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ImmunoTargets and Therapy 2024Medulloblastoma (MB) is the most prevalent paediatric brain tumour. Despite improvements in patient survival with current treatment strategies, the quality of life of...
PURPOSE
Medulloblastoma (MB) is the most prevalent paediatric brain tumour. Despite improvements in patient survival with current treatment strategies, the quality of life of these patients remains poor owing to the sequelae and relapse risk. An alternative, or, in addition to the current standard treatment, could be considered immunotherapy, such as Natural Killer cells (NK). NK cells are cytotoxic innate lymphoid cells that play a major role in cancer immunosurveillance. To date, the mechanism of cytotoxicity of NK cells, especially regarding the steps of adhesion, conjugation, cytotoxic granule polarisation in the cell contact area, perforin and granzyme release in two and three dimensions, and therapeutic efficacy in vivo have not been precisely described.
MATERIALS AND METHODS
Each step of NK cytotoxicity against the three MB cell lines was explored using confocal microscopy for conjugation, Elispot for degranulation, flow cytometry, and luminescence assays for target cell necrosis and lysis and mediators released by cytokine array, and then confirmed in a 3D spheroid model. Medulloblastoma-xenografted mice were treated with NK cells. Their persistence was evaluated by flow cytometry, and their efficacy in tumour growth and survival was determined. In addition, their effects on the tumour transcriptome were evaluated.
RESULTS
NK cells showed variable affinities for conjugation with MB target cells depending on their subgroup and cytokine activation. Chemokines secreted during NK and MB cell co-culture are mainly associated with angiogenesis and immune cell recruitment. NK cell cytotoxicity induces MB cell death in both 2D and 3D co-culture models. NK cells initiated an inflammatory response in a human MB murine model by modulating the MB cell transcriptome.
CONCLUSION
Our study confirmed that NK cells possess both in vitro and in vivo cytotoxic activity against MB cells and are of interest for the development of immunotherapy.
PubMed: 38948503
DOI: 10.2147/ITT.S458278 -
Frontiers in Immunology 2024The Suppressor of Cytokine Signaling (SOCS) family proteins are important negative regulators of cytokine signaling. SOCS1 is the prototypical member of the SOCS family... (Review)
Review
The Suppressor of Cytokine Signaling (SOCS) family proteins are important negative regulators of cytokine signaling. SOCS1 is the prototypical member of the SOCS family and functions in a classic negative-feedback loop to inhibit signaling in response to interferon, interleukin-12 and interleukin-2 family cytokines. These cytokines have a critical role in orchestrating our immune defence against viral pathogens and cancer. The ability of SOCS1 to limit cytokine signaling positions it as an important immune checkpoint, as evidenced by the detection of detrimental variants in patients with cytokine-driven inflammatory and autoimmune disease. SOCS1 has also emerged as a key checkpoint that restricts anti-tumor immunity, playing both a tumor intrinsic role and impacting the ability of various immune cells to mount an effective anti-tumor response. In this review, we describe the mechanism of SOCS1 action, focusing on the role of SOCS1 in autoimmunity and cancer, and discuss the potential for new SOCS1-directed cancer therapies that could be used to enhance adoptive immunotherapy and immune checkpoint blockade.
Topics: Humans; Suppressor of Cytokine Signaling 1 Protein; Neoplasms; Homeostasis; Inflammation; Animals; Signal Transduction; Autoimmunity; Cytokines
PubMed: 38947335
DOI: 10.3389/fimmu.2024.1419951 -
Frontiers in Immunology 2024Lymphodepleting chemotherapy (LDC) is critical to CAR T-cell expansion and efficacy. Despite this, there is not a consensus in the literature regarding the optimal LDC... (Comparative Study)
Comparative Study
INTRODUCTION
Lymphodepleting chemotherapy (LDC) is critical to CAR T-cell expansion and efficacy. Despite this, there is not a consensus in the literature regarding the optimal LDC regimen, including dose and frequency.
