Subject(s)
Colitis , Cytomegalovirus Infections , Cytomegalovirus , Gastrointestinal Hemorrhage , Humans , Cytomegalovirus Infections/complications , Cytomegalovirus Infections/therapy , Cytomegalovirus Infections/virology , Cytomegalovirus Infections/immunology , Gastrointestinal Hemorrhage/therapy , Gastrointestinal Hemorrhage/etiology , Colitis/virology , Colitis/therapy , Colitis/complications , Cytomegalovirus/pathogenicity , Male , Receptors, Chimeric Antigen/immunology , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Middle AgedSubject(s)
Immunotherapy, Adoptive , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Receptors, Chimeric Antigen , Humans , Receptors, Chimeric Antigen/immunology , Immunotherapy, Adoptive/methods , Immunotherapy, Adoptive/adverse effects , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Leukemia, B-Cell/therapyABSTRACT
The activity of anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) with Richter's transformation (RT) to aggressive large B cell lymphoma (LBCL) is largely unknown. In a multicenter retrospective study, we report the safety and efficacy of CAR T cell therapy in patients with RT (n=30) compared to patients with aggressive B cell lymphoma (n=283) and patients with transformed indolent Non-Hodgkins Lymphoma (iNHL) (n=141) between April 2016 and January 2023. Two-thirds of patients received prior therapy for CLL before RT and 89% of them received B-cell receptor and B-cell lymphoma 2 (BCL-2) inhibitors. Toxicities of CAR T cell therapy in RT were similar to other lymphomas, with no fatalities related to cytokine release syndrome or immune effector-cell associated neurotoxicity synderome. The 100-day overall response rate and complete response rates in patients with RT were 57% and 47%, respectively. With a median follow up of 19 months, the median overall survival (OS) was 9.9 months in patients with RT compared to 18 months in de-novo LBCL and not reached in patients with transformed iNHL. The OS at 12 months was 45% in patients with RT compared with 62% and 75% in patients with de novo LBCL and transformed iNHL, respectively. In a multivariate analysis, worse OS was associated with RT histology, elevated LDH, and more prior lines of therapy. CAR T cell therapy can salvage a proportion of patients with CLL and RT exposed to prior targeted agents; however, efficacy in RT is inferior compared to de novo LBCL and transformed iNHL.
ABSTRACT
INTRODUCTION: Using immunotherapy to fight cancer, and specifically, the use of engineered T-cells expressing a chimeric receptor against an antigen found on malignant cells (chimeric antigen receptor, CAR-T cells) constitutes a significant breakthrough in the treatment of the disease. In recent years, several CAR-T therapies have been approved in Europe and the USA, and some are already approved and funded through the national health basket in Israel, for the indications of diffuse large B-cell lymphoma, mantle cell lymphoma and B-cell acute lymphoblastic leukemia, after the failure of at least two lines of treatment. The treatment with CAR-T cells achieves prolonged remissions and even long-term cure of patients who had a very poor prognosis. However, the treatment involves significant side effects, and requires specific expertise in the management of patients both during the period of preparation for cell transplantation, and following the treatment. During the immediate post-infusion period, the most common adverse reactions are cytokine release syndrome (CRS) which stems from the activation of the immune system, and neurological toxicity that can accompany CRS. These effects require close monitoring, grading their severity, and providing anti-cytokine therapy or steroid therapy until control of symptoms is achieved. Later effects can be persistent cytopenias, immune over-activation, and prolonged immune deficiency. Treatments for additional indications and new CAR-T constructs are being developed and will allow more effective and safer treatment. This article summarizes the principles for CAR-T administration that, as currently provided in Israel, include the short- and long-term follow-up of the patients.
