RESUMO
The development of artificial Antigen Presenting Cells (aAPCs) has led to improvements in adoptive T cell therapy (ACT), an immunotherapy, for cancer treatment. aAPCs help to streamline the consistent production and expansion of T cells, thus reducing the time and costs associated with ACT. However, several issues still exist with ACT, such as insufficient T cell potency, which diminishes the translational potential for ACT. While aAPCs have been used primarily to increase production efficiency of T cells for ACT, the intrinsic properties of a biomaterial-based aAPC may affect T cell phenotype and function. In CD8+ T cells, reactive oxygen species (ROS) and oxidative stress accumulation can activate Forkhead box protein O1 (FOXO1) to transcribe antioxidants which reduce ROS and improve memory formation. Alginate, a biocompatible and antioxidant rich biomaterial, is promising for incorporation into an aAPC formulation to modulate T cell phenotype. To investigate its utility, a novel alginate-based aAPC platform was developed that preferentially expanded CD8+ T cells with memory related features. Alginate-based aAPCs allowed for greater control of CD8+ T cell qualities, including, significantly improved in vivo persistence and augmented in vivo anti-tumor T cell responses.
Assuntos
Alginatos , Células Apresentadoras de Antígenos , Linfócitos T CD8-Positivos , Memória Imunológica , Imunoterapia Adotiva , Alginatos/química , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Animais , Imunoterapia Adotiva/métodos , Células Apresentadoras de Antígenos/imunologia , Memória Imunológica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Humanos , Proliferação de Células/efeitos dos fármacosRESUMO
The incidence of Acute myeloid leukemia (AML) increases with advancing age, and the prognosis for elderly patients is significantly poorer compared to younger patients. Although the combination therapy of venetoclax and hypomethylating agents has demonstrated improved prognosis in patients unable to tolerate intensive chemotherapy, there remains a therapeutic blank for those who fail to achieve remission with current treatment regimens. Here, we report the successful clinical utilization of autogenous CLL1 CAR-T therapy combined with hematopoietic stem cell transplantation in a 73-year-old patient diagnosed with refractory AML. The patient achieved morphological complete remission (CR) with incomplete marrow recovery and a slight presence of minimal residual disease (MRD) after receiving CLL1 CAR-T therapy. To further enhance the treatment and promote the recovery of hemopoiesis, we performed bridged allogenic hematopoietic stem cell transplantation (allo-HSCT) 20 days after the infusion of CLL1 CAR-T cells. The patient achieved MRD-negative CR following HSCT treatment. His primary disease maintained a complete remission status during the 11-month follow-up period. The patient encountered grade 2 cytokine release syndrome and grade 4 granulocytopenia subsequent to the infusion of CAR-T cells, while several rounds of infection and graft-versus-host disease were observed following allo-HSCT. Nevertheless, all these concerns were successfully addressed through comprehensive provision of supportive treatments. We have successfully demonstrated a highly effective and safe combination strategy involving CLL1 CAR-T therapy and allo-HSCT, which has exhibited remarkable tolerability and holds great promise even for elderly patients with AML.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Leucemia Mieloide Aguda , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Idoso , Masculino , Leucemia Mieloide Aguda/terapia , Imunoterapia Adotiva/métodos , Terapia Combinada , Resultado do Tratamento , Indução de RemissãoRESUMO
Immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 antibodies have been the three mainstays of myeloma treatment. B-cell maturation antigen (BCMA)-targeted immunotherapy, including chimeric antigen receptor T-cell therapy (CAR-T) and bispecific antibodies (BsAbs), is emerging as another important class of treatment. Two BCMA-targeting CAR-T products, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel, are approved in Japan, but only ide-cel is available for clinical use. Recently, a randomized phase III study comparing ide-cel with standard therapy in patients with refractory myeloma who had received 2 to 4 prior lines of therapy showed that ide-cel was superior in terms of both response rate and PFS. Based on these results, ide-cel was approved as a third-line therapy. The new availability of bispecific antibodies has also raised new clinical questions regarding how to use CAR-T and BsAbs for each patient, and in what order. Limited data have suggested that favorable responses can be achieved when BsAbs are administered after CAR-T, but responses are suboptimal when CAR-T is administered after BsAbs. Finally, it is important to note that coordination between referring centers and treating centers, including aspects such as timing of patient referral, bridging therapy, and long-term follow-up after CAR-T, is critical to optimization of CAR-T.
