RESUMO
ABSTRACT: Relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective antileukemic effect post-HCT. We conducted a phase 1 clinical trial using a novel TCR-T product targeting the minor H antigen, HA-1, to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T after HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8 coreceptor were successfully manufactured from HA-1-disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to 9 HCT recipients who had developed disease recurrence after HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, 4 patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with 1 patient still in remission at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T-cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial was registered at ClinicalTrials.gov as #NCT03326921.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia , Receptores de Antígenos de Linfócitos T , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Leucemia/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Recidiva , Idoso , Receptores de Antígenos Quiméricos/imunologia , OligopeptídeosRESUMO
ABSTRACT: Although initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine plus rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance after induction is often used. Thus, the open-label, randomized phase 2 ECOG-ACRIN Cancer Research Group E1411 trial was designed to test 2 questions: (1) does addition of bortezomib to BR induction (BVR) and/or (2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012 to 2016, 373 previously untreated patients, 87% aged ≥60 years, were enrolled in this trial. At a median follow-up of 7.5 years, there is no difference in the median PFS of BR compared with BVR (5.5 vs 6.4 years; hazard ratio [HR], 0.90; 90% confidence interval [CI], 0.70-1.16). There were no unexpected additional toxicities with BVR treatment compared with BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide did not significantly improve PFS, with median PFS in R vs LR (5.9 vs 7.2 years; HR, 0.84; 90% CI, 0.62-1.15). Most patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with R alone after BR. Nonetheless, the >5-year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by R maintenance as highly effective initial therapy for older patients with MCL. This trial was registered at www.clinicaltrials.gov as #NCT01415752.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Cloridrato de Bendamustina , Bortezomib , Lenalidomida , Linfoma de Célula do Manto , Quimioterapia de Manutenção , Rituximab , Humanos , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/uso terapêutico , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso de 80 Anos ou mais , Adulto , Quimioterapia de Indução , Intervalo Livre de ProgressãoRESUMO
Concurrent administration of pembrolizumab with chemotherapy in untreated classic Hodgkin lymphoma (CHL) has not been studied previously. To investigate this combination, we conducted a single-arm study of concurrent pembrolizumab with AVD (doxorubicin, vinblastine, and dacarbazine; APVD) for untreated CHL. We enrolled 30 patients and met the primary safety end point with no observed significant treatment delays in the first 2 cycles. Twelve patients experienced grade 3 or 4 nonhematologic adverse events (AEs), most commonly febrile neutropenia and infection/sepsis. Grade 3 or 4 immune-related AEs, including alanine aminotransferase elevation and aspartate aminotransferase elevation were observed in 3 patients. One patient experienced an episode of grade 2 colitis and arthritis. Six patients missed at least 1 dose of pembrolizumab because of AEs, primarily grade 2 or higher transaminitis. Among 29 response-evaluable patients, the best overall response rate was 100% and the complete response rate was 90%. With a median follow-up of 2.1 years, the 2-year progression-free survival (PFS) and overall survival were 97% and 100%, respectively. To date, no patient who has withheld or discontinued pembrolizumab because of toxicity has progressed. Clearance of circulating tumor DNA (ctDNA) was associated with superior PFS when measured after cycle 2 and at the end of treatment (EOT). None of the 4 patients with persistent uptake by fluorodeoxyglucose positron emission tomography (PET) at EOT yet negative ctDNA have relapsed to date. Concurrent APVD shows promising safety and efficacy but may yield spurious PET findings in some patients. This trial was registered at www.clinicaltrials.gov as #NCT03331341.