METHODS
We retrospectively reviewed consecutive patients at a single institution that received LDC prior to treatment with the CD19 directed CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel. Patients treated at our center received fludarabine 30 mg/m and cyclophosphamide 500 mg/m for 3 consecutive days prior to May 2019. After this timepoint patients routinely received fludarabine 40 mg/m and cyclophosphamide 500 mg/m for 2 consecutive days. Clinical data from each cohort were obtained from the electronic medical record and compared for differences in CAR T-cell efficacy and toxicity.
RESULTS
From June 2018 to August 2023, LDC was given to 92 patients prior to CD19 directed CAR T-cell therapy for relapsed non-Hodgkin's lymphoma. Twenty-eight patients received a 3-day regimen, and 64 patients received a 2-day regimen. In the total cohort, 75% of patients received axicabtagene ciloleucel and 25% received tisagenlecleucel. The overall response rates in both the 2-day regimen group and the 3-day regimen group were similar (69% vs 75%, p= 0.21) as were the complete response rates (50% vs 54%, p=0.82). There were no significant differences between the 2-day and 3-day regimens for grade 2-4 cytokine release syndrome (55% vs 50%, p=0.82), grade 2-4 immune effector cell associated-neurotoxicity syndrome (42% vs 29%, p=0.25), or time to resolution of neutropenia or thrombocytopenia. The rate of prolonged platelet recovery lasting greater than 60 days was higher with the 3-day regimen (9% vs 27%, p=0.026).
DISCUSSION
As the number of patients eligible for CAR T-cell therapy continues to increase, optimizing each component of therapy is necessary. We show that a 2-day regimen of LDC with fludarabine and cyclophosphamide is feasible without significant impact on CAR T-cell efficacy or toxicity. Prospective studies are necessary to further determine the most effective LDC regimen.
Topics: Humans; Immunotherapy, Adoptive; Male; Middle Aged; Female; Antigens, CD19; Vidarabine; Retrospective Studies; Lymphoma, Non-Hodgkin; Aged; Cyclophosphamide; Adult; Lymphocyte Depletion; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Receptors, Antigen, T-Cell
PubMed: 38947326
DOI: 10.3389/fimmu.2024.1403145 -
Internal Medicine (Tokyo, Japan) 2024Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The...
Activated CD4 T Cell Proportion in the Peripheral Blood Correlates with the Duration of Cytokine Release Syndrome and Predicts Clinical Outcome after Chimeric Antigen Receptor T Cell Therapy.
Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The characteristic toxicities of CAR T cell therapy include cytokine release syndrome (CRS) and prolonged cytopenia. We investigated the factors associated with these complications after CAR T cell therapy by analyzing lymphocyte subsets following CAR T cell infusion. Methods We retrospectively analyzed peripheral blood samples on days 7, 14, and 28 after tisagenlecleucel (tisa-cel) infusion by flow cytometry at our institution between June 2020 and September 2022. Patients Thirty-five patients with R/R DLBCL who received tisa-cel therapy were included. Results A flow cytometry-based analysis of blood samples from these patients revealed that the proportion of CD4CD25CD127 T cells (hereafter referred to as "activated CD4 T cells" ) among the total CD4 T cells on day 7 after tisa-cel infusion correlated with the duration of CRS (r=0.79, p<0.01). In addition, a prognostic analysis of the overall survival (OS) using time-dependent receiver operating characteristic curves indicated a significantly more favorable OS and progression-free survival of patients with a proportion of activated CD4 T cells among the total CD4 T cells <0.73 (p=0.01, and p<0.01, respectively). Conclusion These results suggest that the proportion of activated CD4 T cells on day 7 after tisa-cel infusion correlates with the CRS duration and predicts clinical outcomes after CAR T cell therapy. Further studies with a larger number of patients are required to validate these observations.
Topics: Humans; Male; Female; Cytokine Release Syndrome; Immunotherapy, Adoptive; Middle Aged; Lymphoma, Large B-Cell, Diffuse; Aged; Retrospective Studies; CD4-Positive T-Lymphocytes; Adult; Treatment Outcome; Receptors, Chimeric Antigen; Prognosis; Receptors, Antigen, T-Cell
PubMed: 38945932
DOI: 10.2169/internalmedicine.2556-23 -
Journal For Immunotherapy of Cancer Jun 2024How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown.
BACKGROUND
How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown.
