RESUMO
Diamond-Blackfan anaemia (DBA) is a rare, inherited bone marrow failure syndrome with a ribosomal defect causing slowed globin chain production with normal haem synthesis, causing an overabundance of reactive iron/haem and erythroid-specific cellular toxicity. Eltrombopag, a non-peptide thrombopoietin receptor agonist, is a potent intracellular iron chelator and induced a robust durable response in an RPS19-mutated DBA patient on another trial. We hypothesized eltrombopag would improve RBC production in DBA patients. We conducted a single-centre, single-arm pilot study (NCT04269889) assessing safety and erythroid response of 6 months of daily, fixed-dose eltrombopag for DBA patients. Fifteen transfusion-dependent (every 3-5 weeks) patients (median age 18 [range 2-56]) were treated. One responder had sustained haemoglobin improvement and >50% reduction in RBC transfusion frequency. Of note, 7/15 (41%) patients required dose reductions or sustained discontinuation of eltrombopag due to asymptomatic thrombocytosis. Despite the low response rate, eltrombopag has now improved erythropoiesis in several patients with DBA with a favourable safety profile. Dosing restrictions due to thrombocytosis may cause insufficient iron chelation to decrease haem production and improve anaemia in most patients. Future work will focus on erythropoiesis dynamics in patients and use of haem synthesis inhibitors without an impact on other haematopoietic lineages.
Assuntos
Anemia de Diamond-Blackfan , Benzoatos , Hidrazinas , Pirazóis , Humanos , Anemia de Diamond-Blackfan/tratamento farmacológico , Pirazóis/uso terapêutico , Hidrazinas/uso terapêutico , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Benzoatos/uso terapêutico , Benzoatos/administração & dosagem , Benzoatos/efeitos adversos , Adulto , Masculino , Feminino , Criança , Adolescente , Pessoa de Meia-Idade , Adulto Jovem , Pré-Escolar , Projetos Piloto , Resultado do Tratamento , Receptores de Trombopoetina/agonistas , Recidiva , Eritropoese/efeitos dos fármacosRESUMO
Adoptive transfer of patient-derived T cells modified to express chimeric antigen receptors (CARTs) has demonstrated dramatic success in relapsed/refractory pre-B-cell acute lymphoblastic leukemia (ALL), but response and durability of remission requires exponential CART expansion and persistence. Tumors are known to affect T-cell function, but this has not been well studied in ALL and in the context of chimeric antigen receptor (CAR) expression. Using TCF3/PBX1 and MLL-AF4-driven murine ALL models, we assessed the impact of progressive ALL on T-cell function in vivo. Vaccines protect against TCF3/PBX1.3 but were ineffective when administered after leukemia injection, suggesting immunosuppression induced early during ALL progression. T cells from leukemia-bearing mice exhibited increased expression of inhibitory receptors, including PD1, Tim3, and LAG3, and were dysfunctional following adoptive transfer in a model of T-cell receptor (TCR)-dependent leukemia clearance. Although expression of inhibitory receptors has been linked to TCR signaling, pre-B-cell ALL induced inhibitory receptor expression, at least in part, in a TCR-independent manner. Finally, introduction of a CAR into T cells generated from leukemia-bearing mice failed to fully reverse poor in vivo function.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Células Precursoras de Linfócitos B/patologia , Linfócitos T/patologia , Transferência Adotiva/métodos , Animais , Vacinas Anticâncer/uso terapêutico , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Camundongos Endogâmicos C57BL , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/análiseRESUMO
Tumor-targeted vaccines represent a strategy to enhance the graft-versus-leukemia effect after allogeneic blood and marrow transplantation (BMT). We have previously shown that graft-versus-host disease (GVHD) can negatively impact quantitative responses to vaccines. Using a minor histocompatibility Ag-mismatched BMT (B6 â B6 × C3H.SW) followed by adoptive transfer of HY-specific T cells and HY-expressing dendritic cells, we assessed whether GVHD induced by donor lymphocyte infusion (DLI) affects the persistence, proliferation, and survival of vaccine-responding, nonalloantigen reactive T cells. Both CD8(+) and CD4(+) HY-specific T cells undergo less vaccine-driven proliferation in allogeneic recipients with GVHD. Although vaccine-responding CD8(+) T cells show decreased IFN-γ and CD107a production, CD4(+) T cells exhibit increased programmed death 1 and T cell Ig mucin-like domain 3 expression. In addition, the degree of apoptosis in vaccine-responding CD8(+) T cells was higher in the presence of GVHD, but there was no difference in CD4(+) T cell apoptosis. Using Fas ligand-deficient or TRAIL-deficient DLI had no impact on apoptosis of HY-specific T cells. However, perforin-deficient alloreactive DLI induced significantly less apoptosis of vaccine-responding CD8(+) T cells and resulted in enhanced tumor protection. Thus, diminished vaccine responses during GVHD result from impaired proliferation of CD8(+) and CD4(+) T cells responding to vaccination, with an additional contribution from perforin-mediated CD8(+) T cell apoptosis. These results provide important insights toward optimizing vaccine responses after allogeneic BMT.
