RESUMEN
Using a multimodal approach toward developing a new CD70-targeted Chimeric antigen receptor (CAR) T cell in acute myeloid leukemia, Leick et al.1 report on their synergetic strategy, which incorporates both CAR T cell construct modifications with enhancement of leukemia antigen expression to improve CAR T cell functionality.
Asunto(s)
Ligando CD27 , Inmunoterapia Adoptiva , Leucemia Mieloide Aguda , Receptores Quiméricos de Antígenos , Ligando CD27/genética , Ligando CD27/inmunología , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunologíaRESUMEN
Cyclophosphamide plus fludarabine (C/F) are currently used to improve the expansion and effectiveness of adoptive cell therapy (ACT). However, these chemotherapeutics cause pan-leukopenia and adverse events, suggesting that safer and more effective conditioning treatments are needed to improve ACT outcomes. Previously, we reported that varlilumab, a CD27-targeting antibody, mediates Treg -preferential T cell depletion, CD8-T cell dominant costimulation, and systemic immune activation in hCD27 transgenic mice and cancer patients. We reasoned that the activities induced by varlilumab may provide an effective conditioning regimen for ACT. Varlilumab pretreatment of hCD27 +/+mCD27 - /- mice resulted in prominent proliferation of transferred T cells isolated from wild-type mice. These studies uncovered a critical role for CD27 signaling for the expansion of transferred T cells, as transfer of T cells from CD27 deficient mice or treatment with a CD70 blocking antibody greatly reduced their proliferation. In this model, varlilumab depletes endogenous hCD27+/+ T cells and blocks their subsequent access to CD70, allowing for more CD70 costimulation available to the mCD27 +/+ transferred T cells. CD27-targeted depletion led to a greater expansion of transferred T cells compared to C/F conditioning and resulted in longer median survival and more cures than C/F conditioning in the E.G7 tumor model receiving OT-I cell therapy. We propose that translation of this work could be achieved through engineering of T cells for ACT to abrogate varlilumab binding but preserve CD70 ligation. Thus, varlilumab could be an option to chemotherapy as a conditioning regimen for ACT.
Asunto(s)
Traslado Adoptivo , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales/química , Neoplasias/terapia , Linfocitos T/citología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/química , Animales , Ligando CD27/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Línea Celular Tumoral , Proliferación Celular , Sistema Inmunológico , Inmunoterapia , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neoplasias/metabolismo , Transducción de Señal , Acondicionamiento Pretrasplante , Resultado del TratamientoRESUMEN
Chimeric antigen receptor T-cell (CAR-T) therapy has shown tremendous success in eradicating hematologic malignancies. However, this success has not yet been extrapolated to solid tumors due to the limited infiltration and persistence of CAR-T cells in the tumor microenvironment (TME). In this study, we screened a novel anti-CD70 scFv and generated CD70 CAR-T cells that showed effective antitumor functions against CD70+ renal carcinoma cells (RCCs) both in vitro and in vivo. We further evaluated the effect and explored the molecular mechanism of a PARP inhibitor (PARPi) in CAR-T cell immunotherapy by administering the PARPi to mouse xenografts model derived from human RCC cells. Treatment with the PARPi promoted CAR-T cell infiltration by stimulating a chemokine milieu that promoted CAR-T cell recruitment and the modulation of immunosuppression in the TME. Moreover, our data demonstrate that PARPi modulates the TME by activating the cGAS-STING pathway, thereby altering the balance of immunostimulatory signaling and enabling low-dose CAR-T cell treatment to induce effective tumor regression. These data demonstrate the application of CD70 CAR-T cell therapeutic strategies for RCC and the cross-talk between targeting DNA damage responses and antitumor CAR-T cell therapy. These findings provide insight into the mechanisms of PARPis in CAR-T cell therapy for RCC and suggest a promising adjuvant therapeutic strategy for CAR-T cell therapy in solid tumors.