Assuntos
Imunoterapia Adotiva , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Encaminhamento e Consulta , Receptores de Antígenos Quiméricos/imunologia , Antígeno de Maturação de Linfócitos B/imunologiaRESUMO
Chimeric antigen receptor (CAR) T-cell therapy is an innovative treatment for B-cell malignancies and multiple myeloma. CAR T-cell therapy is now approved in Japan and has become one of the essential therapeutic options for chemotherapy-resistant disease. It has many unique features that distinguish it from conventional chemotherapies, including the limitations imposed by the production of CAR-T cells from autologous T cells, and the limited availability and mandatory waiting period for treatment. Importantly, each patient has only one opportunity to receive CAR T-cell therapy. To achieve the maximum therapeutic benefit from CAR T-cell therapy, it is necessary to understand all aspects of CAR T-cell therapy, including factors that influence its efficacy. The design of the entire treatment sequence, including before and after CAR T-cell therapy, is also important to optimize clinical outcomes. In addition, since this treatment is only available at a limited number of facilities, effective coordination between local hospitals and treatment centers is also important. This educational session will focus on the practical aspects of CAR T-cell therapy in adults and will provide indispensable knowledge for providing CAR T-cell therapy to patients with B-cell lymphoma and multiple myeloma.
Assuntos
Imunoterapia Adotiva , Humanos , Adulto , Mieloma Múltiplo/terapia , Mieloma Múltiplo/imunologia , Receptores de Antígenos Quiméricos/imunologia , Guias de Prática Clínica como Assunto , Receptores de Antígenos de Linfócitos T , Linfócitos T/imunologiaRESUMO
Tisagenlecleucel, a commercially available CD19-targeted CAR-T cell product, has dramatically changed the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Tisagenlecleucel infusion has been linked to distinct acute adverse events, including cytokine release syndrome, neurotoxicity, hemophagocytic lymphohistiocytosis and prolonged pancytopenia, which are rare with cytocidal chemotherapy. In addition, recent retrospective studies have revealed pre-infusion prognostic factors including high tumor burden (bone marrow leukemia cell fraction ≥5%) and non-response to blinatumomab, another CD19-targeting agent. Not only physicians providing CAR-T cell therapy but also those referring patients for this therapy should thoroughly understand the indications and limitations, characteristic acute complications, pre-treatment factors affecting prognosis, and late complications. This article outlines the current understanding regarding the use of tisagenlecleucel in children and adolescents with B-ALL.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Criança , Adolescente , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos TRESUMO
Over the years, CAR-T cell therapy has achieved remarkable success in treating hematological malignancies. However, this efficacy has not been replicated in the context of glioblastoma (GBM). In this study, a PD1CD28 chimeric molecule was introduced into EGFRvâ ¢-directed CAR-T cells, generating EGFRvâ ¢-P2A-PD1CD28 CAR-T cells. Notably, this modification significantly increased IL-2 secretion and enhanced antigen-dependent activation of CAR-T cells, especially when programmed cell death ligand 1 (PD-L1) was present in vitro. In addition, the in vivo xenograft experiments revealed that the PD1CD28 chimeric molecule played a pivotal role in reducing recurrence rates, effectively controlling recurrent tumor volume, and ultimately prolonging the survival of mice. Collectively, these findings suggest that EGFRvâ ¢-directed CAR-T cells co-expressing the PD1CD28 chimeric molecule have the potential to significantly enhance the treatment efficacy against GBM.