Assuntos
Doença de Hodgkin , Humanos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin , Doxorrubicina/efeitos adversos , Doença de Hodgkin/patologiaRESUMO
BTK inhibitors, Bcl-2 inhibitors, and other targeted therapies have significantly improved the outcomes of patients with chronic lymphocytic leukemia (CLL). With increased survivorship, monitoring disease and deciphering potential mechanisms of resistance to these agents are critical for devising effective treatment strategies. We used duplex sequencing, a technology that enables detection of mutations at ultra-low allelic frequencies, to identify mutations in five genes associated with drug resistance in CLL and followed their evolution in two patients who received multiple targeted therapies and ultimately developed disease progression on pirtobrutinib. In both patients we detected variants that expanded and reached significant cancer cell fractions (CCF). In patient R001, multiple known resistance mutations in both BTK and PLCG2 appeared following progression on zanubrutinib (BTK p.L528W, p.C481S; PLCG2 S707F, L845F, R665W, and D993H). In contrast, patient R002 developed multiple BTK mutations following acalabrutinib treatment, including known resistance mutations p.C481R, p.T474I and p.C481S. We found that pirtobrutinib was able to suppress, but not completely eradicate, BTK p.C481S mutations in both patients, but other resistance mutations such as mutations in PLCG2 and new BTK mutations increased while the patients were receiving pirtobrutinib. For example, BTK p.L528W in patient R001 increased in frequency more than 1,000-fold (from a CCF of 0.02% to 35%), and the CCF in p.T474I in patient R002 increased from 0.03% to 4.2% (more than 100-fold). Our data illuminate the evolutionary dynamics of resistant clones over the patients' disease course and under selective pressure from different targeted treatments.
Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Células Clonais , Frequência do GeneRESUMO
BACKGROUND: γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma. METHODS: We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50â×â106 CAR T cells, 150â×â106 CAR T cells, 300â×â106 CAR T cells, and 450â×â106 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals. FINDINGS: 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450â×â106 CAR+ cells, and the recommended phase 2 dose was not reached. INTERPRETATIONS: Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials. FUNDING: Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health.
Assuntos
Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Masculino , Humanos , Feminino , Mieloma Múltiplo/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/uso terapêutico , Antígeno de Maturação de Linfócitos B , Imunoterapia Adotiva/efeitos adversos , Linfócitos TRESUMO
BACKGROUND: High hepatitis B virus (HBV) DNA level is an independent risk factor for postoperative HBV-associated liver cancer recurrence. We sought to examine whether HBV DNA level and antiviral therapy are associated with survival outcomes in patients with advanced hepatocellular carcinoma (HCC) treated with anti-programmed cell death protein 1 (PD-1)based immunotherapy. METHODS: This single-institution retrospective analysis included 217 patients with advanced HBV-related HCC treated from 1 June 2018, through 30 December 2020. Baseline information was compared between patients with low and high HBV DNA levels. Overall survival (OS) and progression-free survival (PFS) were compared, and univariate and multivariate analyses were applied to identify potential risk factors for oncologic outcomes. RESULTS: The 217 patients included in the analysis had a median survival time of 20.6 months. Of these HBV-associated HCC patients, 165 had known baseline HBV DNA levels. Baseline HBV DNA level was not significantly associated with OS (P = 0.59) or PFS (P = 0.098). Compared to patients who did not receive antiviral therapy, patients who received antiviral therapy had significantly better OS (20.6 vs 11.1 months, P = 0.020), regardless of HBV DNA levels. Moreover, antiviral status (adjusted HR = 0.24, 95% CI 0.094-0.63, P = 0.004) was an independent protective factor for OS in a multivariate analysis of patients with HBV-related HCC. CONCLUSIONS: HBV viral load does not compromise the clinical outcome of patients with HBV-related HCC treated with anti-PD-1-based immunotherapy. The use of antiviral therapy significantly improves survival time of HBV-related HCC patients.
Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Inibidores de Checkpoint Imunológico , Neoplasias Hepáticas , Humanos , Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/virologia , DNA Viral , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/virologia , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos RetrospectivosRESUMO
BACKGROUND: Anti-angiogenic drugs increase anti-tumor efficacy of immune checkpoint inhibitors (ICIs). However, the optimal dose of anti-angiogenic drugs remains unclear. METHODS: We retrospectively analyzed efficacy and safety data from patients diagnosed with advanced or metastatic non-small cell lung cancer (NSCLC) that received PD-1 blockade with low-doses of anlotinib, a highly selective receptor tyrosine kinase inhibitor mainly targeting vascular endothelial growth factor receptors, as second or later line therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety profile. Univariate and multivariate analyses were used to identify prognostic factors. RESULTS: A total of 40 eligible patients were included. The median PFS was 11.4 months. The median OS of the entire cohort was 27.0 months. ORR was achieved in 16 patients (40.0%) and DCR was maintained in 33 patients (82.5%). The overall incidence of adverse events (AEs) was 52.5%, and the most common all grade AE was gastrointestinal reactions, which occurred in four patients (10.0%). Treatment-related grade 3/4 toxicity was observed in one patient (2.5%). Conclusions Low-dose anlotinib may be an effective and well-tolerated anti-angiogenesis partner for combination therapy with ICIs in second-line and later settings for advanced NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Quinolinas , Humanos , Inibidores da Angiogênese/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos , Quinolinas/uso terapêutico , Indóis/uso terapêuticoRESUMO
CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet, CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (acute lymphoblastic leukemia [ALL], n = 14; chronic lymphocytic leukemia [CLL], n = 9; non-Hodgkin lymphoma [NHL], n = 21) who received CART2 on a phase 1/2 trial (NCT01865617) at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 cytokine release syndrome, 9%; grade ≥3 neurotoxicity, 11%). After CART2, complete response (CR) was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before the first CAR T-cell infusion (CART1) and an increase in the CART2 dose compared with CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received cyclophosphamide and fludarabine (Cy-Flu) lymphodepletion before CART1 and a higher CART2 compared with CART1 cell dose. The identification of 2 modifiable pretreatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.
Assuntos
Antígenos CD19/metabolismo , Imunoterapia Adotiva , Leucemia de Células B/terapia , Leucemia Linfocítica Crônica de Células B/terapia , Linfoma não Hodgkin/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Idoso , Proliferação de Células , Ciclofosfamida/uso terapêutico , Síndrome da Liberação de Citocina/complicações , Feminino , Humanos , Leucemia de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Linfoma não Hodgkin/imunologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Intervalo Livre de Progressão , Linfócitos T/imunologia , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
BACKGROUND: Although lung cancer screening (LCS) for high-risk individuals reduces lung cancer mortality in clinical trial settings, many questions remain about how to implement high-quality LCS in real-world programs. With the increasing use of telemedicine in healthcare, studies examining this approach in the context of LCS are urgently needed. We aimed to identify sociodemographic and other factors associated with screening completion among individuals undergoing telemedicine Shared Decision Making (SDM) for LCS. METHODS: This retrospective study examined patients who completed Shared Decision Making (SDM) via telemedicine between May 4, 2020 - March 18, 2021 in a centralized LCS program. Individuals were categorized into Complete Screening vs. Incomplete Screening subgroups based on the status of subsequent LDCT completion. A multi-level, multivariate model was constructed to identify factors associated with incomplete screening. RESULTS: Among individuals undergoing telemedicine SDM during the study period, 20.6% did not complete a LDCT scan. Bivariate analysis demonstrated that Black/African-American race, Medicaid insurance status, and new patient type were associated with greater odds of incomplete screening. On multi-level, multivariate analysis, individuals who were new patients undergoing baseline LDCT or resided in a census tract with a high level of socioeconomic deprivation had significantly higher odds of incomplete screening. Individuals with a greater level of education experienced lower odds of incomplete screening. CONCLUSIONS: Among high-risk individuals undergoing telemedicine SDM for LCS, predictors of incomplete screening included low education, high neighborhood-level deprivation, and new patient type. Future research should focus on testing implementation strategies to improve LDCT completion rates while leveraging telemedicine for high-quality LCS.
