients failed to achieve sustainable tumor...
Chimeric antigen receptor (CAR)-T therapy has shown superior efficacy against hematopoietic malignancies. However, many patients failed to achieve sustainable tumor control partially due to CAR-T cell exhaustion and limited persistence. In this study, by performing single-cell multi-omics data analysis on patient-derived CAR-T cells, we identify CD38 as a potential hallmark of exhausted CAR-T cells, which is positively correlated with exhaustion-related transcription factors and further confirmed with in vitro exhaustion models. Moreover, inhibiting CD38 activity reverses tonic signaling- or tumor antigen-induced exhaustion independent of single-chain variable fragment design or costimulatory domain, resulting in improved CAR-T cell cytotoxicity and antitumor response. Mechanistically, CD38 inhibition synergizes the downregulation of CD38-cADPR -Ca signaling and activation of the CD38-NAD-SIRT1 axis to suppress glycolysis. Collectively, our findings shed light on the role of CD38 in CAR-T cell exhaustion and suggest potential clinical applications of CD38 inhibition in enhancing the efficacy and persistence of CAR-T cell therapy.
Topics: Humans; T-Lymphocytes; Immunotherapy, Adoptive; Neoplasms; Antigens, Neoplasm; Single-Chain Antibodies
PubMed: 38307031
DOI: 10.1016/j.xcrm.2024.101400 -
Clinical and Experimental Medicine Dec 2023Cancer remains a major health problem despite numerous new medical interventions that have been introduced in recent years. One of the major choices for cancer therapy... (Review)
Review
Cancer remains a major health problem despite numerous new medical interventions that have been introduced in recent years. One of the major choices for cancer therapy is so-called adoptive cell therapy (ACT). ACT can be performed using both innate immune cells, including dendritic cells (DCs), natural killer (NK) cells, and γδ T cells and acquired immune T cells. It has become possible to utilize these cells in both their native and modified states in clinical studies. Because of considerable success in cancer treatment, ACT now plays a role in advanced therapy protocols. Genetic engineering of autologous and allogeneic immune cells (T lymphocytes, NK cells, macrophages, etc.) with chimeric antigen receptors (CAR) is a powerful new tool to target specific antigens on cancer cells. The Food and Drug Administration (FDA) in the US has approved certain CAR-T cells for hematologic malignancies and it is hoped that their use can be extended to incorporate a variety of cells, in particular NK cells. However, the ACT method has some limitations, such as the risk of rejection in allogeneic engrafts. Accordingly, numerous efforts are being made to eliminate or minimize this and other complications. In the present review, we have developed a guide to breast cancer (BC) therapy from conventional therapy, through to cell-based approaches, in particular novel technologies including CAR with emphasis on NK cells as a new and safer candidate in this field as well as the more recent aptamer technology, which can play a major role in BC immunotherapy.
Topics: Humans; Female; Immunotherapy, Adoptive; Breast Neoplasms; Immunotherapy; T-Lymphocytes; Receptors, Chimeric Antigen; Neoplasms
PubMed: 37658246
DOI: 10.1007/s10238-023-01177-z -
International Journal of Biological... 2023The immune checkpoint B7-H3 (CD276), a member of the B7 family with immunoregulatory properties, has been identified recently as a novel target for immunotherapy for... (Review)
Review
The immune checkpoint B7-H3 (CD276), a member of the B7 family with immunoregulatory properties, has been identified recently as a novel target for immunotherapy for refractory blood cancers and solid malignant tumors. While research on B7-H3 in brain malignancies is limited, there is growing interest in exploring its therapeutic potential in this context. B7-H3 plays a crucial role in regulating the functions of immune cells, cancer-associated fibroblasts, and endothelial cells within the tumor microenvironment, contributing to the creation of a pro-tumorigenic milieu. This microenvironment promotes uncontrolled cancer cell proliferation, enhanced metabolism, increased cancer stemness, and resistance to standard treatments. Blocking B7-H3 and terminating its immunosuppressive function is expected to improve anti-tumor immune responses and, in turn, ameliorate the progression of tumors. Results from preclinical or observative studies and early-phase trials targeting B7-H3 have revealed promising anti-tumor efficacy and acceptable toxicity in glioblastoma (GBM), diffuse intrinsic pontine glioma (DIPG), medulloblastoma, neuroblastoma, craniopharyngioma, atypical teratoid/rhabdoid tumor, and brain metastases. Ongoing clinical trials are now investigating the use of CAR-T cell therapy and antibody-drug conjugate therapy, either alone or in combination with standard treatments or other therapeutic approaches, targeting B7-H3 in refractory or recurrent GBMs, DIPGs, neuroblastomas, medulloblastomas, ependymomas, and metastatic brain tumors. These trials hold promise for providing effective treatment options for these challenging intracranial malignancies in both adult and pediatric populations.