Asunto(s)
Ligando CD27/antagonistas & inhibidores , Carcinoma de Células Renales/terapia , Inmunoterapia Adoptiva/métodos , Neoplasias Renales/terapia , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Anticuerpos de Cadena Única/uso terapéutico , Animales , Ligando CD27/inmunología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/inmunología , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Humanos , Neoplasias Renales/genética , Neoplasias Renales/inmunología , Proteínas de la Membrana/inmunología , Ratones , Nucleotidiltransferasas/inmunología , Transducción de SeñalRESUMEN
CD27 is a tumor necrosis factor (TNF) receptor, which stimulates lymphocytes and promotes their differentiation upon activation by TNF ligand CD70. Activation of the CD27 receptor provides a costimulatory signal to promote T cell, B cell, and NK cell activity to facilitate antitumor and anti-infection immunity. Aberrant increased and focused expression of CD70 on many tumor cells renders CD70 an attractive therapeutic target for direct tumor killing. However, despite their use as drug targets to treat cancers, the molecular basis and atomic details of CD27 and CD70 interaction remain elusive. Here we report the crystal structure of human CD27 in complex with human CD70. Analysis of our structure shows that CD70 adopts a classical TNF ligand homotrimeric assembly to engage CD27 receptors in a 3:3 stoichiometry. By combining structural and rational mutagenesis data with reported disease-correlated mutations, we identified the key amino acid residues of CD27 and CD70 that control this interaction. We also report increased potency for plate-bound CD70 constructs compared with solution-phase ligand in a functional activity to stimulate T-cells in vitro. These findings offer new mechanistic insight into this critical costimulatory interaction.
Asunto(s)
Ligando CD27/química , Complejos Multiproteicos/química , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/química , Ligando CD27/genética , Ligando CD27/inmunología , Cristalografía por Rayos X , Humanos , Complejos Multiproteicos/genética , Complejos Multiproteicos/inmunología , Estructura Cuaternaria de Proteína , Linfocitos T/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunologíaRESUMEN
The prognosis of patients with acute myeloid leukemia (AML) remains dismal, highlighting the need for novel innovative treatment strategies. The application of chimeric antigen receptor (CAR) T-cell therapy to patients with AML has been limited, in particular by the lack of a tumor-specific target antigen. CD70 is a promising antigen to target AML, as it is expressed on most leukemic blasts, whereas little or no expression is detectable in normal bone marrow samples. To target CD70 on AML cells, we generated a panel of CD70-CAR T cells that contained a common single-chain variable fragment (scFv) for antigen detection, but differed in size and flexibility of the extracellular spacer and in the transmembrane and the costimulatory domains. These CD70scFv CAR T cells were compared with a CAR construct that contained human CD27, the ligand of CD70 fused to the CD3ζ chain (CD27z). The structural composition of the CAR strongly influenced expression levels, viability, expansion, and cytotoxic capacities of CD70scFv-based CAR T cells, but CD27z-CAR T cells demonstrated superior proliferation and antitumor activity in vitro and in vivo, compared with all CD70scFv-CAR T cells. Although CD70-CAR T cells recognized activated virus-specific T cells (VSTs) that expressed CD70, they did not prevent colony formation by normal hematopoietic stem cells. Thus, CD70-targeted immunotherapy is a promising new treatment strategy for patients with CD70-positive AML that does not affect normal hematopoiesis but will require monitoring of virus-specific T-cell responses.
Asunto(s)
Ligando CD27/inmunología , Inmunoterapia Adoptiva , Leucemia Mieloide Aguda , Proteínas de Neoplasias/inmunología , Receptores Quiméricos de Antígenos/inmunología , Anticuerpos de Cadena Única/inmunología , Linfocitos T/inmunología , Células HEK293 , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Células THP-1RESUMEN
Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a heterogeneous clinical and biological behavior. SOX11 oncogenic expression contributes to the aggressiveness of these tumors by different mechanisms, including tumor and stromal cell interactions. However, the precise composition of the immune cell microenvironment of MCL, its possible relationship to SOX11 expression, and how it may contribute to tumor behavior is not well known. Here, we performed an integrative transcriptome analysis of 730 immune-related genes combined with the immune cell phenotype analysis by immunohistochemistry in SOX11+ and SOX11- primary nodal MCL cases and non-neoplastic reactive lymph nodes. SOX11+ MCL had a significant lower T-cell intratumoral infiltration compared with negative cases. A reduced expression of MHCI/II-like and T-cell costimulation and signaling activation related transcripts was significantly associated with poor clinical outcome. Moreover, we identified CD70 as a SOX11 direct target gene, whose overexpression was induced in SOX11+, but not SOX11- tumor cells by CD40L in vitro. CD70 was overexpressed in primary SOX11+ MCL and it was associated with an immune unbalance of the tumor microenvironment characterized by increased number of effector regulatory t (Treg) cell infiltration, higher proliferation, and aggressive clinical course. CD27 was expressed with moderate to strong intensity in 76% of cases. Overall, our results suggest that SOX11 expression in MCL is associated with an immunosuppressive microenvironment characterized by CD70 overexpression in tumor cells, increased Treg cell infiltration and downmodulation of antigen processing, and presentation and T-cell activation that could promote MCL progression and represent a potential target for tailored therapies.