Assuntos
Neoplasias Pulmonares , Telemedicina , Humanos , Estados Unidos , Tomada de Decisão Compartilhada , Tomada de Decisões , Detecção Precoce de Câncer , Estudos Retrospectivos , Neoplasias Pulmonares/diagnóstico , Programas de RastreamentoRESUMO
Chimeric antigen receptor T-cell (CAR T) therapy has shown promising efficacy in relapsed and refractory diffuse large B cell lymphoma (DLBCL). While most patients undergo CAR T infusion with active disease, the impact of some clinical variables, such as responsiveness to the pre-CAR T chemotherapy on the response to CAR T, is unknown. In this single-institution study, we studied the impact of several pre-CAR T variables on the post-CAR outcomes. Sixty patients underwent apheresis for axicabtagene-ciloleucel (axi-cel) and 42 of them (70.0%) had primary refractory disease. Bridging therapy between apheresis and lymphodepletion was given in 34 patients (56.7%). After axi-cel, the overall response rate was 63.3%. Responsiveness to the immediate pre-CAR T therapy did not show a significant association with response to axi-cel, progression-free (PFS) or overall (OS) survival. Multivariable analysis determined that bulky disease before lymphodepletion was independently associated with inferior outcomes, and patients that presented with high-burden disease unresponsive to immediate pre-CAR T therapy had a dismal outcome. This data supports proceeding with treatment in CAR T candidates regardless of their response to immediate pre-CAR T therapy. Interim therapeutic interventions should be considered in patients who have known risk factors for poor outcomes (bulky disease, high LDH).
Assuntos
Produtos Biológicos , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Humanos , Antígenos CD19 , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfócitos TRESUMO
Prior reports evaluating SARS-CoV-2 vaccine efficacy in chronic lymphocytic leukaemia (CLL) used semiquantitative measurements of anti-S to evaluate immunity; however, neutralization assays were used to assess functional immunity in the trials leading to vaccine approval. Here, we identified decreased rates of seroconversion in vaccinated CLL patients and lower anti-S levels compared to healthy controls. Notably, we demonstrated similar results with the Roche anti-S assay and neutralization activity. Durable responses were seen at six months; augmentation with boosters was possible in responding patients. Absence of normal B cells, frequently seen in patients receiving Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors, was a strong predictor of lack of seroconversion.
Assuntos
COVID-19 , Leucemia Linfocítica Crônica de Células B , COVID-19/prevenção & controle , Vacinas contra COVID-19/uso terapêutico , Humanos , Leucemia Linfocítica Crônica de Células B/terapia , SARS-CoV-2 , Eficácia de VacinasRESUMO
BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a rescue procedure used for cardiac and pulmonary dysfunction. Patients on ECMO often require blood transfusions to maintain oxygen delivery and recover from bleeding complications. Goals of the current study were to determine transfusion requirements while on ECMO, and incidence and transfusion requirements for bleeding complications. METHODS: Packed red blood cell (PRBC) transfusions and bleeding complications were identified by retrospective chart review of patients on ECMO from 2010 to 2018 at our institution. Patients were categorized into those who did not bleed (group A) and those who bled (group B). Incidence, sites of bleed, and transfusion requirement for each bleeding were analyzed. RESULTS: Among 217 patients including veno-arterial (VA) (n = 148) and veno-venous (VV) (n = 69) ECMO, we identified 62 patients without bleeding complications (group A) and 155 patients with bleeding complications (group B). In group A, transfusion requirement was 0.6 PRBC/day for VA-ECMO (n = 42) and 0.2 PRBC/day for VV-ECMO (n = 20) (p = 0.0015). In group B, number of PRBC given per event per day for bleeding complications during ECMO was mediastinal/thoracic bleed (83 events, 4.7 PRBC/event/day), gastrointestinal bleed (59 events, 4.8 PRBC/event/day), cannulation site bleed (88 events, 3.6 PRBC/event/day), and nasopharyngeal bleed (103 events, 2.8 PRBC/event/day). Thirty-day hospital mortality rate was co-related to transfusion requirement (area under ROC curve: 0.70). CONCLUSION: Patients without clinical bleeding still required transfusion, with higher rates observed with VA- than VV-ECMO. Transfusion requirements dramatically increased when patients developed various bleeding complications and had a significant impact on 30-day mortality rate.
