RESUMO
For inoperable esophageal adenocarcinoma (EAC), identifying patients likely to benefit from recently approved immunochemotherapy (ICI+CTX) treatments remains a key challenge. We address this using a uniquely designed window-of-opportunity trial (LUD2015-005), in which 35 inoperable EAC patients received first-line immune checkpoint inhibitors for four weeks (ICI-4W), followed by ICI+CTX. Comprehensive biomarker profiling, including generation of a 65,000-cell single-cell RNA-sequencing atlas of esophageal cancer, as well as multi-timepoint transcriptomic profiling of EAC during ICI-4W, reveals a novel T cell inflammation signature (INCITE) whose upregulation correlates with ICI-induced tumor shrinkage. Deconvolution of pre-treatment gastro-esophageal cancer transcriptomes using our single-cell atlas identifies high tumor monocyte content (TMC) as an unexpected ICI+CTX-specific predictor of greater overall survival (OS) in LUD2015-005 patients and of ICI response in prevalent gastric cancer subtypes from independent cohorts. Tumor mutational burden is an additional independent and additive predictor of LUD2015-005 OS. TMC can improve patient selection for emerging ICI+CTX therapies in gastro-esophageal cancer.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Monócitos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , ImunoterapiaRESUMO
PURPOSE: PD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers. PATIENTS AND METHODS: MGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n = 40). Bevacizumab-naïve, recurrent patients received durvalumab alone (cohort B; n = 31) or in combination with standard bevacizumab (cohort B2; n = 33) or low-dose bevacizumab (cohort B3; n = 33). Bevacizumab-refractory patients received durvalumab plus bevacizumab (cohort C; n = 22). Primary endpoints were: OS-12 (A), PFS-6 (B, B2, B3), and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative, and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS). RESULTS: No cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naïve cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent patients compared with newly diagnosed patients that was partially due to dexamethasone use. A trend of increased CD8+Ki67+ T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome. CONCLUSIONS: Patients with recurrent glioblastoma have markedly lower baseline levels of multiple circulating immune cell subsets compared with newly diagnosed patients. An early increase in systemic Ki67+CD8+ cells may warrant further evaluation as a potential biomarker of therapeutic benefit among patients with glioblastoma undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective.
Assuntos
Dexametasona , Glioblastoma , Recidiva Local de Neoplasia , Anticorpos Monoclonais , Antígeno B7-H1/antagonistas & inibidores , Bevacizumab/uso terapêutico , Biomarcadores Tumorais/análise , Dexametasona/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Antígeno Ki-67 , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologiaRESUMO
Ephrin type-A 2 (EphA2) is a transmembrane receptor expressed in epithelial cancers. We report on a phase I dose escalation and biodistribution study of DS-8895a, an anti-EphA2 antibody, in patients with advanced EphA2 positive cancers. DS-8895a was administered at 1, 3, 10 or 20 mg/kg every 2 weeks to determine safety, pharmacokinetics and anti-tumor efficacy. All patients underwent 89Zr trace-labelled infusion of DS-8895a (89Zr-DS-8995a) positron emission tomography imaging to determine the biodistribution of DS-8895a, and correlate findings with EphA2 expression, receptor saturation and response. Nine patients were enrolled on study. Of patients enrolled, seven patients received at least one infusion of DS-8895a: four patients received 1 mg/kg dose (Cohort 1) and three patients received 3 mg/kg dose (Cohort 2). Median age was 67.0 years (range 52-81), majority male (71%), and median number of prior systemic therapies was three (range 0-8). The primary cancer diagnosis was colorectal cancer (two patients) and one patient each had gastric, head and neck, high-grade serous adenocarcinoma, lung, and pancreatic cancers. No dose-limiting toxicities or treatment-related adverse events reported. The best response for the patients in Cohort 1 was stable disease and in Cohort 2 was progressive disease. 89Zr-DS-8895a demonstrated no normal tissue uptake and specific low-grade uptake in most tumours. DS-8895a had limited therapeutic efficacy at doses evaluated and 89Zr-DS-8895a demonstrated low tumour uptake. The biodistribution data from this study were key in halting further development of DS-8895a, highlighting the importance of biodistribution studies in drug development. (Trial registration: ClinicalTrials.gov Identifier NCT02252211).