Assuntos
Antígeno B7-H1 , Receptores ErbB , Glioblastoma , Imunoterapia Adotiva , Receptor de Morte Celular Programada 1 , Receptores de Antígenos Quiméricos , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Humanos , Camundongos , Glioblastoma/terapia , Glioblastoma/imunologia , Imunoterapia Adotiva/métodos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores ErbB/metabolismo , Receptores ErbB/imunologia , Linhagem Celular Tumoral , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Interleucina-2/metabolismoRESUMO
BACKGROUND: Tumor-reactive T cells play a crucial role in anti-tumor responses, but T cells induced by DNA vaccination are time-consuming processes and exhibit limited anti-tumor efficacy. Therefore, we evaluated the anti-tumor effectiveness of reactive T cells elicited by electroporation (EP)-mediated DNA vaccine targeting epidermal growth factor receptor variant III (pEGFRvIII plasmid), in conjunction with adoptive cell therapy (ACT), involving the transfer of lymphocytes from a pEGFRvIII EP-vaccinated healthy donor. METHODS: The validation of the established pEGFRvIII plasmid and EGFRvIII-positive cell model was confirmed through immunofluorescence and western blot analysis. Flow cytometry and cytotoxicity assays were performed to evaluate the functionality of antigen-specific reactive T cells induced by EP-mediated pEGFRvIII vaccines, ACT, or their combination. The anti-tumor effectiveness of EP-mediated pEGFRvIII vaccines alone or combined with ACT was evaluated in the B16F10-EGFRvIII tumor model. RESULTS: EP-mediated pEGFRvIII vaccines elicited serum antibodies and a robust cellular immune response in both healthy and tumor-bearing mice. However, this response only marginally inhibited early-stage tumor growth in established tumor models. EP-mediated pEGFRvIII vaccination followed by adoptive transfer of lymphocytes from vaccinated healthy donors led to notable anti-tumor efficacy, attributed to the synergistic action of antigen-specific CD4+ Th1 cells supplemented by ACT and antigen-specific CD8+ T cells elicited by the EP-mediated DNA vaccination. CONCLUSIONS: Our preclinical studies results demonstrate an enhanced anti-tumor efficacy of EP-mediated DNA vaccination boosted with adoptively transferred, vaccinated healthy donor-derived allogeneic lymphocytes.
Assuntos
Vacinas Anticâncer , Eletroporação , Vacinas de DNA , Animais , Vacinas de DNA/imunologia , Eletroporação/métodos , Camundongos , Vacinas Anticâncer/imunologia , Camundongos Endogâmicos C57BL , Imunoterapia Adotiva/métodos , Feminino , Humanos , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Modelos Animais de Doenças , Linhagem Celular Tumoral , Células Alógenas/imunologia , Receptores ErbB/imunologiaRESUMO
Natural killer (NK) cells are frontline defenders against cancer and are capable of recognizing and eliminating tumor cells without prior sensitization or antigen presentation. Due to their unique HLA mismatch tolerance, they are ideal for adoptive cell therapy (ACT) because of their ability to minimize graft-versus-host-disease risk. The therapeutic efficacy of NK cells is limited in part by inhibitory immune checkpoint receptors, which are upregulated upon interaction with cancer cells and the tumor microenvironment. Overexpression of inhibitory receptors reduces NK cell-mediated cytotoxicity by impairing the ability of NK cells to secrete effector cytokines and cytotoxic granules. T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), a well-known checkpoint receptor involved in T-cell exhaustion, has recently been implicated in the exhaustion of NK cells. Overcoming TIGIT-mediated inhibition of NK cells may allow for a more potent antitumor response following ACT. Here, we describe a novel approach to TIGIT inhibition using self-delivering RNAi compounds (INTASYL™) that incorporates the features of RNAi and antisense technology. INTASYL compounds demonstrate potent activity and stability, are rapidly and efficiently taken up by cells, and can be easily incorporated into cell product manufacturing. INTASYL PH-804, which targets TIGIT, suppresses TIGIT mRNA and protein expression in NK cells, resulting in increased cytotoxic capacity and enhanced tumor cell killing in vitro. Delivering PH-804 to NK cells before ACT has emerged as a promising strategy to counter TIGIT inhibition, thereby improving the antitumor response. This approach offers the potential for more potent off-the-shelf products for adoptive cell therapy, particularly for hematological malignancies.