Asunto(s)
Ligando CD27/inmunología , Linfoma de Células del Manto/inmunología , Factores de Transcripción SOXC/inmunología , Linfocitos T Reguladores/inmunología , Presentación de Antígeno , Ligando CD27/análisis , Humanos , Activación de Linfocitos , Linfoma de Células del Manto/patología , Factores de Transcripción SOXC/análisis , Linfocitos T Reguladores/patología , Microambiente TumoralRESUMEN
BACKGROUND: Uterine leiomyosarcoma is a rare and aggressive gynecologic malignancy originating in the myometrium of the uterine corpus that tends to recur even after complete surgical excision. Current therapeutic agents have only modest effects on uterine leiomyosarcoma. Although antibodies and antibody-drug conjugates have been recognized as useful targeted therapies for other cancers, no study has yet evaluated the effects of this approach on uterine leiomyosarcoma. OBJECTIVE: This study aimed to examine the activity of tumoral CD70 in uterine leiomyosarcoma and assess the antitumor activity of CD70-antibody-drug conjugate treatment in uterine leiomyosarcoma. STUDY DESIGN: Target membrane proteins were screened by profiling and comparing membrane protein expression in 3 uterine leiomyosarcoma cell lines (SK-UT-1, SK-LMS-1, and SKN) and normal uterine myometrium cells using the isobaric tags for relative and absolute quantitation labeling method. Western blotting, fluorescence-activated cell sorting analyses, and immunohistochemistry were used to examine CD70 expression in the membrane proteins in uterine leiomyosarcoma cell lines and clinical samples. We developed an antibody-drug conjugate with a monoclonal antibody of the target membrane protein linked to monomethyl auristatin F and investigated its antitumor effects against uterine leiomyosarcoma (in vitro, in vivo, and in patient-derived xenograft models). RESULTS: CD70 was identified as a specific antigen highly expressed in uterine leiomyosarcoma cell lines. Of the 3 uterine leiomyosarcoma cell lines, CD70 expression was confirmed in SK-LMS-1 cells by western blotting and fluorescence-activated cell sorting analysis. CD70 overexpression was observed in 19 of 21 (90.5%) tumor specimens from women with uterine leiomyosarcoma. To generate CD70-antibody-drug conjugate, anti-CD70 monoclonal antibody was conjugated with a novel derivative of monomethyl auristatin F. CD70-antibody-drug conjugate showed significant antitumor effects on SK-LMS-1 cells (half maximal inhibitory concentration, 0.120 nM) and no antitumor effects on CD70-negative uterine leiomyosarcoma cells. CD70-antibody-drug conjugate significantly inhibited tumor growth in the SK-LMS-1 xenograft mouse model (tumor volume, 129.8 vs 285.5 mm3; relative reduction, 54.5%; P<.001) and patient-derived xenograft mouse model (tumor volume, 128.1 vs 837.7 mm3; relative reduction, 84.7%; P<.001). CONCLUSION: Uterine leiomyosarcoma tumors highly express CD70 and targeted therapy with CD70-antibody-drug conjugate may have a potential therapeutic implication in the treatment of uterine leiomyosarcoma.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Ligando CD27/inmunología , Proliferación Celular/efectos de los fármacos , Inmunoconjugados/uso terapéutico , Leiomiosarcoma/metabolismo , Miometrio/metabolismo , Oligopéptidos/farmacología , Neoplasias Uterinas/metabolismo , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Western Blotting , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Citometría de Flujo , Humanos , Leiomiosarcoma/tratamiento farmacológico , Ratones , Persona de Mediana Edad , Trasplante de Neoplasias , Oligopéptidos/uso terapéutico , Proteómica , Neoplasias Uterinas/tratamiento farmacológico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Tumour-associated antigens (TAAs) comprise a large set of non-mutated cellular antigens recognized by T cells in human and murine cancers. Their potential as targets for immunotherapy has been explored for more than two decades1, yet the origins of TAA-specific T cells remain unclear. While tumour cells may be an important source of TAAs for T cell priming2, several recent studies suggest that infection with some viruses, including Epstein-Barr virus and influenza virus can elicit T cell responses against abnormally expressed cellular antigens that function as TAAs3,4. However, the cellular and molecular basis of such responses remains undefined. Here we show that expression of the Epstein-Barr virus signalling protein LMP1 in B cells provokes T cell responses to multiple TAAs. LMP1 signalling leads to overexpression of many cellular antigens previously shown to be TAAs, their presentation on major histocompatibility complex classes I (MHC-I) and II (MHC-II) (mainly through the endogenous pathway) and the upregulation of costimulatory ligands CD70 and OX40L, thereby inducing potent cytotoxic CD4+ and CD8+ T cell responses. These findings delineate a mechanism of infection-induced anti-tumour immunity. Furthermore, by ectopically expressing LMP1 in tumour B cells from patients with cancer and thereby enabling them to prime T cells, we develop a general approach for rapid production of autologous cytotoxic CD4+ T cells against a wide range of endogenous tumour antigens, such as TAAs and neoantigens, for treating B cell malignancies. This work stresses the need to revisit classical concepts concerning viral and tumour immunity, which will be critical to fully understand the impact of common infections on human health and to improve the rational design of immune approaches to treatment of cancers.