Subject(s)
Hematologic Neoplasms , Receptors, Chimeric Antigen , Transfusion Medicine , Humans , Adult , Israel , B-Lymphocytes , Hematologic Neoplasms/therapyABSTRACT
The optimal duration of empiric antimicrobial therapy of febrile neutropenia in patients after cellular therapy is unclear. Early deescalation has been suggested by some authorities; however, data are lacking for cellular therapy recipients. We performed a randomized controlled study of cellular therapy recipients with febrile neutropenia to evaluate the safety and noninferiority of an early deescalation and discontinuation antibiotic strategy (EDD arm) versus standard broad-spectrum antibiotic treatment until recovery of neutropenia (standard duration arm). The primary outcome was the fraction of antibiotic-free neutropenia days. We randomized 110 patients to the standard duration arm (n = 51) or EDD arm (n = 59). The fraction of antibiotic-free neutropenia days was higher in the EDD arm compared to the standard duration arm (median, .8 [interquartile range (IQR), .62 to .86] versus .51 [IQR, .17 to .86]; P = .016). This was true for the per-protocol, allogeneic hematopoietic cell transplantation (HCT), autologous HCT, and anti-CD19 chimeric antigen receptor T cell therapy subgroups. Treatment success rate, subsequent fever, death within 30 days, and other common cellular therapy-related toxicities were all similar between the 2 study arms. An EDD antibiotic strategy in patients after cellular therapy was safe and associated with a substantial reduction in broad-spectrum antibiotic utilization without compromising cellular therapy outcomes.
Subject(s)
Anti-Infective Agents , Febrile Neutropenia , Humans , Anti-Bacterial Agents/therapeutic use , Prospective Studies , Fever/drug therapy , Fever/etiology , Febrile Neutropenia/drug therapyABSTRACT
Chimeric antigen receptor T-cells (CAR-T) are widely used for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL). The data for CAR-T cell therapy in patients with extra-nodal (EN) lymphoma is restricted. We included 126 consecutive patients with DLBCL treated with commercially available CAR-T cells (tisagenlecleucel, n = 100, 79.4% and axicabtagene ciloleucel, n = 26, 20.6%). At lymphodepletion, 72 of 126 (57%) patients had EN disease, 42 of 126 (33%) patients had nodal disease (ND)-only and 12 of 126 (10%) showed no disease assessed by PET-CT. There were no significant differences in CAR-T related toxicities and in the median Progression free survival (PFS) between EN patients and ND (10.76 [95% CI: 7.8-13.6] vs. 14.1 [95% CI: 10-18.1] months, p = .126). Similarly, median overall survival (OS) was not significantly different (15.36 [95% CI 12.5-18.2] vs. 18.4 [95% CI 14.8-22.1] months, p = .100). Subgroup analysis according to the number of EN involved sites showed that median PFS and OS were significantly higher in patients with <3 EN sites (12.3 months [95% CI 9-15.5] vs. 4.28 months [95% CI 0.6-7.9], p = .010) compared to patients with >2 EN sites, respectively (16.5 months [95% CI 13.4-19.6] vs. 8.7 months [95% CI 4.6-12.8], p = .05). In multivariate cox regression analysis, increased number sites of EN disease and high lactate dehydrogenase (LDH) at lymphodepletion negatively impacted PFS (p = .021 and <.001, respectively), while sex, type of product administered, age and performance status did not predict PFS and OS. Of note, all the patients with involvement of gastrointestinal tract (n = 9), urinary tract (n = 9), or pharynx (n = 3) at lymphodepletion, progressed or had an early relapse. In conclusions, patients with >2 EN sites at lymphodepletion have significantly worse clinical outcomes compared to patients with <3 EN sites. Patients with specific sites of EN disease may demonstrate grim prognosis.