Assuntos
Imunoterapia Adotiva , Células Matadoras Naturais , Neoplasias , Receptores Imunológicos , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Receptores Imunológicos/imunologia , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Neoplasias/imunologia , Citotoxicidade Imunológica , Interferência de RNA , Linhagem Celular Tumoral , RNA Interferente Pequeno/genéticaRESUMO
BACKGROUND: Lung cancer brain metastasis has a devastating prognosis, necessitating innovative treatment strategies. While chimeric antigen receptor (CAR) T-cell show promise in hematologic malignancies, their efficacy in solid tumors, including brain metastasis, is limited by the immunosuppressive tumor environment. The PD-L1/PD-1 pathway inhibits CAR T-cell activity in the tumor microenvironment, presenting a potential target to enhance therapeutic efficacy. This study aims to evaluate the impact of anti-PD-1 antibodies on CAR T-cell in treating lung cancer brain metastasis. METHODS: We utilized a murine immunocompetent, syngeneic orthotopic cerebral metastasis model for repetitive intracerebral two-photon laser scanning microscopy, enabling in vivo characterization of red fluorescent tumor cells and CAR T-cell at a single-cell level over time. Red fluorescent EpCAM-transduced Lewis lung carcinoma cells (EpCAM/tdtLL/2 cells) were implanted intracranially. Following the formation of brain metastasis, EpCAM-directed CAR T-cell were injected into adjacent brain tissue, and animals received either anti-PD-1 or an isotype control. RESULTS: Compared to controls receiving T-cell lacking a CAR, mice receiving EpCAM-directed CAR T-cell showed higher intratumoral CAR T-cell densities in the beginning after intraparenchymal injection. This finding was accompanied with reduced tumor growth and translated into a survival benefit. Additional anti-PD-1 treatment, however, did not affect intratumoral CAR T-cell persistence nor tumor growth and thereby did not provide an additional therapeutic effect. CONCLUSION: CAR T-cell therapy for brain malignancies appears promising. However, additional anti-PD-1 treatment did not enhance intratumoral CAR T-cell persistence or effector function, highlighting the need for novel strategies to improve CAR T-cell therapy in solid tumors.
Assuntos
Neoplasias Encefálicas , Molécula de Adesão da Célula Epitelial , Imunoterapia Adotiva , Neoplasias Pulmonares , Receptor de Morte Celular Programada 1 , Receptores de Antígenos Quiméricos , Animais , Camundongos , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Imunoterapia Adotiva/métodos , Molécula de Adesão da Célula Epitelial/imunologia , Molécula de Adesão da Célula Epitelial/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/terapia , Carcinoma Pulmonar de Lewis/patologia , Feminino , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/imunologiaRESUMO
BACKGROUNDS: The incidence of extramedullary diseases (EMDs) in patients diagnosed with acute myeloid leukemia (AML) is approximately 10-20%. These patients exhibit a significantly distinct etiology, therapeutic response, and prognosis compared to patients without EMDs. CLL1 CAR-T therapy has been demonstrated satisfactory efficacy and safety in the treatment of refractory and relapsed AML patients. However, concerns have been raised regarding the potential impact of extramedullary niduses on the effectiveness of CLL1 CAR-T therapy. METHODS: A total of 47 patients were enrolled in this study, including 27 patients with isolated AML tumor bone marrow infiltration and 20 patients with both extramedullary and bone marrow infiltration of AML. CLL1 CAR-T cells were manufactured and subjected to rigorous quality control in the hematology laboratory of Tianjin First Central Hospital. The efficacy and adverse reactions were assessed following CAR-T cell infusion, while expansion of CAR-T cells, levels of cytokines releasing, and other indicators were closely monitored. RESULTS: Among the 20 patients with EMDs and the 27 individuals without EMDs, complete remission in bone marrow was achieved by 65.00% and 81.48% of patients, respectively. Meanwhile, among the patients with EMDs, 55.00% achieved complete remission while 10.00% achieved partial remission when assessing the efficacy of CLL1 CAR-T cells against extramedullary niduses. Although the overall survival, progression-free survival, and duration of remission period appeared to be shorter for patients with EMDs compared to those without EMDs, this difference did not reach statistical significance. The incidence rates of complications were comparable between both groups. Meanwhile, there were no significant differences observed in the levels of CAR-T cell expansion and accompanying cytokines release between patients with and without EMDs. CONCLUSIONS: Our study findings have demonstrated the efficacy of CLL1 CAR-T therapy in the treatment of AML patients with EMDs, while also indicating manageable occurrence rates of complications within a tolerable range. The CLL1 CAR-T therapy, serving as an ideal strategy for AML patients irrespective of the presence of EMDs, effectively ameliorates the conditions of AML patients and provides them with an opportunity to undergo curative hematopoietic stem cell transplantation while significantly enhancing their prognosis.