Asunto(s)
Linfocitos B/inmunología , Linfocitos B/virología , Linfocitos T CD4-Positivos/inmunología , Herpesvirus Humano 4/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Linfocitos T Citotóxicos/inmunología , Proteínas de la Matriz Viral/inmunología , Animales , Antígenos de Neoplasias/inmunología , Ligando CD27/inmunología , Línea Celular Tumoral , Células Cultivadas , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ligando OX40/inmunologíaRESUMEN
Purpose: Given that heterogeneous expression and variants of antigens on solid tumors are responsible for relapse after chimeric antigen receptor (CAR)-T cell therapy, we hypothesized that combinatorial targeting two tumor-associated antigens would lessen this problem and enhance the antitumor activity of T cells. Methods: The co-expression level of CD70 and B7-H3 was analyzed in multiple tumor tissue samples. Further, two putative antigens were identified in The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis database. Two CD70 targeted CARs with different antigen binding domain, truncated CD27 and CD70 specific single-chain antibody fragment (scFv), were designed to screen a more suitable target-antigen binding moiety. Accordingly, we designed a bivalent tandem CAR (TanCAR) and further assessed the anti-tumor efficacy of TanCAR-T cells in vitro and in vivo. Results: Our results indicated that co-expression of CD70 and B7-H3 was observed on multiple tumor types including kidney, breast, esophageal, liver, colon cancer, glioma as well as melanoma. The CD70 targeted CAR-T cells with binding moiety of CD70 specific scFv exhibit a higher affinity and antitumor effect against CD70+ tumor cells. TanCAR-T cells induced enhanced ability of cytolysis and cytokine release over unispecific CAR-T cells when encountering tumor cells expressing two target-antigens. Further, low doses of TanCAR-T cells could also effectively control the lung cancer and melanoma xenografts and improved overall survival of the treated animals. Conclusion: TanCAR-T cells targeting CD70 and B7-H3 exhibit enhanced antitumor functionality and improve the problem of antigenic heterogeneity and variant in the treatment against solid tumor and melanoma.
Asunto(s)
Inmunoterapia Adoptiva/métodos , Neoplasias/terapia , Anticuerpos de Cadena Única/farmacología , Linfocitos T/trasplante , Animales , Antígenos de Neoplasias/inmunología , Antígenos B7/antagonistas & inhibidores , Antígenos B7/inmunología , Ligando CD27/antagonistas & inhibidores , Ligando CD27/inmunología , Línea Celular Tumoral , Femenino , Humanos , Ratones , Neoplasias/inmunología , Receptores Quiméricos de Antígenos/inmunología , Anticuerpos de Cadena Única/uso terapéutico , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Autologous monocyte-derived mRNA co-electroporated dendritic cells with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively activated TLR4 (caTLR4) (referred to as TriMixDC-MEL) have anti-tumor activity in advanced melanoma patients. We investigated the safety and activity of adjuvant TriMixDC-MEL in stage III/IV melanoma patients. MATERIALS AND METHODS: Forty-one patients were randomly assigned to treatment with TriMixDC-MEL (n = 21) and standard follow-up (n = 20). "Cross-over" was allowed at the time of non-salvageable recurrence. The primary endpoint was the percentage of patients alive and disease-free at 1-year. For a subset of patients, (formalin-fixed paraffin-embedded), tumor tissue samples were available for mRNA expression profiling and PD-L1 immunohistochemical staining. RESULTS: Baseline characteristics were well balanced. One-year after randomization, 71% of patients in the study arm were alive and free of disease compared to 35% in the control arm. After a median follow-up of 53 months (range 3-67), 23 patients experienced a non-salvageable melanoma recurrence (TriMixDC-Mel arm n = 9 and control arm n = 14).The median time to non-salvageable recurrence was superior in the TriMixDC-MEL arm (median 8 months (range 1-6) vs. not reached; log-rank p 0.044). TriMixDC-MEL-related adverse events (AE) consisted of transient local skin reactions, flu-like symptoms and post-infusion chills. No grade ≥ 3 AE's occurred. The mRNA expression profiling revealed four genes (STAT2, TPSAB1, CD9 and CSF2) as potential predictive biomarkers. CONCLUSION: TriMixDC-MEL id/iv as adjuvant therapy is tolerable and may improve the 1-year disease-free survival rate. Combination of optimized autologous monocyte-derived DC-formulations warrants further investigation in combination with currently approved adjuvant therapy options.
