-
Cancer Cell Nov 2023Chimeric antigen receptor (CAR) T cell therapies are limited by antigen escape and on-target/off-tumor toxicity. In addressing these challenges, Haubner et al. develop...
Chimeric antigen receptor (CAR) T cell therapies are limited by antigen escape and on-target/off-tumor toxicity. In addressing these challenges, Haubner et al. develop an "IF-BETTER" strategy. Their combinatorial chimeric co-stimulatory receptor with an attenuated CAR enhances acute myeloid leukemia (AML) killing while protecting healthy progenitors, highlighting the potential to leverage cooperative CAR designs.
Topics: Humans; Leukemia, Myeloid, Acute; Immunotherapy, Adoptive
PubMed: 37832553
DOI: 10.1016/j.ccell.2023.09.015 -
Cancer Immunology Research Jul 2023In this issue, Tsimberidou and colleagues report the results of a first-in-human clinical trial using a personalized, multi-target, endogenous T-cell therapy in patients...
In this issue, Tsimberidou and colleagues report the results of a first-in-human clinical trial using a personalized, multi-target, endogenous T-cell therapy in patients with metastatic solid tumors. This, and results of other recently published clinical trials, confirms the rationale of multi-target approaches that can increase tumor responses and counteract tumor heterogeneity and mechanisms of immune evasion. See related article by Tsimberidou et al., p. 925 (4).
Topics: Humans; Immunotherapy, Adoptive; Feasibility Studies; Neoplasms; Cell- and Tissue-Based Therapy; T-Lymphocytes
PubMed: 37347991
DOI: 10.1158/2326-6066.CIR-23-0160 -
Immunological Reviews Nov 2023
Topics: Humans; Immunotherapy; Neoplasms; Immunotherapy, Adoptive
PubMed: 37872646
DOI: 10.1111/imr.13283 -
Cancer Research Jan 2024Generating stem-like memory T cells (TSCM) is a potential strategy to improve adoptive immunotherapy. Elucidating optimal ways to modulate signaling pathways that enrich...
UNLABELLED
Generating stem-like memory T cells (TSCM) is a potential strategy to improve adoptive immunotherapy. Elucidating optimal ways to modulate signaling pathways that enrich TSCM properties could identify approaches to achieve this goal. We discovered herein that blocking the PI3Kδ pathway pharmaceutically to varying degrees can generate T cells with increasingly heightened stemness properties, based on the progressive enrichment of the transcription factors Tcf1 and Lef1. T cells with enhanced stemness features exhibited metabolic plasticity, marked by improved mitochondrial function and glucose uptake after tumor recognition. Conversely, T cells with low or medium stemness were less metabolically dynamic, vulnerable to antigen-induced cell death, and expressed more inhibitory checkpoint receptors. Only T-cell receptor-specific or chimeric antigen receptor (CAR)-specific T cells with high stemness persisted in vivo and mounted protective immunity to tumors. Likewise, the strongest level of PI3Kδ blockade in vitro generated human tumor-infiltrating lymphocytes and CAR T cells with elevated stemness properties, in turn bolstering their capacity to regress human solid tumors. The stemness level of T cells in vitro was important, ultimately impacting their efficacy in mice bearing three distinct solid tumors. Lef1 and Tcf1 sustained antitumor protection by donor high CD8+ TSCM or CD4+ Th17SCM, as deletion of either one compromised the therapeutic efficacy. Collectively, these findings highlight the importance of strategic modulation of PI3Kδ signaling in T cells to induce stemness and lasting protective responses to solid tumors.
SIGNIFICANCE
Elevating T-cell stemness by progressively blocking PI3Kδ signaling during ex vivo manufacturing of adoptive cell therapies alters metabolic and functional properties to enhance antitumor immunity dependent on Tcf1 and Lef1.
Topics: Humans; Mice; Animals; T-Lymphocytes; Neoplasms; Immunotherapy, Adoptive; Lymphocytes, Tumor-Infiltrating; Receptors, Antigen, T-Cell; CD8-Positive T-Lymphocytes
PubMed: 37801615
DOI: 10.1158/0008-5472.CAN-23-0801 -
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 -
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 -
Journal of Translational Medicine Oct 2023Antibody technology is widely used in the fields of biomedical and clinical therapies. Nonetheless, the complex in vitro expression of recombinant proteins, long... (Review)
Review
Antibody technology is widely used in the fields of biomedical and clinical therapies. Nonetheless, the complex in vitro expression of recombinant proteins, long production cycles, and harsh storage conditions have limited their applications in medicine, especially in clinical therapies. Recently, this dilemma has been overcome to a certain extent by the development of mRNA delivery systems, in which antibody-encoding mRNAs are enclosed in nanomaterials and delivered to the body. On entering the cytoplasm, the mRNAs immediately bind to ribosomes and undergo translation and post-translational modifications. This process produces monoclonal or bispecific antibodies that act directly on the patient. Additionally, it eliminates the cumbersome process of in vitro protein expression and extends the half-life of short-lived proteins, which significantly reduces the cost and duration of antibody production. This review focuses on the benefits and drawbacks of mRNA antibodies compared with the traditional in vitro expressed antibodies. In addition, it elucidates the progress of mRNA antibodies in the prevention of infectious diseases and oncology therapy.