Assuntos
Imunoterapia Adotiva , Leucemia Mieloide Aguda , Humanos , Masculino , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patologia , Feminino , Pessoa de Meia-Idade , Adulto , Imunoterapia Adotiva/efeitos adversos , Resultado do Tratamento , Idoso , Adulto Jovem , Medula Óssea/patologia , Receptores de Antígenos Quiméricos , AdolescenteRESUMO
Cancers eventually kill hosts even when infiltrated by cancer-specific T cells. We examined whether cancer-specific T cell receptors of CD4+ T cells (CD4TCRs) from tumor-bearing hosts can be exploited for adoptive TCR therapy. We focused on CD4TCRs targeting an autochthonous mutant neoantigen that is only presented by stroma surrounding the MHC class II-negative cancer cells. The 11 most common tetramer-sorted CD4TCRs were tested using TCR-engineered CD4+ T cells. Three TCRs were characterized by convergent recombination for which multiple T cell clonotypes differed in their nucleotide sequences but encoded identical TCR α and ß chains. These preferentially selected TCRs destroyed tumors equally well and halted progression through reprogramming of the tumor stroma. TCRs represented by single T cell clonotypes were similarly effective only if they shared CDR elements with preferentially selected TCRs in both α and ß chains. Selecting candidate TCRs on the basis of these characteristics can help identify TCRs that are potentially therapeutically effective.
Assuntos
Linfócitos T CD4-Positivos , Imunoterapia Adotiva , Linfócitos T CD4-Positivos/imunologia , Animais , Imunoterapia Adotiva/métodos , Camundongos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/genética , Camundongos Endogâmicos C57BL , Humanos , Camundongos Transgênicos , Feminino , Recombinação Genética/imunologiaRESUMO
Natural Killer (NK) cells are exciting candidates for cancer immunotherapy with potent innate cytotoxicity and distinct advantages over T cells for Chimeric Antigen Receptor (CAR) therapy. Concerns regarding the safety, cost, and scalability of viral vectors has ignited research into non-viral alternatives for gene delivery. This review comprehensively analyses recent advancements and challenges with non-viral genetic modification of NK cells for allogeneic CAR-NK therapies. Non-viral alternatives including electroporation and multifunctional nanoparticles are interrogated with respect to CAR expression and translational responses. Crucially, the link between NK cell biology and design of drug delivery technologies are made, which is essential for development of future non-viral approaches. This review provides valuable insights into the current state of non-viral CAR-NK cell engineering, aimed at realising the full potential of NK cell-based immunotherapies.
Assuntos
Engenharia Celular , Técnicas de Transferência de Genes , Imunoterapia Adotiva , Células Matadoras Naturais , Receptores de Antígenos Quiméricos , Células Matadoras Naturais/imunologia , Humanos , Receptores de Antígenos Quiméricos/genética , Animais , Imunoterapia Adotiva/métodos , Engenharia Celular/métodos , Nanopartículas/química , Neoplasias/terapia , Neoplasias/imunologia , Eletroporação/métodos , Imunoterapia/métodosRESUMO
Malignant tumors of the hematologic system have a high degree of malignancy and high mortality rates. Chimeric antigen receptor T cell (CAR-T) therapy has become an important option for patients with relapsed/refractory tumors, showing astonishing therapeutic effects and thus, it has brought new hope to the treatment of malignant tumors of the hematologic system. Despite the significant therapeutic effects of CAR-T, its toxic reactions, such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), cannot be ignored since they can cause damage to multiple systems, including the cardiovascular system. We summarize biomarkers related to prediction, diagnosis, therapeutic efficacy, and prognosis, further exploring potential monitoring indicators for toxicity prevention. This review aims to summarize the effects of CAR-T therapy on the cardiovascular, hematologic, and nervous systems, as well as potential biomarkers, and to explore potential monitoring indicators for preventing toxicity, thereby providing references for clinical regulation and assessment of therapeutic effects.