METHODS
CD4 T cells with a transgenic T-cell receptor that recognize tyrosinase-related peptide (TRP)-1 melanoma antigen were polarized to the T helper 17 (Th17) phenotype and then transferred into melanoma-bearing mice preconditioned with either total body irradiation or chemotherapy.
RESULTS
We found that preconditioning mice with a non-myeloablative dose of total body irradiation (TBI of 5 Gy) was more effective than using an equivalently dosed non-myeloablative chemotherapy (cyclophosphamide (CTX) of 200 mg/kg) at augmenting therapeutic activity of antitumor TRP-1 Th17 cells. Antitumor Th17 cells engrafted better following preconditioning with TBI and regressed large established melanoma in all animals. Conversely, only half of mice survived long-term when preconditioned with CTX and infused with anti-melanoma Th17 cells. Interleukin (IL)-17 and interferon-γ, produced by the infused Th17 cells, were detected in animals given either TBI or CTX preconditioning. Interestingly, inflammatory cytokines (granulocyte colony stimulating factor, IL-6, monocyte chemoattractant protein-1, IL-5, and keratinocyte chemoattractant) were significantly elevated in the serum of mice preconditioned with TBI versus CTX after Th17 therapy. The addition of fludarabine (FLU, 200 mg/kg) to CTX (200 mg/kg) improved the antitumor response to the same degree mediated by TBI, whereas FLU alone with Th17 therapy was ineffective.
CONCLUSIONS
Our results indicate, for the first time, that the antitumor response, persistence, and cytokine profiles resulting from Th17 therapy are impacted by the specific regimen of host preconditioning. This work is important for understanding mechanisms that promote long-lived responses by adoptive cellular therapy, particularly as CD4 based T-cell therapies are now emerging in the clinic.
Topics: Animals; Th17 Cells; Mice; Mice, Inbred C57BL; Immunotherapy, Adoptive; Whole-Body Irradiation; Melanoma, Experimental; Cyclophosphamide; Adoptive Transfer; Female; Melanoma
PubMed: 38945552
DOI: 10.1136/jitc-2023-008715 -
Molecular Therapy : the Journal of the... Jun 2024NK cells eliminate infected or cancer cells via their cytotoxic capacity. NKG2A is an inhibitory receptor on NK cells and cancer cells often overexpress its ligand HLA-E...
NK cells eliminate infected or cancer cells via their cytotoxic capacity. NKG2A is an inhibitory receptor on NK cells and cancer cells often overexpress its ligand HLA-E to evade NK cell surveillance. Given the successes of immune checkpoint blockade in cancer therapy, NKG2A is an interesting novel target. However, anti-NKG2A antibodies have shown limited clinical response. In the pursuit of enhancing NK cell-mediated anti-tumor responses, we devised a Cas9-based strategy to delete KLRC1, encoding NKG2A, in human primary NK cells. Our approach involved electroporation of KLRC1-targeting Cas9-ribonucleoprotein resulting in effective ablation of NKG2A expression. Compared to anti-NKG2A antibody blockade, NKG2A-knockout NK cells exhibited enhanced activation, reduced suppressive signaling, and elevated expression of key transcription factors. NKG2A-deficient NK cells overcame inhibition from HLA-E, significantly boosting NK cell activity against solid and hematologic cancer cells. We validated this efficacy across multiple cell lines, a xenograft mouse model, and primary human leukemic cells. Combining NKG2A knockout with antibody-coating of tumor cells further enhanced cytotoxicity through ADCC. Thus, we provide a comprehensive comparison of inhibition of the NKG2A pathway using genetic ablation and antibodies and provide novel insight in the observed differences molecular mechanisms, which can be translated to enhance adoptive NK cell immunotherapy.
PubMed: 38943249
DOI: 10.1016/j.ymthe.2024.06.034 -
Journal of Nanobiotechnology Jun 2024Lipid nanoparticles (LNPs) have proven themselves as transformative actors in chimeric antigen receptor (CAR) T cell therapy, surpassing traditional methods and... (Review)
Review
Lipid nanoparticles (LNPs) have proven themselves as transformative actors in chimeric antigen receptor (CAR) T cell therapy, surpassing traditional methods and addressing challenges like immunogenicity, reduced toxicity, and improved safety. Promising preclinical results signal a shift toward safer and more effective CAR T cell treatments. Ongoing research aims to validate these findings in clinical trials, marking a new era guided by LNPs utility in CAR therapy. Herein, we explore the preference for LNPs over traditional methods, highlighting the versatility of LNPs and their effective delivery of nucleic acids. Additionally, we address key challenges in clinical considerations, heralding a new era in CAR T cell therapy.