Assuntos
Oxigenação por Membrana Extracorpórea , Transfusão de Sangue , Transfusão de Eritrócitos/efeitos adversos , Transfusão de Eritrócitos/métodos , Oxigenação por Membrana Extracorpórea/métodos , Hemorragia/etiologia , Hemorragia/terapia , Humanos , Estudos RetrospectivosRESUMO
Minimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD-negative to ≤10-5, which is concerning because MRD-negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant subclones. Virtually all MM clones are exquisitely sensitive to radiation, and the α-emitter astatine-211 (211At) deposits prodigious energy within 3 cell diameters, which is ideal for eliminating MRD if effectively targeted. CD38 is a proven MM target, and we conjugated 211At to an anti-CD38 monoclonal antibody to create an 211At-CD38 therapy. When examined in a bulky xenograft model of MM, single-dose 211At-CD38 at 15 to 45 µCi at least doubled median survival of mice relative to untreated controls (P < .003), but no mice achieved complete remission and all died within 75 days. In contrast, in a disseminated disease model designed to reflect low-burden MRD, 3 studies demonstrated that single-dose 211At-CD38 at 24 to 45 µCi produced sustained remission and long-term survival (>150 days) for 50% to 80% of mice, where all untreated mice died in 20 to 55 days (P < .0001). Treatment toxicities were transient and minimal. These data suggest that 211At-CD38 offers the potential to eliminate residual MM cell clones in low-disease-burden settings, including MRD. We are optimistic that, in a planned clinical trial, addition of 211At-CD38 to an autologous stem cell transplant (ASCT) conditioning regimen may improve ASCT outcomes for MM patients.
Assuntos
ADP-Ribosil Ciclase 1 , Astato/uso terapêutico , Imunoconjugados/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , ADP-Ribosil Ciclase 1/análise , Astato/administração & dosagem , Astato/farmacocinética , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/farmacocinética , Masculino , Mieloma Múltiplo/patologia , Neoplasia Residual/patologiaRESUMO
Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease-negative (MRD-negative) complete remission (CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase 1/2 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 CAR T-cell therapy and were evaluable for response achieved MRD-negative CR by high-resolution flow cytometry. With a median follow-up of 30.9 months, event-free survival (EFS) and overall survival (OS) were significantly better in the patients who achieved MRD-negative CR compared with those who did not (median EFS, 7.6 vs 0.8 months; P < .0001; median OS, 20.0 vs 5.0 months; P = .014). In patients who achieved MRD-negative CR by flow cytometry, absence of the index malignant clone by IGH deep sequencing was associated with better EFS (P = .034). Stepwise multivariable modeling in patients achieving MRD-negative CR showed that lower prelymphodepletion lactate dehydrogenase concentration (hazard ratio [HR], 1.38 per 100 U/L increment increase), higher prelymphodepletion platelet count (HR, 0.74 per 50 000/µL increment increase), incorporation of fludarabine into the lymphodepletion regimen (HR, 0.25), and allogeneic hematopoietic cell transplantation (HCT) after CAR T-cell therapy (HR, 0.39) were associated with better EFS. These data allow identification of patients at higher risk of relapse after CAR T-cell immunotherapy who might benefit from consolidation strategies such as allogeneic HCT. This trial was registered at www.clinicaltrials.gov as #NCT01865617.
Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Indução de Remissão/métodos , Adulto , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Depleção Linfocítica , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Receptores de Antígenos Quiméricos , Terapia de Salvação/métodos , Adulto JovemRESUMO
Factors associated with durable remission after CD19 chimeric antigen receptor (CAR)-modified T-cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) have not been identified. We report multivariable analyses of factors affecting response and progression-free survival (PFS) in patients with aggressive NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by 2 × 106 CD19-directed CAR T cells/kg. The best overall response rate was 51%, with 40% of patients achieving complete remission. The median PFS of patients with aggressive NHL who achieved complete remission was 20.0 months (median follow-up, 26.9 months). Multivariable analysis of clinical and treatment characteristics, serum biomarkers, and CAR T-cell manufacturing and pharmacokinetic data showed that a lower pre-lymphodepletion serum lactate dehydrogenase (LDH) level and a favorable cytokine profile, defined as serum day 0 monocyte chemoattractant protein-1 (MCP-1) and peak interleukin-7 (IL-7) concentrations above the median, were associated with better PFS. MCP-1 and IL-7 concentrations increased after lymphodepletion, and higher intensity of cyclophosphamide and fludarabine lymphodepletion was associated with higher probability of a favorable cytokine profile. PFS was superior in patients who received high-intensity lymphodepletion and achieved a favorable cytokine profile compared with those who received the same intensity of lymphodepletion without achieving a favorable cytokine profile. Even in high-risk patients with pre-lymphodepletion serum LDH levels above normal, a favorable cytokine profile after lymphodepletion was associated with a low risk of a PFS event. Strategies to augment the cytokine response to lymphodepletion could be tested in future studies of CD19 CAR T-cell immunotherapy for aggressive B-cell NHL. This trial was registered at www.clinicaltrials.gov as #NCT01865617.
Assuntos
Antígenos CD19/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Baseada em Transplante de Células e Tecidos/métodos , Imunoterapia/métodos , Depleção Linfocítica/métodos , Linfoma não Hodgkin/mortalidade , Receptores de Antígenos de Linfócitos T/imunologia , Terapia Combinada , Ciclofosfamida/administração & dosagem , Feminino , Seguimentos , Humanos , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. The first-line immunologically-replete setting may be an opportune time for PD-1 inhibition. We evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Eligible patients were age 18 or older, had adequate organ function, and had DLBCL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP, primarily to assess toxicity. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Among 30 patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 expression was associated with non-GCB subtype, and improved PFS and survival. Pembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, supporting evaluation of PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Linfoma Difuso de Grandes Células B , Proteínas de Neoplasias/metabolismo , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Pretargeted radioimmunotherapy (PRIT) has demonstrated remarkable efficacy targeting tumor antigens, but immunogenicity and endogenous biotin blocking may limit clinical translation. We describe a new PRIT approach for the treatment of multiple myeloma (MM) and other B-cell malignancies, for which we developed an anti-CD38-bispecific fusion protein that eliminates endogenous biotin interference and immunogenic elements. In murine xenograft models of MM and non-Hodgkin lymphoma (NHL), the CD38-bispecific construct demonstrated excellent blood clearance and tumor targeting. Dosimetry calculations showed a tumor-absorbed dose of 43.8 Gy per millicurie injected dose of 90Y, with tumor-to-normal organ dose ratios of 7:1 for liver and 15:1 for lung and kidney. In therapy studies, CD38-bispecific PRIT resulted in 100% complete remissions by day 12 in MM and NHL xenograft models, ultimately curing 80% of mice at optimal doses. In direct comparisons, efficacy of the CD38 bispecific proved equal or superior to streptavidin (SA)-biotin-based CD38-SA PRIT. Each approach cured at least 75% of mice at the highest radiation dose tested (1200 µCi), whereas at 600- and 1000-µCi doses, the bispecific outperformed the SA approach, curing 35% more mice overall (P < .004). The high efficacy of bispecific PRIT, combined with its reduced risk of immunogenicity and endogenous biotin interference, make the CD38 bispecific an attractive candidate for clinical translation. Critically, CD38 PRIT may benefit patients with unresponsive, high-risk disease because refractory disease typically retains radiation sensitivity. We posit that PRIT might not only prolong survival, but possibly cure MM and treatment-refractory NHL patients.