Subject(s)
Lymphoma, Follicular , Lymphoma, Large B-Cell, Diffuse , Lymphoma, Non-Hodgkin , Receptors, Chimeric Antigen , Humans , Positron Emission Tomography Computed Tomography , Lymphoma, Large B-Cell, Diffuse/therapy , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Immunotherapy, Adoptive/adverse effects , Lymphoma, Follicular/drug therapy , T-Lymphocytes , Retrospective Studies , Antigens, CD19ABSTRACT
Anti CD-19 chimeric antigen receptor T (CAR-T) cells demonstrate effective early anti-tumor response; however, impaired hematopoietic recovery is observed in about 30% of patients with prolonged cytopenia appearing as an unmet need for optimal treatment. All adult patients given commercially available anti CD-19 CAR-T for diffuse large B cell lymphoma (DLBCL) were screened at 21-28 days after CAR-T infusion for cytopenia. In case of severe persistent cytopenia, patients were given TPO receptor agonists. Initial dose of eltrombopag was 50 mg/day and gradually increased to a maximal dose of 150 mg/day. Romiplostim was given as subcutaneous injection once a week for 2 doses (125 mcg). Response was defined as transfusion independency along with resolution of severe neutropenia (ANC > 500 /microL) and/or platelets > 20,000/microL for three consecutive values on different days. TPO receptor agonists were tapered down when response was met. From May 2019 to December 2021, 93 patients were eligible (74%, tisagenlecleucel and 26%, axicabtagene ciloleucel). The median age was 69 (range, 19-85) years. Six patients (6.5%) (tisagenlecleucel, n = 4 or axicabtagene ciloleucel, n = 2) demonstrated prolonged severe cytopenia and were treated with TPO receptor agonists (eltrombopag, n = 4; romiplastim, n = 1, both drugs, n = 1). Median time from CAR-T infusion to initiation of TPO receptor agonist was 43 (range, 21-55) days. All patients were transfusion-dependent and were given daily GCSF prior to TPO receptor agonist administration. Response to TPO receptor agonists was seen in all 6 patients. Median time from TPO receptor agonist initiation to resolution of cytopenia was 22 (range, 8-124) days for Hb, 27 (range, 6-38) days for platelets, and 29 (range, 7-61) days for neutrophils. A complete resolution of all blood counts (ANC > 500 /microL and platelets > 20,000/microL and hemoglobin > 8 gr/dL) was seen in 5/6 patients. No toxicity was observed during the therapy course. This paper supports further investigation of TPO receptor agonists in the treatment of persistent cytopenia following CAR-T cell therapy.
Subject(s)
Anemia, Aplastic , Hematologic Agents , Lymphoma, Large B-Cell, Diffuse , Receptors, Chimeric Antigen , Thrombocytopenia , Adult , Aged , Anemia, Aplastic/drug therapy , Antigens, CD19 , Bone Marrow/pathology , Hematologic Agents/therapeutic use , Humans , Lymphoma, Large B-Cell, Diffuse/pathology , Receptors, Thrombopoietin/agonists , T-Lymphocytes , Thrombocytopenia/chemically induced , Thrombopoietin/adverse effectsABSTRACT
Patients with delayed B-cell reconstitution/B-cell aplasia after cellular therapy show decreased immunogenicity to the BNT162b2 mRNA COVID-19 vaccine. We prospectively evaluated both humoral and cellular immune response to a third vaccine dose in patients after allogeneic HCT (n = 10) or CD19-based chimeric antigen receptor T cells (CAR-T) therapy (n = 6) with low absolute B cell numbers and who failed to mount a humeral response after 2 vaccine doses. Humoral response was documented in 40% and 17% after allogeneic HCT and CAR-T therapy, respectively. None of the patients with complete B-cell aplasia developed anti-vaccine antibodies. Cellular response was documented in all patients after allogeneic HCT and in 83% of the patients after CAR-T. T-cell subclasses levels were not predictive for response, while a longer duration from infusion of cells was associated with a better cellular response. We conclude that cellular response develops with repeated vaccine doses even in patients with B-cell aplasia or delayed B-cell reconstitution, and these patients should therefore be vaccinated. These results should be considered in future studies analyzing immunogenicity in this population. Larger and longer follow-up studies are required to confirm whether cellular immunogenicity translates into vaccine efficacy.