Assuntos
Síndrome da Liberação de Citocina , Imunoterapia Adotiva , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Síndrome da Liberação de Citocina/prevenção & controle , Síndrome da Liberação de Citocina/etiologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Biomarcadores , Animais , Receptores de Antígenos Quiméricos/imunologia , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/imunologia , Neoplasias/terapia , Neoplasias/imunologiaRESUMO
Gamma/delta T (γδ T)cells possess a unique mechanism for killing tumors, making them highly promising and distinguished among various cell therapies for tumor treatment. This review focuses on the major histocompatibility complex (MHC)-independent recognition of antigens and the interaction between γδ T cells and solid tumor cells. A comprehensive review is provided regarding the classification of human gamma-delta T cell subtypes, the characteristics and mechanisms underlying their functions, as well as their r545egulatory effects on tumor cells. The involvement of γδ T cells in tumorigenesis and migration was also investigated, encompassing potential therapeutic targets such as apoptosis-related molecules, the TNF receptor superfamily member 6(FAS)/FAS Ligand (FASL) pathways, butyrophilin 3A-butyrophilin 2A1 (BTN3A-BTN2A1) complexes, and interactions with CD4, CD8, and natural killer (NK) cells. Additionally, immune checkpoint inhibitors such as programmed cell death protein 1/Programmed cell death 1 ligand 1 (PD-1/PD-L1) have the potential to augment the cytotoxicity of γδ T cells. Moreover, a review on gamma-delta T cell therapy products and their corresponding clinical trials reveals that chimeric antigen receptor (CAR) gamma-delta T therapy holds promise as an approach with encouraging preclinical outcomes. However, practical issues pertaining to manufacturing and clinical aspects need resolution, and further research is required to investigate the long-term clinical side effects of CAR T cells. In conclusion, more comprehensive studies are necessary to establish standardized treatment protocols aimed at enhancing the quality of life and survival rates among tumor patients utilizing γδ T cell immunotherapy.
Assuntos
Neoplasias , Receptores de Antígenos de Linfócitos T gama-delta , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Animais , Imunoterapia Adotiva/métodos , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Imunoterapia/métodos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genéticaRESUMO
Batroxobin, isolated from Bothrops moojeni, is a defibrinogenating agent used as a thrombin-like serine protease against fibrinogen for improving microcirculation. Here, we investigated whether, and if so, how batroxobin acts in concert with NK cells in terms of anti-tumor effects. CD3+/CD56+ NK cells were isolated and cultured from C57BL/6 mouse spleen. NK cells' viability was tested via Lactate dehydrogenase (LDH) assay. Lewis lung cancer cell (1*107 cell/ml) was used to build animal models. All animals were divided into five groups and treated with Batroxobin and NK cells respectively. HE staining was used to detect the pathological morphology of tumor tissue. The contents of fibrinogen and TNF-α in serum were determined by ELISA. The protein expression levels of MMP2, MMP9, VEGF and CD44 in tumor tissues were detected by Western Blot or immunohistochemistry. Compared with Control group, Tumor growth was not significantly affected in the group treated with Batroxobin or NK cells alone, However, tumor growth was significantly inhibited in the NK cell combined with the Batroxobin group. Serum levels of Fbg and TNF-αin mice treated with Batroxobin combined with NK cells dropped significantly, bringing them closer to normal levels. WB results showed that the expression levels of MMP2/9, VEGF and CD44 in Batroxobin combined with NK cell group also significantly decreased. Batroxobin combined with adoptive immunotherapy with NK cells significantly inhibited the growth of Lewis lung cancer in mice.