Topics: Humans; B7 Antigens; Brain Neoplasms; Endothelial Cells; Immunotherapy; Immunotherapy, Adoptive; Neuroblastoma; Tumor Microenvironment
PubMed: 37564196
DOI: 10.7150/ijbs.85813 -
Trends in Immunology Oct 2023Broadening immune responses through antigen spreading remains the 'Holy Grail' of cancer immunotherapy. A study by Ma and colleagues reveals that vaccine boosting of...
Broadening immune responses through antigen spreading remains the 'Holy Grail' of cancer immunotherapy. A study by Ma and colleagues reveals that vaccine boosting of chimeric antigen receptor (CAR)-T cells in mice promotes endogenous immunity and elicits antigen spread to eliminate antigenically heterogenous solid tumors through a mechanism crucially dependent on interferon (IFN)γ.
Topics: Mice; Animals; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive; Neoplasms; T-Lymphocytes
PubMed: 37652814
DOI: 10.1016/j.it.2023.08.002 -
The New England Journal of Medicine Sep 2023
Topics: Humans; Antigens, CD19; Immunotherapy, Adoptive; Lymphoma, B-Cell
PubMed: 37733322
DOI: 10.1056/NEJMc2309399 -
The New England Journal of Medicine Sep 2023
Topics: Humans; Immunotherapy, Adoptive; T-Lymphocytes; Cell- and Tissue-Based Therapy; Cell Engineering
PubMed: 37672700
DOI: 10.1056/NEJMe2304744 -
Hematology/oncology Clinics of North... Dec 2023We review chimeric antigen receptor (CAR) T-cell therapy for solid tumors. We discuss patient selection factors and aspects of clinical management. We describe... (Review)
Review
We review chimeric antigen receptor (CAR) T-cell therapy for solid tumors. We discuss patient selection factors and aspects of clinical management. We describe challenges including physical and molecular barriers to trafficking CAR-Ts, an immunosuppressive tumor microenvironment, and difficulty finding cell surface target antigens. The application of new approaches in synthetic biology and cellular engineering toward solid tumor CAR-Ts is described. Finally, we summarize reported and ongoing clinical trials of CAR-T therapies for select disease sites such as head and neck (including thyroid cancer), lung, central nervous system (glioblastoma, neuroblastoma, glioma), sarcoma, genitourinary (prostate, renal, bladder, kidney), breast and ovarian cancer.
Topics: Humans; Neoplasms; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Tumor Microenvironment; T-Lymphocytes; Clinical Trials as Topic
PubMed: 37353377
DOI: 10.1016/j.hoc.2023.05.009 -
Revue Medicale Suisse Jun 2024
Topics: Humans; Receptors, Chimeric Antigen; Autoimmune Diseases; Immunotherapy, Adoptive; T-Lymphocytes; Severity of Illness Index; Receptors, Antigen, T-Cell
PubMed: 38836401
DOI: 10.53738/REVMED.2024.20.877.1139 -
Immunological Reviews Nov 2023Digestive tract cancers (DTC) belong to the most investigated family of tumors. The incidence, prevalence, and mortality rate of DTC remain high, especially for patients... (Review)
Review
Digestive tract cancers (DTC) belong to the most investigated family of tumors. The incidence, prevalence, and mortality rate of DTC remain high, especially for patients with pancreatic cancer. Even though immunotherapy such as immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid cancer types, ICI are still restricted to a very small group of patients and seem to be more efficacious in combination with chemotherapy. Cellular immunotherapy such as CAR T-cell therapy has entered clinical routine in hematological malignancies with outstanding results. There is growing interest on translating this kind of immunotherapy and success into patients with solid malignancies, such as DTC. This review attempts to describe the major advances in preclinical and clinical research with CAR T cells in DTC, considering the most relevant hurdles in each subtype of DTC.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; T-Lymphocytes; Neoplasms; Pancreatic Neoplasms; Gastrointestinal Tract
PubMed: 37694970
DOI: 10.1111/imr.13273