Assuntos
Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos , Neoplasias , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos , Antineoplásicos Imunológicos/farmacocinética , Antineoplásicos Imunológicos/uso terapêutico , Efrina-A2/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Receptor EphA2/efeitos dos fármacos , Distribuição TecidualRESUMO
Ipilimumab (IPI) can enhance immunity to the cancer-testis antigen NY-ESO-1. A clinical trial was designed to assess safety, immunogenicity, and clinical responses with IPI + NY-ESO-1 vaccines and effects on the tumor microenvironment (TME). Patients with measurable NY-ESO-1+ tumors were enrolled among three arms: A) IPI + NY-ESO-1 protein + poly-ICLC (pICLC) + incomplete Freund's adjuvant (IFA); B) IPI + NY-ESO-1 overlapping long peptides (OLP) + pICLC + IFA; and C) IPI + NY-ESO-1 OLP + pICLC. Clinical responses were assessed by irRC. T cell and Ab responses were assessed by ex vivo IFN-gamma ELIspot and ELISA. Tumor biopsies pre- and post-treatment were evaluated for immune infiltrates. Eight patients were enrolled: 5, 2, and 1 in Arms A-C, respectively. There were no DLTs. Best clinical responses were SD (4) and PD (4). T-cell and antibody (Ab) responses to NY-ESO-1 were detected in 6 (75%) and 7 (88%) patients, respectively, and were associated with SD. The breadth of Ab responses was greater for patients with SD than PD (p = .036). For five patients evaluable in the TME, treatment was associated with increases in proliferating (Ki67+) CD8+ T cells and decreases in RORγt+ CD4+ T cells. T cell densities increased for those with SD. Detection of T cell responses to NY-ESO-1 ex vivo in most patients suggests that IPI may have enhanced those responses. Proliferating intratumoral CD8+ T cells increased after vaccination plus IPI suggesting favorable impact of IPI plus NY-ESO-1 vaccines on the TME. List of Abbreviations: Ab = antibody; CTCAE = NCI Common Terminology Criteria for Adverse Events; DHFR/DHRP = dihydrofolate reductase; DLT = Dose-limiting toxicity; ELISA = enzyme-linked immunosorbent assay; IFA = incomplete Freund's adjuvant (Montanide ISA-51); IFNγ = Interferon gamma; IPI = Ipilimumab; irRC = immune-related response criteria; mIFH = multispectral immunofluorescence histology; OLP = NY-ESO-1 overlapping long peptides; PBMC = peripheral blood mononuclear cells; PD = Progressive disease; pICLC = poly-ICLC (Hiltonol), a TLR3/MDA-5 agonist; RLT = Regimen-limiting Toxicity; ROI = regions of interest; RT = room temperature; SAE = serious adverse event; SD = stable disease; TEAE = treatment-emergent adverse events; TLR = toll-like receptor; TME = tumor microenvironment; TRAE = treatment-related adverse events.
Assuntos
Vacinas Anticâncer , Melanoma , Antígenos de Neoplasias , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Vacinas Anticâncer/efeitos adversos , Humanos , Ipilimumab/uso terapêutico , Leucócitos Mononucleares , Masculino , Melanoma/tratamento farmacológico , Microambiente TumoralRESUMO
BACKGROUND: Pre-clinical studies indicated that arginine-deprivation therapy using pegylated arginine deiminase (pegargiminase, ADI-PEG 20) may be effective in patients with argininosuccinate synthetase 1 (ASS1)-deficient small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients were enrolled into either a 'sensitive' disease cohort (≥ 90 days response to first-line chemotherapy) or a 'refractory' disease cohort (progression while on chemotherapy or < 90 days afterwards or ≥ third-line treatment). Patients received weekly intramuscular pegargiminase, 320 IU/m2 (36.8 mg/m2), until unacceptable toxicity or disease progression. The primary endpoint was tumor response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with secondary endpoints including tolerability, pharmacodynamics, and immunogenicity. RESULTS: Between January 2011 and January 2014, 22 patients were enrolled: 9 in the sensitive disease cohort and 13 in the refractory disease cohort. At a pre-planned interim analysis, the best overall response observed was stable disease in 2 patients in each cohort (18.2%). Owing to the lack of response and slow accrual in the sensitive disease cohort, the study was terminated early. Pegargiminase treatment was well-tolerated with no unexpected adverse events or discontinuations. CONCLUSION: Although pegargiminase monotherapy in SCLC failed to meet its primary endpoint of RECIST-confirmed responses, more recent molecular stratification, including MYC status, may provide new opportunities moving forward.