Assuntos
Apoptose/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/imunologia , Imunoterapia , Proteínas Citotóxicas Formadoras de Poros/fisiologia , Subpopulações de Linfócitos T/imunologia , Vacinação , Transferência Adotiva , Animais , Animais Congênicos , Vacinas Anticâncer/uso terapêutico , Carcinoma de Células de Transição/imunologia , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/terapia , Divisão Celular , Técnicas de Cocultura , Proteína Ligante Fas/deficiência , Proteína Ligante Fas/imunologia , Feminino , Antígeno H-Y/imunologia , Epitopos Imunodominantes/imunologia , Transfusão de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/imunologia , Quimera por Radiação , Organismos Livres de Patógenos Específicos , Ligante Indutor de Apoptose Relacionado a TNF/deficiência , Ligante Indutor de Apoptose Relacionado a TNF/imunologiaRESUMO
We present an 18-year-old male patient who presented with a 16 cm testicular tumor alongside multiple lesions in the lungs, right pelvis with involvement of the ischio/pubic bone, and enlarged pelvic lymph nodes on imaging, suspicious for metastatic disease. Histologic and immunohistochemical examinations revealed an embryonic type neuroectodermal tumor (somatic-type malignancy, 10%) arising in a malignant mixed germ cell tumor composed of teratoma (50%), embryonal carcinoma (10%) and yolk sac tumor (30%). After treatment with chemotherapy and radiation, repeat imaging demonstrated a right pelvic sidewall mass that decreased in size from 40 mm at 11 months after the initial diagnosis to 18 mm at 22 months after the initial diagnosis. A right pelvis medial thigh wall mass that had a lytic bone component showed a slight increase in size from 151 mm at 11 months after the initial diagnosis to 154 mm at 22 months after the diagnosis. On biopsies performed at 3, 10, and 26 months after the initial diagnosis, this lytic lesion consistently demonstrated a neoplasm composed of low-grade neuroglial differentiation. This is the first case in the medical literature where a residual malignant germ cell tumor consisting of low-grade neuroglial neoplasm is in a site that is not amenable to resection without significant morbidity. The tumor initially regressed with the traditional first-line chemo-radiotherapy regimen but regrew and stabilized with a second regimen of chemotherapy. The clinical course of this case invites consideration for an active surveillance approach in cases with similar characteristics.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Humanos , Masculino , AdolescenteRESUMO
Chimeric antigen receptor (CAR)-T cells have emerged as a promising treatment modality for various hematologic and solid malignancies over the past decade. Animal models remain the cornerstone of pre-clinical evaluation of human CAR-T cell products and are generally required by regulatory agencies prior to clinical translation. However, pharmacokinetics and pharmacodynamics of adoptively transferred T cells are dependent on various recipient factors, posing challenges for accurately predicting human engineered T cell behavior in non-human animal models. For example, murine xenograft models did not forecast now well-established cytokine-driven systemic toxicities of CAR-T cells seen in humans, highlighting the limitations of animal models that do not perfectly recapitulate complex human immune systems. Understanding the concordance as well as discrepancies between existing pre-clinical animal data and human clinical experiences, along with established advantages and limitations of each model, will facilitate investigators' ability to appropriately select and design animal models for optimal evaluation of future CAR-T cell products. We summarize the current state of animal models in this field, and the advantages and disadvantages of each approach depending on the pre-clinical questions being asked.
RESUMO
PURPOSE OF REVIEW: Genetically engineered T cells expressing a chimeric antigen receptor (CAR-T) targeting specific antigens present on acute lymphoblastic leukemia (ALL) blasts have generated promising results in children and adults with relapsed and refractory disease. We review the current evidence for CAR-T cell therapy in ALL, associated toxicities, and efforts to improve durable response to therapy. RECENT FINDINGS: CD19-directed CAR-T cells have recently been approved by the FDA for use in children and young adults with ALL and in adults with diffuse large B cell lymphoma (DLBCL) in the relapsed/refractory setting. CD22-directed CAR-T cells have shown efficacy against leukemia as well in a recent clinical trial, representing the first alternative CAR target to approach comparable efficacy to CD19 CAR-T cells. Standardization of toxicity grading and management, strategies to combat significant relapse rates after CAR-T therapy, and applicability of CAR-T cells to treat central nervous system (CNS) disease remain challenges in the field and represent priorities for continued research. CAR-T cells are a feasible, effective, and rapidly evolving therapy for patients with relapsed and refractory B cell malignancies.