Asunto(s)
Células Dendríticas/trasplante , Melanoma/terapia , Recurrencia Local de Neoplasia/epidemiología , ARN Mensajero/inmunología , Neoplasias Cutáneas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Ligando CD27/genética , Ligando CD27/inmunología , Ligando de CD40/genética , Ligando de CD40/inmunología , Terapia Combinada/métodos , Células Dendríticas/metabolismo , Supervivencia sin Enfermedad , Electroporación , Femenino , Estudios de Seguimiento , Humanos , Inmunoterapia/métodos , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , ARN Mensajero/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Procedimientos Quirúrgicos Operativos , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Trasplante Autólogo/métodos , Adulto JovenAsunto(s)
Infecciones por Coronavirus/inmunología , Susceptibilidad a Enfermedades/inmunología , Sistema Inmunológico , Neumonía Viral/inmunología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunología , Linfocitos B/inmunología , Ligando CD27/inmunología , COVID-19 , Niño , Humanos , Memoria Inmunológica/inmunología , PandemiasRESUMEN
PURPOSE: Successful tumor eradication primarily depends on generation and maintenance of a large population of tumor-reactive CD8 T cells. Dendritic cells (DCs) are well-known potent antigen-presenting cells and have applied to clinics as potent antitumor therapeutic agents. However, high cost and difficulty in obtaining sufficient amounts for clinical use are the crucial drawbacks of DC-based vaccines. Here, we aimed to develop T cell-based vaccine capable of eliciting potent antitumor therapeutic effects by providing effective costimulatory signals. MATERIALS AND METHODS: Antigenic peptide-loaded T cells transfected with retrovirus encoding costimulatory ligands CD70, CD80, OX40L, or 4-1BBL were assessed for antigen-specific CD8 T-cell responses and evaluated antitumor effects along with immunization of a mixture of synthetic peptides, poly-IC and anti-CD40 antibodies (TriVax). RESULTS: T cells expressing CD70 (CD70-T) exhibited similar level of stimulatory functionality and therapeutic efficacy as DCs. Moreover, CD70-T prime followed by TriVax booster heterologous vaccination elicited therapeutic antitumor effect against B16 melanoma where mediated by CD8 T cells but not CD4 T cells or natural killer cells. The combination with programmed death-ligand 1 blockade led to potent therapeutic efficacy which exhibited increased tumor-infiltrating CD8 T cells. CD70-T pulsed with multi-antigenic peptide generated multiple antigen-specific polyvalent CD8 T cells that were capable of inhibiting tumor growth effectively. Moreover, CD70-T vaccination resulted in higher expansion and migration of adoptively transferred T cells into tumor sites and elicits enhanced therapeutic effects with peptide-based booster immu-nization. CONCLUSION: These results imply that T cells endowed with CD70 enable the design of effective vaccination strategies against solid cancer, which may overcome current limitations of DC-based vaccines.
Asunto(s)
Antígenos de Neoplasias/inmunología , Ligando CD27/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Células Dendríticas/inmunología , Inmunidad Celular/inmunología , Melanoma Experimental/terapia , Animales , Presentación de Antígeno/inmunología , Femenino , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BLRESUMEN
Transcutaneous immunization (TCI) is a novel vaccination strategy that utilizes skin-associated lymphatic tissue to induce immune responses. Employing T-cell epitopes and the TLR7 agonist imiquimod onto intact skin mounts strong primary, but limited memory CTL responses. To overcome this limitation, we developed a novel imiquimod-containing vaccination platform (IMI-Sol) rendering superior primary CD8+ and CD4+ T-cell responses. However, it has been unclear whether IMI-Sol per se is restricted in terms of memory formation and tumor protection. In our present work, we demonstrate that the combined administration of IMI-Sol and CD40 ligation unleashes fullblown specific T-cell responses in the priming and memory phase, strongly enhancing antitumor protection in mice. Interestingly, these effects were entirely CD4+ T cell independent, bypassing the necessity of helper T cells. Moreover, blockade of CD70 in vivo abrogated the boosting effect of CD40 ligation, indicating that the adjuvant effect of CD40 in TCI is mediated via CD70 on professional APCs. Furthermore, this work highlights the so far underappreciated importance of the CD70/CD27 interaction as a promising adjuvant target in TCI. Summing up, we demonstrate that the novel formulation IMI-Sol represents a powerful vaccination platform when applied in combination with sufficient adjuvant thereby overcoming current limitations of TCI.