Assuntos
ADP-Ribosil Ciclase 1/imunologia , Anticorpos Biespecíficos/uso terapêutico , Leucemia de Células B/radioterapia , Linfoma de Células B/radioterapia , Mieloma Múltiplo/radioterapia , Radioimunoterapia/métodos , ADP-Ribosil Ciclase 1/metabolismo , Animais , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Feminino , Humanos , Leucemia de Células B/patologia , Linfoma de Células B/patologia , Camundongos Nus , Terapia de Alvo Molecular , Mieloma Múltiplo/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The adoptive transfer of genetically engineered T cells modified to express a chimeric antigen receptor (CAR) has shown remarkable activity and induces long-term remissions in patients with advanced hematologic malignancies. To date, little is known about predictive indicators of therapeutic efficacy or serious toxicity after CAR T-cell therapy in clinical practice. Biomarkers are not only potentially able to inform physicians and researchers of immunotherapy targets in particular but could also be used to monitor the effectiveness of treatments and to predict incidence of side effects in some circumstances. Identification of new biomarkers can therefore not only contribute to the development of new therapeutic and prognostic strategies for CAR T-cell therapy for cancer but also help to generate improved clinical practices for early recognition and minimization of adverse effects while preserving the antitumor activity of the CAR T cells. Herein, we will consider a variety of predictive and therapeutic biomarkers in CAR T-cell therapy and the state of current understanding of their clinical utility. The incorporation of biomarker studies in CAR T-cell clinical trials and practice will help to realize the potential clinical benefit of biomarker-guided therapy.
Assuntos
Neoplasias Hematológicas/terapia , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/transplante , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/metabolismo , Humanos , Imagem Molecular , Valor Preditivo dos Testes , Receptores de Antígenos Quiméricos/genética , Linfócitos T/imunologia , Resultado do TratamentoRESUMO
Although remarkable results have been attained by adoptively transferring T cells expressing fully murine and/or humanized anti-CD19 chimeric antigen receptors (CARs) to treat B cell malignancies, evidence of human anti-mouse immune responses against CARs provides a rationale for the development of less immunogenic CARs. By developing a fully human CAR (huCAR), these human anti-mouse immune responses are likely eliminated. This, perhaps, not only increases the persistence of anti-CD19 CAR T cells-thereby reducing the risk of tumor relapse-but also facilitates administration of multiple, temporally separated doses of CAR T cells to the same recipient. To these ends, we have designed and constructed a second-generation fully human anti-CD19 CAR (or huCAR19) containing a fully human single-chain variable fragment (ScFv) fused with a CD8a hinge, a 4-1BB transmembrane domain and intracellular T cell signaling domains of 4-1BB and CD3z. T cells expressing this CAR specifically recognized and lysed CD19+ target cells produced cytokines and proliferated in vitro. Moreover, cell volume data revealed that our huCAR construct cannot induce antigen-independent tonic signaling in the absence of cognate antigen. Considering our results, our anti-CD19 huCAR may overcome issues of transgene immunogenicity that plague trials utilizing CARs containing mouse-derived ScFvs. These results suggest that this huCAR19 be safely and effectively applied for adaptive T cell immunotherapy in clinical practice.
Assuntos
Antígenos CD19/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo , Proliferação de Células , Citocinas/biossíntese , Citotoxicidade Imunológica , Células HEK293 , Humanos , Lentivirus/genética , Ativação Linfocitária/imunologia , Transdução de SinaisRESUMO
Intravascular large B-cell lymphoma (IVLBCL) is a rare entity, with a generally aggressive course that may vary based on geographic presentation. While a United States (US) registry study showed relatively good outcomes with IVLBCL, clinicopathological and treatment data were unavailable. We performed a detailed retrospective review of cases identified at 8 US medical centres, to improve understanding of IVLBCL and inform management. We compiled data retrieved via an Institutional Review Board-approved review of IVLBCL cases identified from 1999 to 2015 at nine academic institutions across the US. We characterized the cohort's clinical status at time of diagnosis, presenting diagnostic and clinical features of the disease, treatment modalities used and overall prognostic data. Our cohort consisted of 54 patients with varying degrees of clinical features. Adjusting for age, better performance status at presentation was associated with increased survival time for the patients diagnosed in vivo (hazard ratio: 2·12, 95% confidence interval 1·28, 3·53). Based on the data we have collected, it would appear that the time interval to diagnosis is a significant contributor to outcomes of patients with IVLBCL.