Assuntos
Neoplasias do Sistema Nervoso Central/terapia , Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/imunologia , Adolescente , Adulto , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Recidiva , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologiaRESUMO
Recent studies have suggested that pan inhibitors of dipeptidyl peptidase-4 activity and/or structure homologs (DASH), including ARI-4175, can mediate tumor regression by immune-mediated mechanisms. This study assessed the potential of combining ARI-4175 with cancer vaccines. We evaluated ARI-4175's effect on immunogenic modulation, ability to sensitize tumor cells to antigen-specific CTL killing, effect on immune-cell subsets and function, and antitumor activity in 2 tumor models, both as a monotherapy and in combination with a recombinant viral or dendritic cell (DC)-based tumor-cell vaccine. ARI-4175's effects on the growth, surface phenotype, and antigen-specific CTL-mediated lysis of murine and human carcinoma cell lines were assessed in vitro. In vivo, C57BL-6 mice were treated orally with ARI-4175, after which splenocytes were assessed by flow cytometry and functional assays. Antitumor studies were performed in murine models of colon carcinoma (MC38-CEA(+) in CEA-transgenic C57BL-6 mice) and rhabdomyosarcoma (M3-9-M in C57BL-6 mice). Mice received oral ARI-4175 alone or in combination with a vaccine consisting of recombinant vaccinia/fowlpox CEA-TRICOM (colon model) or a DC-based tumor-cell vaccine (rhabdomyosarcoma model). Exposure to ARI-4175 had no effect on the proliferation or viability of carcinoma cells in vitro; however, it did alter tumor phenotype, making murine and human tumor cells more sensitive to antigen-specific CTL killing. Assessment of immune-cell subsets and function indicated that ARI-4175 increased levels of natural killer cells and DCs. Detrimental immune effects, including reduced T effector cells and increased immunosuppressive cells (Tregs, MDSCs), were normalized when treatment stopped, suggesting that scheduling is critical when combining this agent with vaccine. As a monotherapy, ARI-4175 had potent antitumor activity in both tumor models, and had even greater effects when combined with a vaccine (either DC-based or poxviral vector based). These findings provide the rationale for the combined use of cancer immunotherapy with DASH enzyme inhibitors such as ARI-4175.
Assuntos
Adjuvantes Imunológicos/farmacologia , Compostos de Boro/farmacologia , Vacinas Anticâncer/imunologia , Dipeptídeos/farmacologia , Linfócitos T Citotóxicos/imunologia , Administração Oral , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/prevenção & controle , Inibidores da Dipeptidil Peptidase IV/farmacologia , Feminino , Humanos , Subpopulações de Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transplante de Neoplasias , Rabdomiossarcoma/prevenção & controleRESUMO
Multimodality therapy consisting of surgery, chemotherapy, and radiation will fail in approximately 40% of patients with pediatric sarcomas and result in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid tumors typically generate antigen-specific responses too weak to overcome considerable tumor burden and tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (dipeptidyl peptidase IV activity and/or structural homologs) enzymes can mediate tumor regression by immune-mediated mechanisms. Herein, we demonstrate that the DASH inhibitor, ARI-4175, can induce regression and eradication of well-established solid tumors, both as a single agent and as an adjuvant to a dendritic cell (DC) vaccine and adoptive cell therapy (ACT) in mice implanted with the M3-9-M rhabdomyosarcoma cell line. Treatment with effective doses of ARI-4175 correlated with recruitment of myeloid (CD11b) cells, particularly myeloid DCs, to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11bLy6-CLy6-G) myeloid-derived suppressor cells. In immunocompetent mice, combining ARI-4175 with a DC vaccine or ACT with tumor-primed T cells produced significant improvements in tumor responses against well-established M3-9-M tumors. In M3-9-M-bearing immunodeficient (Rag1) mice, ACT combined with ARI-4175 produced greater tumor responses and significantly improved survival compared with either treatment alone. These studies warrant the clinical investigation of ARI-4175 for treatment of sarcomas and other malignancies, particularly as an adjuvant to tumor vaccines and ACT.