Asunto(s)
Ligando CD27/inmunología , Ligando de CD40/administración & dosificación , Imiquimod/administración & dosificación , Melanoma Experimental/terapia , Neoplasias Cutáneas/terapia , Linfocitos T Citotóxicos/efectos de los fármacos , Administración Cutánea , Aloinjertos , Animales , Ligando CD27/genética , Citotoxicidad Inmunológica/efectos de los fármacos , Expresión Génica , Rechazo de Injerto , Inmunización/métodos , Memoria Inmunológica/efectos de los fármacos , Inmunoterapia/métodos , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/administración & dosificación , Piel/efectos de los fármacos , Piel/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/patología , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/inmunologíaRESUMEN
The anticancer effects of immune checkpoint inhibitors against CTLA4 and CD274-PDCD1 axes are evident. However, these immunotherapies for colorectal cancers (CRCs) are now limited to a small subset of patients with microsatellite unstable tumors. Thus, therapeutics targeting other types of CRCs is desired. The CD70-CD27 axis plays a co-stimulatory role in promoting the expansion and differentiation of T-lymphocytes through the activation of NFκB pathway. Aberrant activation of the CD70-CD27 axis accelerates tumor cell proliferation, survival, and immune evasion of tumor cells. Based on these observations, drugs modulating the CD70-CD27 axis have been developed with expectation of anticancer effects. In the present study, 269 primary CRCs were evaluated immunohistochemically for CD70, CD27, and FOXP3 expression to assess their clinical usage and the application of CD70-CD27 axis modulating drugs. CRC tumor cells rarely (2.2%) expressed CD70. In contrast, tumor-surrounding fibroblasts showed various CD70 expressions (fCD70) in 14.9%. The logistic regression analysis revealed significant association of fCD70 expression with incomplete resection status (OR, 2.60; 95% CI, 1.10-6.13; P = 0.029). Overall survival was significantly decreased in the cohort of the patients with fCD70-positive tumor (P = 0.0078). Furthermore, significantly more CD27+ tumor-associated lymphocytes were detected within the primary CRCs without metastases (P = 0.024). Thus, the CD70-CD27 axis may have several roles in CRCs independent from their mismatch repair (MMR) system status. CD70-CD27 pathway-modulating therapies may be applied to CRC patients regardless of their tumor MMR status.
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Ligando CD27/biosíntesis , Fibroblastos Asociados al Cáncer/inmunología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Adulto , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/inmunología , Ligando CD27/análisis , Ligando CD27/inmunología , Neoplasias Colorrectales/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/biosíntesis , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunologíaRESUMEN
PURPOSE: This study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of the anti-CD27L antibody-drug conjugate AMG 172 in patients with relapsed/refractory clear cell renal cell carcinoma (ccRCC). METHODS: This was an open-label, adaptive dose-exploration study in patients with relapsed/refractory ccRCC. The study was conducted in two parts for dose exploration and dose expansion on a biweekly dosing schedule. AMG 172 doses of 0.15, 0.3, 0.6, 1.2, 1.6, 1.8, and 2.4 mg/kg were studied in the dose-exploration phase. RESULTS: The 1.6 mg/kg dose of AMG 172 was identified as the maximum tolerated dose (MTD). The most common adverse events were thrombocytopenia (59%), nausea (54%), decreased appetite (49%), vomiting (46%), and fatigue (35%). The most common dose-limiting toxicity (DLT) was thrombocytopenia. Thrombocytopenia and liver injury constituted DLTs that required discontinuation of treatment. Of the 10 patients treated at the MTD in part 2 of the study, 2 patients had grade 3 hepatocellular injury with aspartate aminotransferase or alanine aminotransferase elevation. Pharmacokinetic profiles indicated low levels of circulating unconjugated antibody and unconjugated cytotoxin. Dose-proportional increases in plasma exposure were observed over the dose range of 0.3-2.4 mg/kg. Following multiple biweekly doses, plasma accumulation was less than two-fold. Two patients (5.4%) had a partial response, 6 patients (16.2%) had stable disease, and 13 patients (35.1%) had progressive disease. CONCLUSION: AMG 172 exhibited a favorable pharmacokinetic profile in patients with relapsed/refractory ccRCC and showed evidence suggestive of limited antitumor activity. Safety and tolerability were as expected for a maytansinoid antibody-drug conjugate.