Topics: Humans; RNA, Messenger; Pharmaceutical Preparations; Immunization, Passive; Antibodies, Bispecific; Recombinant Proteins; Immunotherapy
PubMed: 37794448
DOI: 10.1186/s12967-023-04553-1 -
Journal For Immunotherapy of Cancer Aug 2023CD8 T cells are a highly diverse population of cells with distinct phenotypic functions that can influence immunotherapy outcomes. Further insights on the roles of CD8...
BACKGROUND
CD8 T cells are a highly diverse population of cells with distinct phenotypic functions that can influence immunotherapy outcomes. Further insights on the roles of CD8 specificities and TCR avidity of naturally arising tumor-specific T cells, where both high and low avidity T cells recognizing the same peptide-major histocompatibility complex (pMHC) coexist in the same tumor, are crucial for understanding T cell exhaustion and resistance to PD-1 immunotherapy.
METHODS
CT26 models were treated with anti-PD-1 on days 3, 6 and 9 following subcutaneous tumor implantation generating variable responses during early tumor development. Tetramer staining was performed to determine the frequency and avidity of CD8 T cells targeting the tumor-specific epitope GSW11 and confirmed with tetramer competition assays. Functional characterization of high and low avidity GSW11-specific CD8 T cells was conducted using flow cytometry and bulk RNA-seq. In vitro cytotoxicity assays and in vivo adoptive transfer experiments were performed to determine the cytotoxicity of high and low avidity populations.
RESULTS
Treatment success with anti-PD-1 was associated with the preferential expansion of low avidity (Tet) GSW11-specific CD8 T cells with Vβ TCR expressing clonotypes. High avidity T cells (Tet), if present, were only found in progressing PD-1 refractory tumors. Tet demonstrated precursor exhausted or progenitor T cell phenotypes marked by higher expression of Tcf-1 and T-bet, and lower expression of the exhaustion markers CD39, PD-1 and Eomes compared with Tet, whereas Tet cells were terminally exhausted. Transcriptomics analyses showed pathways related to TCR signaling, cytotoxicity and oxidative phosphorylation were significantly enriched in Tet found in both regressing and progressing tumors compared with Tet, whereas genes related to DNA damage, apoptosis and autophagy were downregulated. In vitro studies showed that Tet exhibits higher cytotoxicity than Tet. Adoptive transfer of Tet showed more effective tumor control than Tet, and curative responses were achieved when Tet was combined with two doses of anti-PD-1.
CONCLUSIONS
Targeting subdominant T cell responses with lower avidity against pMHC affinity neoepitopes showed potential for improving PD-1 immunotherapy. Future interventions may consider expanding low avidity populations via vaccination or adoptive transfer.
Topics: Humans; Adoptive Transfer; Apoptosis; CD8-Positive T-Lymphocytes; Neoplasms; Receptors, Antigen, T-Cell; Immunotherapy
PubMed: 37586767
DOI: 10.1136/jitc-2023-007114 -
Best Practice & Research. Clinical... Sep 2023Donor lymphocyte infusion (DLI) is an important treatment modality in the management of relapsed hematological malignancies after allogeneic hematopoietic cell... (Review)
Review
Donor lymphocyte infusion (DLI) is an important treatment modality in the management of relapsed hematological malignancies after allogeneic hematopoietic cell transplantation (allo-HCT). Donor T lymphocytes can be used in a therapeutic, pre-emptive or prophylactic manner in an attempt to stimulate a graft versus leukemia (GVL) effect and eradicate residual disease or even prevent relapse in a high-risk setting. DLIs are not without complications, however, graft versus host disease (GVHD) in particular. Data to date is limited to retrospective and small prospective studies. This review summarizes the available literature on approaches to managing relapse, dosing and timing of DLI, complications and potential future therapies.
Topics: Humans; Prospective Studies; Retrospective Studies; Immunotherapy, Adoptive; Leukemia, Myeloid, Acute; Lymphocytes
PubMed: 37612002
DOI: 10.1016/j.beha.2023.101484