Subject(s)
COVID-19 , Receptors, Chimeric Antigen , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunity, Cellular , Immunity, Humoral , Prospective Studies , RNA, Messenger , SARS-CoV-2ABSTRACT
The characteristics of infections following chimeric antigen receptor T (CAR-T) cells targeting CD19 in real-word population are obscure. We analyzed infections' characteristics in the first month among consecutive patients with diffuse large B-cell lymphoma (DLBCL) (n = 60, median age, 69.3 years), treated with commercial CAR-T cells. ECOG performance status (PS) was 2-3 in most patients (58%). Infections were observed in 45% of patients (16, 27%, bacterial infections, and 14, 23%, viral infections). Bacterial infection included clinically documented infection in 7 (Pneumonia, n = 5; periodontal infection, n = 1; and cellulitis, n = 1) and microbiology documented infection (MDI) in 9 patients (Gram-negative rod, n = 5; Gram-positive cocci, n = 3, bacteremia; polymicrobial, n = 1). The most common viral infection was cytomegalovirus (CMV) reactivation (n = 10, 17%) leading to initiation of anti-CMV treatment in 6 (60%) among these patients. None had CMV disease. In univariate analysis, immune effector cell-associated neurotoxicity syndrome (ICANS) was associated with higher incidence of bacterial infection (OR=4.5, P = .018), while there was a trend for lower incidence of bacterial infections in patients with chemosensitive disease to bridging therapy (OR=0.375, P = .074). Age or PS was not associated with increased risk of bacterial infection. Increase in C-reactive protein (CRP) prior to fever onset was associated with microbiologically documented infections. We conclude that infections are common in the first month following CAR-T-cell administration, however, were not increased in elderly patients or those presenting with poorer PS. Increase in CRP prior to fever onset could support infection over cytokine release syndrome.
Subject(s)
Antigens, CD19/immunology , Immunotherapy, Adoptive/adverse effects , Infections/etiology , Receptors, Chimeric Antigen/immunology , Adult , Aged , Aged, 80 and over , Bacterial Infections/diagnosis , Bacterial Infections/drug therapy , Bacterial Infections/etiology , Comorbidity , Disease Management , Disease Susceptibility , Female , Humans , Immunotherapy, Adoptive/methods , Incidence , Infections/diagnosis , Infections/therapy , Lymphoma, Large B-Cell, Diffuse/complications , Lymphoma, Large B-Cell, Diffuse/therapy , Male , Middle Aged , Odds Ratio , Risk Factors , Treatment Outcome , Young AdultABSTRACT
PURPOSE: The introduction of CD19-specific chimeric antigen receptor T-cell therapy (CAR-T) for treatment of relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) gives hope to patients with otherwise dismal prognosis. Therapy outcomes, however, depend upon selection of patients and accurate early identification of non-responders. Patients treated with CAR-T usually undergo [18F]FDG PET-CT at time of decision (TD), time of CAR-T transfusion (TT), 1 month (M1), and 3 months (M3) post-therapy. The purpose of the current study was to identify the specific parameters that should be addressed when reporting PET-CT studies in the clinical setting of CAR-T therapy. METHODS: A total of 138 PET-CT scans (30 TD, 42 TT, 44 M1, 22 M3) of 48 patients treated with CAR-T were included. SUVmax, TMTV, and TLG were calculated in all scans. Response was assessed using the Deauville scale and ΔSUVmax method. Overall survival (OS) was the primary endpoint. Median follow-up was 12.8 (IQR 6.4-16.0) months from CAR-T infusion. RESULTS: In a univariate analysis, TD-SUVmax > 17.1 and TT-SUVmax > 12.1 were associated with shorter OS (Pv < 0.05). In a multivariate analysis, three factors were significantly associated with shorter OS: TD-SUVmax > 17.1 (HR 10.3; Pv < 0.01), LDH > 450 U/l (HR 7.7; Pv < 0.01), and ECOG score > 1 (HR 5.5; Pv = 0.04). Data from TD and TT PET-CT scans were not predictive of toxicity. On M1-PET-CT, patients with a Deauville score > 3 had significantly shorter OS (median 7.9 months, versus not reached, Pv < 0.01). ΔSUVmax ≤ 66% on M1-PET-CT predicted shorter OS when M1-SUVmax was compared to TD-SUVmax (Pv = 0.02) but not to TT-SUVmax (Pv = 0.38). CONCLUSION: Pre-treatment SUVmax may guide patient selection for CAR-T therapy. On M1-PET-CT, Deauville score and ΔSUVmax from TD may identify early therapy failure. These parameters are easy to obtain and should be included in the PET-CT report.