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Anticuerpos Monoclonales/administración & dosificación , Ligando CD27/inmunología , Carcinoma de Células Renales/tratamiento farmacológico , Inmunoconjugados/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/farmacología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: Cluster of differentiation 70 (CD70) is frequently expressed in renal cell carcinoma (RCC) and has immunomodulatory properties. An antibody-drug conjugate targeting CD70, SGN-CD70A, was developed to treat patients with CD70-positive RCC. METHODS: The objective of this phase 1, open-label, dose-escalation, multicenter study was to evaluate the safety and tolerability of SGN-CD70A and establish its maximum tolerated dose in patients with CD70-positive, metastatic RCC (mRCC). All subtypes of RCC were permitted, and no limit was set on the number of prior therapies. Safety assessments consisted of monitoring and recording all adverse events (AEs) and dose-limiting toxicities (DLTs). Treatment response was assessed by radiographic tumor evaluation according to the Response Evaluation Criteria for Solid Tumors, version 1.1. A model-based, modified continual-reassessment method was used to estimate the probabilities of DLT and response. RESULTS: The maximum tolerated dose was determined to be 30 µg/kg, with thrombocytopenia as the DLT. The most common AEs were fatigue (67%), anemia (61%), and thrombocytopenia (56%). Of 18 enrolled patients, 1 achieved a partial response and 13 achieved stable disease, for a clinical benefit rate of 78%. Limitations of the study included the heavily pretreated nature of patients, receipt of a median of 4 prior lines of therapy (range, 1-8 prior lines of therapy), and diminishing response potential. CONCLUSIONS: The modest antitumor activity of SGN-CD70A does not support its development in mRCC. However, given the high disease control rate in a heavily pretreated population and the modest toxicity profile, CD70 remains of interest because of its immunomodulatory properties.
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Benzodiazepinas/uso terapéutico , Ligando CD27/inmunología , Carcinoma de Células Renales/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Pirroles/uso terapéutico , Anciano , Anemia/inducido químicamente , Ligando CD27/metabolismo , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/secundario , Edema/inducido químicamente , Fatiga/inducido químicamente , Femenino , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Trombocitopenia/inducido químicamenteRESUMEN
Purpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg. Due to observations of prolonged thrombocytopenia, the study was amended to dose every 6 weeks (q6wk). Results Twenty patients were enrolled and treated with SGN-CD70A. The maximum tolerated dose of SGN-CD70A was 30 mcg/kg q6wk. The most common adverse events (AEs) reported were thrombocytopenia (75%), nausea (55%), anemia (50%), and fatigue (50%). The onset for treatment-related thrombocytopenia typically occurred during Cycle 1. Most of the treatment-related events of thrombocytopenia were ≥ Grade 3. Antitumor activity in patients included 1 complete remission (CR) and 3 partial remissions (PRs), 2 of which were ongoing for at least 42.9 weeks. SGN-CD70A exposures were approximately dose proportional, with a mean terminal half-life of 3 to 5 days. Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure.
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Anticuerpos Monoclonales/uso terapéutico , Ligando CD27/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células del Manto/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/farmacocinética , Benzodiazepinas/química , Biomarcadores de Tumor/metabolismo , Ligando CD27/inmunología , Ligando CD27/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Estudios de Seguimiento , Humanos , Inmunoconjugados/farmacocinética , Inmunoconjugados/uso terapéutico , Linfoma de Células B/inmunología , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células del Manto/inmunología , Linfoma de Células del Manto/metabolismo , Linfoma de Células del Manto/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Pronóstico , Pirroles/química , Distribución TisularRESUMEN
BACKGROUND: Systemic lupus erythematous (SLE) is an autoimmune disease characterized by the production of autoantibodies directed against various autoantigens. But the expression profiles and functions of circular RNAs (circRNAs) in SLE are still scarce. OBJECTIVES: To explore the roles of circRNA in SLE and its potential diagnostic potential in SLE. METHODS: SLE patients and healthy control subjects were recruited. CD4+ T cells were isolated, circRNA microarray analysis were used to screen for circRNA candidate in CD4+ T cells. Expression of DNMT1, CD11a and CD70, and methylation level of CD11a and CD70 were detected after transfecting hsa_circ_0012919-targetted siRNA. The network analysis of hsa_circ_0012919 was used by bioinformatics. Luciferase reporter assay and fluorescence in situ hybridization (FISH) assay were used for screening for which miRNAs could bind with hsa_circ_0012919. RESULTS: Twelve circRNAs were up-regulated and two circRNAs were down-regulated in SLE patients group after circRNA microarray analysis. Hsa_circ_0012919 was further confirmed to be significantly different between healthy control and SLE patients (P<0.05) and associated with SLE characters (P<0.05). Down-regulation of hsa_circ_0012919 (i) increased the expression of DNMT1 and reduced the expression of CD70, CD11a, (ii) reversed the DNA hypomethylation of CD11a and CD70 in CD4+ T cells of SLE, but it could be reversed by down-regulation of DNMT1. Hsa_circ_0012919 regulated KLF13 and RANTES by miR-125a Conclusion: Hsa_circ_0012919 could be regarded as a biomarker for SLE and hsa_circ_0012919 was the competitive endogenous RNA (ceRNA) for miR-125a-3p.