Topics: Nanoparticles; Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Animals; Lipids; T-Lymphocytes; Neoplasms; Liposomes
PubMed: 38943167
DOI: 10.1186/s12951-024-02630-1 -
Medicine Jun 2024Multiple myeloma (MM) with extramedullary disease (EMD) is rare in clinical practice, and B cell maturation antigen (BCMA) CAR-T cell therapy is a novel therapy for... (Review)
Review
INTRODUCTION
Multiple myeloma (MM) with extramedullary disease (EMD) is rare in clinical practice, and B cell maturation antigen (BCMA) CAR-T cell therapy is a novel therapy for hematologic malignancies. Very few reports have been published on the effect of CAR-T-cell therapy in MM with EMD. Here, we report a case of MM with extramedullary lesions treated with BCMA CAR-T therapy.
CASE PRESENTATION
A 66-year-old female patient presented to our hospital with an enlarged left maxillary gingiva.
DIAGNOSIS
Diagnosis of indolent MM stage III (DS staging) and stage III (ISS and R ISS) with extramedullary lesions.
INTERVENTION
The patient underwent a clinical trial of humanized anti-BCMA CAR T cell therapy.
RESULTS
Symptoms improved; left gingival hyperplasia and swelling resolved; left buccal mass resolved; and neck and submandibular masses resolved. Pathological examination of the exfoliated masses showed necrotic tissue.
CONCLUSION
MM with extramedullary lesions often has limited treatment options, and traditional chemotherapy methods are ineffective; however, BCMA CAR-T cell therapy can significantly improve the symptoms of extramedullary lesions in MM.
Topics: Humans; Multiple Myeloma; Female; Aged; B-Cell Maturation Antigen; Immunotherapy, Adoptive
PubMed: 38941416
DOI: 10.1097/MD.0000000000038541 -
Emerging Microbes & Infections Dec 2024Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral...
Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (= 0.048) and 96 (= 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010-37.377; = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770). ClinicalTrials.gov identifier: NCT04098770. ClinicalTrials.gov identifier: NCT02651376.
Topics: Humans; Male; Female; Adult; Middle Aged; Immunotherapy, Adoptive; Immunocompromised Host; HLA Antigens; Acquired Immunodeficiency Syndrome; Treatment Outcome; AIDS-Related Opportunistic Infections; Transplantation, Homologous; CD4-Positive T-Lymphocytes; CD4 Lymphocyte Count
PubMed: 38935839
DOI: 10.1080/22221751.2024.2364744 -
Frontiers in Immunology 2024Triple-negative breast cancer (TNBC) is a subtype of breast cancer that presents significant therapeutic challenges due to the absence of estrogen receptor (ER),... (Review)
Review
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that presents significant therapeutic challenges due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. As a result, conventional hormonal and targeted therapies are largely ineffective, underscoring the urgent need for novel treatment strategies. γδT cells, known for their robust anti-tumor properties, show considerable potential in TNBC treatment as they can identify and eliminate tumor cells without reliance on MHC restrictions. These cells demonstrate extensive proliferation both and , and can directly target tumors through cytotoxic effects or indirectly by promoting other immune responses. Studies suggest that expansion and adoptive transfer strategies targeting Vδ2 and Vδ1 γδT cell subtypes have shown promise in preclinical TNBC models. This review compiles and discusses the existing literature on the primary subgroups of γδT cells, their roles in cancer therapy, their contributions to tumor cell cytotoxicity and immune modulation, and proposes potential strategies for future γδT cell-based immunotherapies in TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Animals; Female; Receptors, Antigen, T-Cell, gamma-delta; Intraepithelial Lymphocytes; Immunotherapy, Adoptive; Immunotherapy
PubMed: 38933280
DOI: 10.3389/fimmu.2024.1420107