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Receptors, Chimeric Antigen , Cell- and Tissue-Based Therapy , Fluorodeoxyglucose F18 , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/therapy , Positron Emission Tomography Computed Tomography/methods , Positron-Emission Tomography , Prognosis , Receptors, Chimeric Antigen/therapeutic use , Retrospective StudiesABSTRACT
Data are scarce regarding both the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing immune cell therapy; thus, we prospectively evaluated these two domains in patients receiving this vaccine after allogeneic hematopoietic cell transplantation (HCT; n = 66) or after CD19-based chimeric antigen receptor T cell (CART) therapy (n = 14). Overall, the vaccine was well tolerated, with mild non-hematologic vaccine-reported adverse events in a minority of the patients. Twelve percent of the patients after the first dose and 10% of the patients after the second dose developed cytopenia, and there were three cases of graft-versus-host disease exacerbation after each dose. A single case of impending graft rejection was summarized as possibly related. Evaluation of immunogenicity showed that 57% of patients after CART infusion and 75% patients after allogeneic HCT had evidence of humoral and/or cellular response to the vaccine. The Cox regression model indicated that longer time from infusion of cells, female sex, and higher CD19+ cells were associated with a positive humoral response, whereas a higher CD4+/CD8+ ratio was correlated with a positive cellular response, as confirmed by the ELISpot test. We conclude that the BNT162b2 mRNA COVID-19 vaccine has impressive immunogenicity in patients after allogeneic HCT or CART. Adverse events were mostly mild and transient, but some significant hematologic events were observed; hence, patients should be closely monitored.
Subject(s)
COVID-19 , Hematopoietic Stem Cell Transplantation , BNT162 Vaccine , COVID-19 Vaccines , Female , Humans , Prospective Studies , RNA, Messenger/genetics , SARS-CoV-2ABSTRACT
PURPOSE OF REVIEW: To discuss the important advances in CAR T cell therapy over the past year, focusing on clinical results where available. RECENT FINDINGS: Approximately 30 years after they were first conceived of and 15 years after the first small-scale single-center clinical trials, the past 3 years represent a major milestone in the development of CAR T cells. In the United States, the Food and Drug Administration (FDA) approved Tisagenlecleucel for the treatment of relapsed/refractory B-ALL and Axicabtagene Ciloleucel, for adults with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) in 2017. Tisagenlecleucel received a second indication in adults with R/R DLBCL in 2018. Regulatory approval for CAR T cells was then granted in Europe, Canada, Australia, and Japan. Most recently, in July 2020 the FDA granted regulatory approval to a third CAR T cell product, Brexucabtagene Autoleucel for mantle cell lymphoma. All products target the CD19 antigen but differ in the costimulatory molecule within the CAR construct. Currently, it is unknown whether there are any differences in clinical activity or toxicity between these products. SUMMARY: The CAR T cell the platform is evolving at a rapid pace and is expected to further improve the therapeutic outcomes of hematological malignancies.