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Antígeno CD11a/genética , Ligando CD27/genética , Linfocitos T CD4-Positivos/metabolismo , Metilación de ADN , Lupus Eritematoso Sistémico/genética , MicroARNs/genética , ARN/genética , Adulto , Antígeno CD11a/inmunología , Antígeno CD11a/metabolismo , Ligando CD27/inmunología , Ligando CD27/metabolismo , Linfocitos T CD4-Positivos/inmunología , Estudios de Casos y Controles , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Marcadores Genéticos , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , MicroARNs/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN/metabolismo , ARN Circular , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
There is currently much interest in how different APC subsets shape the immune response. We recently described a division of labor between classical dendritic cells (cDC) and inflammatory monocyte-derived APC in provision of costimulatory ligands to T cells early during chronic lymphocytic choriomeningitis clone 13 (LCMV 13) infection in mice. At day 2 of LCMV 13 infection, cDC preferentially express CD80 and CD86, whereas TNF superfamily ligands GITRL, 4-1BBL, CD70, and OX40L are preferentially induced by type I IFN on inflammatory monocyte-derived APC, with minimal expression on cDC. In this study, we further investigate the expression of TNF and B7 family ligands on APC over the course of LCMV 13 infection. OX40L and 4-1BBL remain above baseline through the chronic stage of infection, with predominant expression on inflammatory APC compared with cDC in the spleen, partially blocked by anti-IFN-γR Ab pretreatment. Conversely, CD70, like GITRL, returns to baseline on the APC within a few days postinfection. In the lung, TNF family ligands were also preferentially expressed on inflammatory monocyte-derived APC. CD86 was generally higher on cDC than inflammatory APC in the spleen, but in the lung CD86 was highest on inflammatory APC. Moreover, in the spleen, CD80 levels on different APC subsets fluctuated over the course of the infection. We also show that LPS induction of TNF superfamily ligands is largely mediated through type I IFN. This study highlights the importance of IFNs and monocyte-derived APC in TNF superfamily ligand expression in both secondary lymphoid organs and tissues during chronic viral infection.
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Células Presentadoras de Antígenos/inmunología , Infecciones por Arenaviridae/inmunología , Interferón Tipo I/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Ligando 4-1BB/inmunología , Animales , Antígeno B7-1/inmunología , Antígeno B7-2/inmunología , Antígeno B7-H1/inmunología , Ligando CD27/inmunología , Técnicas de Cultivo de Célula , Femenino , Antígenos de Histocompatibilidad Clase II/inmunología , Ligandos , Macrófagos/inmunología , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología , Ligando OX40 , Bazo/inmunología , Linfocitos T/inmunología , Factores de Necrosis Tumoral/inmunologíaRESUMEN
Background: Cancer immunotherapy represents a promising treatment approach for malignant gliomas but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified cluster of differentiation (CD)70 as a novel immunosuppressive ligand and glioma target. Methods: Normal tissues derived from 52 different organs and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression. The association between CD70 and patients' overall survival and its impact on T-cell death was also evaluated. Human and mouse CD70-specific chimeric antigen receptors (CARs) were tested respectively against human primary GBMs and murine glioma lines. The antitumor efficacies of these CARs were also examined in orthotopic xenograft and syngeneic models. Results: CD70 was not detected in peripheral and brain normal tissues but was constitutively overexpressed by isocitrate dehydrogenase (IDH) wild-type primary LGGs and GBMs in the mesenchymal subgroup and recurrent tumors. CD70 was also associated with poor survival in these subgroups, which may link to its direct involvement in glioma chemokine productions and selective induction of CD8+ T-cell death. To explore the potential for therapeutic targeting of this newly identified immunosuppressive axis in GBM tumors, we demonstrate that both human and mouse CD70-specific CAR T cells recognize primary CD70+ GBM tumors in vitro and mediate the regression of established GBM in xenograft and syngeneic models without illicit effect. Conclusion: These studies identify a previously uncharacterized and ubiquitously expressed immunosuppressive ligand CD70 in GBMs that also holds potential for serving as a novel CAR target for cancer immunotherapy in gliomas.