Assuntos
Batroxobina , Carcinoma Pulmonar de Lewis , Fibrinogênio , Imunoterapia Adotiva , Células Matadoras Naturais , Neoplasias Pulmonares , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa , Animais , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Carcinoma Pulmonar de Lewis/terapia , Batroxobina/farmacologia , Fibrinogênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptores de Hialuronatos/metabolismo , Linhagem Celular TumoralAssuntos
Antineoplásicos Imunológicos , Imunoterapia Adotiva , Linfoma de Células B , Linfoma de Células T , Segunda Neoplasia Primária , Humanos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Produtos Biológicos/administração & dosagem , Produtos Biológicos/efeitos adversos , Síndrome da Liberação de Citocina/imunologia , Herpesvirus Humano 4/isolamento & purificação , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Linfoma de Células B/virologia , Linfoma de Células T/diagnóstico , Linfoma de Células T/imunologia , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/imunologia , Receptores de Antígenos Quiméricos/imunologia , RiscoAssuntos
Antineoplásicos Imunológicos , Hematopoiese Clonal , Imunoterapia Adotiva , Linfoma de Células B , Linfoma de Células T , Segunda Neoplasia Primária , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Linfoma de Células T/imunologia , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/imunologia , Receptores de Antígenos Quiméricos/imunologia , Risco , Hematopoiese Clonal/genética , Hematopoiese Clonal/imunologia , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Linfoma de Células B/virologia , Herpesvirus Humano 4/isolamento & purificação , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Produtos Biológicos/administração & dosagem , Produtos Biológicos/efeitos adversos , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/imunologiaRESUMO
Tumor-infiltrating lymphocyte (TIL) therapy represents a groundbreaking advancement in the solid cancer treatment, offering new hope to patients and their families with high response rates and long overall survival. TIL therapy involves extracting immune cells from a patient's tumor tissue, expanding them ex vivo, and infusing them back into the patient to target and eliminate cancer cells. This revolutionary approach harnesses the power of the immune system to combat cancers, ushering in a new era of T cell-based therapies along with CAR-T and TCR-therapies. In this comprehensive review, we aim to elucidate the remarkable potential of TIL therapy by delving into recent advancements in basic and clinical researches. We highlight on the evolving landscape of TIL therapy as a prominent immunotherapeutic strategy, its multifaceted applications, and the promising outcomes. Additionally, we explore the future horizons of TIL therapy, next-generation TILs, and combination therapy, to overcome the limitations and improve clinical efficacy of TIL therapy.
Assuntos
Imunoterapia Adotiva , Linfócitos do Interstício Tumoral , Neoplasias , Humanos , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia Adotiva/métodos , Animais , Terapia Combinada/métodosRESUMO
Durable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due to CART cell exhaustion. Here, we investigate the regulation of CART cell exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using an in vitro model for exhaustion, RNA and ATAC sequencing on baseline and exhausted CART cells, and RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the ZUMA-1 clinical trial. Each of these approaches identify interleukin (IL)-4 as a regulator of CART cell dysfunction. Further, IL-4-treated CD8+ CART cells develop signs of exhaustion independently of the presence of CD4+ CART cells. Conversely, IL-4 pathway editing or the combination of CART cells with an IL-4 monoclonal antibody improves antitumor efficacy and reduces signs of CART cell exhaustion in mantle cell lymphoma xenograft mouse models. Therefore, we identify both a role for IL-4 in inducing CART exhaustion and translatable approaches to improve CART cell therapy.
Assuntos
Linfócitos T CD8-Positivos , Interleucina-4 , Humanos , Animais , Interleucina-4/metabolismo , Interleucina-4/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Camundongos Endogâmicos NOD , FemininoRESUMO
While adoptive cell therapy has shown success in hematological malignancies, its potential against solid tumors is hindered by an immunosuppressive tumor microenvironment (TME). In recent years, members of the hypoxia-inducible factor (HIF) family have gained recognition as important regulators of T-cell metabolism and function. The role of HIF signalling in activated CD8 T cell function in the context of adoptive cell transfer, however, has not been explored in full depth. Here we utilize CRISPR-Cas9 technology to delete prolyl hydroxylase domain-containing enzymes (PHD) 2 and 3, thereby stabilizing HIF-1 signalling, in CD8 T cells that have already undergone differentiation and activation, modelling the T cell phenotype utilized in clinical settings. We observe a significant boost in T-cell activation and effector functions following PHD2/3 deletion, which is dependent on HIF-1α, and is accompanied by an increased glycolytic flux. This improvement in CD8 T cell performance translates into an enhancement in tumor response to adoptive T cell therapy in mice, across various tumor models, even including those reported to be extremely resistant to immunotherapeutic interventions. These findings hold promise for advancing CD8 T-cell based therapies and overcoming the immune suppression barriers within challenging tumor microenvironments.