Subject(s)
Immunotherapy, Adoptive/methods , Leukemia/therapy , Lymphoma/therapy , Multiple Myeloma/therapy , Receptors, Chimeric Antigen/therapeutic use , Animals , Antigens, CD19/adverse effects , Antigens, CD19/therapeutic use , Biological Products , Clinical Trials as Topic , Humans , Immunotherapy, Adoptive/adverse effects , Receptors, Antigen, T-Cell/therapeutic use , Treatment OutcomeABSTRACT
Multiple myeloma (MM) is a plasma cell neoplasia commonly treated with proteasome inhibitors such as bortezomib. Although bortezomib has demonstrated enhanced survival benefit, some patients relapse and subsequently develop resistance to such therapy. Here, we investigate the mechanisms underlying relapse and refractory MM following bortezomib treatment. We show that bortezomib-exposed proinflammatory macrophages promote an enrichment of MM-tumor-initiating cells (MM-TIC) both in vitro and in vivo. These effects are regulated in part by IL1ß, as blocking the IL1ß axis by a pharmacologic or genetic approach abolishes bortezomib-induced MM-TIC enrichment. In MM patients treated with bortezomib, high proinflammatory macrophages in the bone marrow negatively correlate with survival rates (HR, 1.722; 95% CI, 1.138-2.608). Furthermore, a positive correlation between proinflammatory macrophages and TICs in the bone marrow was also found. Overall, our results uncover a protumorigenic cross-talk involving proinflammatory macrophages and MM cells in response to bortezomib therapy, a process that enriches the MM-TIC population. IMPLICATIONS: Our findings suggest that proinflammatory macrophages in bone marrow biopsies represent a potential prognostic biomarker for acquired MM resistance to bortezomib therapy.
Subject(s)
Antineoplastic Agents/pharmacology , Bortezomib/pharmacology , Drug Resistance, Neoplasm , Multiple Myeloma/drug therapy , Proteasome Inhibitors/pharmacology , Adult , Animals , Biopsy , Bone Marrow/pathology , Cell Line, Tumor , Female , Humans , Macrophages/pathology , Mice , Multiple Myeloma/immunology , Multiple Myeloma/pathology , Neoplastic Stem Cells/pathology , Recurrence , Young AdultABSTRACT
Autologous stem cell transplantation (ASCT), intensifying anti-leukemic effects without significant treatment-related mortality (TRM), is particularly appealing in AML with favorable genetic/molecular profile. This study retrospectively evaluated the outcomes of post-remission treatment in consecutive favorable-risk AML patients. Sixty-six patients were included: 32 had mutated NPM1/wild-type FLT-ITD, 16 had t(8:21) and 18 - inv(16). Forty patients received chemotherapy alone, 26 underwent ASCT upfront. In time-dependent analysis, the ASCT group demonstrated higher relapse-free (RFS) (p = .001) and overall survivals (OS) (p = .0007). The 1-year RFS and OS were 44.2% vs 88% and 71% vs 96% for chemotherapy and ASCT, respectively. The corresponding TRM was 4/40 (10.0%) and 0/26 (0%), with relapse rates of 70.0% and 19.2% (p = .0002). In multivariate analysis, ASCT was associated with superior OS and RFS. In conclusion, ASCT offers significantly superior RFS and OS in favorable-risk AML in first complete remission. These data support the recent resurgence of interest in ASCT for AML.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Adolescent , Adult , Aged , Combined Modality Therapy , Disease Management , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Induction Chemotherapy , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/etiology , Male , Middle Aged , Nucleophosmin , Prognosis , Retrospective Studies , Transplantation, Autologous , Treatment Outcome , Young AdultABSTRACT
Acute myeloid leukemia (AML) is a rapidly progressive, poor-prognosis malignancy arising from hematopoietic stem/progenitor cells. The long history of successful use of allogeneic hematopoietic cell transplantation (alloHCT) in AML indicates that this disease is immunoresponsive, leading to optimism that novel immunotherapies such as bispecific antibodies, chimeric antigen receptor T cells, and immune checkpoint inhibitors will generate meaningful disease control. However, emerging data on the immunoevasive tactics employed by AML blasts at diagnosis and at relapse indicate that optimism must be tempered by an understanding of this essential paradox. Furthermore, AML has a low mutational burden, thus presenting few neoantigens for attack by autologous T cells, even after attempted reversal of inhibitory receptor/ligand interactions. In this review, we outline the known AML targets, explore immune evasion mechanisms, and describe recent data and current clinical trials of single and combination immunotherapies. Clin Cancer Res; 24(22); 5502-15. ©2018 AACR.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Immunotherapy , Leukemia, Myeloid, Acute/drug therapy , Animals , Antigens, Neoplasm/immunology , Antigens, Neoplasm/pharmacology , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , Clinical Trials as Topic , Humans , Immunotherapy/methods , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/mortality , Molecular Targeted Therapy , Treatment Outcome , Tumor Escape/drug effectsABSTRACT
Stromal cells residing in the tumor microenvironment contribute to the development of therapy resistance. Here we show that chemotherapy-educated mesenchymal stem cells (MSC) promote therapy resistance via cross-talk with tumor-initiating cells (TIC), a resistant tumor cell subset that initiates tumorigenesis and metastasis. In response to gemcitabine chemotherapy, MSCs colonized pancreatic adenocarcinomas in large numbers and resided in close proximity to TICs. Furthermore, gemcitabine-educated MSCs promoted the enrichment of TICs in vitro and enhance tumor growth in vivo These effects were dependent on the secretion of CXCL10 by gemcitabine-educated MSCs and subsequent activation of the CXCL10-CXCR3 axis in TICs. In an orthotopic pancreatic tumor model, targeting TICs using nanovesicles (called nanoghosts) derived from MSC membranes and loaded with a CXCR3 antagonist enhanced therapy outcome and delayed tumor regrowth when administered in combination with gemcitabine. Overall, our results establish a mechanism through which MSCs promote chemoresistance, and propose a novel drug delivery system to target TICs and overcome this resistance.Significance: These results establish a mechanism by which mesenchyme stem cells in the tumor microenvironment promote chemoresistance, and they propose a novel drug delivery system to overcome this challenge. Cancer Res; 78(5); 1253-65. ©2018 AACR.
Subject(s)
Biomarkers, Tumor/metabolism , Cell Transformation, Neoplastic/pathology , Deoxycytidine/analogs & derivatives , Lung Neoplasms/pathology , Mesenchymal Stem Cells/pathology , Neoplastic Stem Cells/pathology , Pancreatic Neoplasms/pathology , Animals , Antimetabolites, Antineoplastic/pharmacology , Apoptosis , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Communication , Cell Proliferation , Cell Transformation, Neoplastic/drug effects , Cell Transformation, Neoplastic/metabolism , Chemokine CXCL10/genetics , Chemokine CXCL10/metabolism , Deoxycytidine/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Mice , Mice, SCID , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Receptors, CXCR3/genetics , Receptors, CXCR3/metabolism , Tumor Cells, Cultured , Tumor Microenvironment , Xenograft Model Antitumor Assays , Gemcitabine , Pancreatic NeoplasmsABSTRACT
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, characterized by the presence of long-lived circulating leukemic cells in the peripheral blood that may infiltrate all organs, particularly those of the reticulo-endothelial system. Liver enlargement and elevation of liver enzymes related to specific involvement by the underlying disease are well-recognized features in these patients. In CLL, the differential diagnosis of liver disorders is broad and includes liver infiltration by leukemic cells, immunologic manifestations associated with CLL, primary and secondary hepatic malignancies, drug-induced hepatotoxicity, infections, and Richter transformation. The above conditions can cause serious and even fatal complications such as acute liver failure. The aim of this study was to summarize all available published literature on hepatic manifestations encountered in CLL. This review contains sections on liver enlargement because of leukemic infiltration, autoimmune-induced hepatic dysfunction, acute liver failure, drug-induced liver toxicity, and associated malignancies. A high index of clinical suspicion and appropriate diagnostic evaluation, including liver biopsy in special circumstances, are important for both accurate diagnosis and deciding on the most appropriate treatment to prevent the development of fatal complications of acute liver failure.