Assuntos
Arginina/deficiência , Resistencia a Medicamentos Antineoplásicos , Hidrolases/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Terapia de Salvação , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Ensaios Clínicos Controlados não Aleatórios como Assunto , Prognóstico , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/patologiaRESUMO
BACKGROUND: To compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence. METHODS: Participants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity. RESULTS: The ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse; 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913; 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4+ and CD8+ responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1)+/Human Leukocyte Antigen (HLA) class I+ double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants. CONCLUSIONS: The vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Colesterol/administração & dosagem , Melanoma/terapia , Recidiva Local de Neoplasia/epidemiologia , Fosfolipídeos/administração & dosagem , Saponinas/administração & dosagem , Neoplasias Cutâneas/terapia , Adjuvantes Imunológicos/efeitos adversos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Biópsia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Colesterol/efeitos adversos , Procedimentos Cirúrgicos Dermatológicos , Intervalo Livre de Doença , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Imunogenicidade da Vacina , Masculino , Melanoma/diagnóstico , Melanoma/imunologia , Melanoma/mortalidade , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Fosfolipídeos/efeitos adversos , Saponinas/efeitos adversos , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidadeRESUMO
PURPOSE: Preclinical data suggest that radiotherapy (RT) is beneficial in combination with immune checkpoint blockade. Clinical trials have explored RT with single-agent immune checkpoint blockade, but no trials have reported RT with the combination of nivolumab and ipilimumab. PATIENTS AND METHODS: We conducted a phase 1 study of patients with stage IV melanoma receiving nivolumab and ipilimumab with two different dose-fractionation schemes of RT. Patients had at least one melanoma metastasis that would benefit from palliative RT and one metastasis that would not be irradiated. Nivolumab 1 mg/kg + ipilimumab 3 mg/kg and extracranial RT with a dose of 30 Gy in 10 fractions was administered in Cohort A, and then 27 Gy in 3 fractions was administered in Cohort B. The primary outcome was safety. RESULTS: Twenty patients were treated (10 in each cohort). The rates of treatment-related grade 3-4 adverse events in Cohort A and B were 40% and 30%, respectively. There were no grade ≥3 adverse events attributed to RT. Patients responded to treatment outside of the irradiated volume (Cohort A 5/10; Cohort B 1/9). No evaluable patients had progression of irradiated metastases. Immunologic changes were seen in the peripheral blood with increases in T-cell receptor diversity in some responding patients. CONCLUSIONS: RT with nivolumab and ipilimumab was safe compared with historical data of nivolumab and ipilimumab alone. Immunologic effects were observed in the peripheral blood. Randomized studies are ongoing to assess whether RT increases the efficacy of nivolumab and ipilimumab.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/patologia , Melanoma/terapia , Terapia Neoadjuvante , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Quimiorradioterapia , Feminino , Humanos , Ipilimumab/administração & dosagem , Masculino , Melanoma/etiologia , Melanoma/mortalidade , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Metástase Neoplásica , Estadiamento de Neoplasias , Nivolumabe/administração & dosagem , Prognóstico , Resultado do TratamentoRESUMO
Autologous stem cell transplant (autoSCT), the standard consolidation therapy for multiple myeloma, improves disease-free survival, but is not curative. This could be an ideal setting for immunologic therapy. However, the immune milieu is impaired after autoSCT. We hypothesized that autologous lymphocyte infusion would restore immune competence, allowing immunotherapies such as cancer vaccines to elicit tumor antigen-specific immunity in the setting of autoSCT. In this pilot study (NCT01380145), we investigated safety, immunologic, and clinical outcomes of autologous lymphocyte infusion combined with peri-autoSCT immunotherapy with recombinant MAGE-A3 (a multiple myeloma-associated antigen) and adjuvant. Thirteen patients with multiple myeloma undergoing autoSCT were enrolled. Autologous lymphocyte infusion and MAGE vaccination were well tolerated. Combination immunotherapy resulted in high-titer humoral immunity and robust, antigen-specific CD4+ T-cell responses in all subjects, and the responses persisted at least one year post-autoSCT. CD4+ T cells were polyfunctional and Th1-biased. CD8+ T-cell responses were elicited in 3 of 13 subjects. These cells recognized naturally processed MAGE-A3 antigen. Median progression-free survival was 27 months, and median overall survival was not reached, suggesting no differences from standard-of-care. In 4 of 8 subjects tested, MAGE-A protein expression was not detected by IHC in multiple myeloma cells at relapse, suggesting therapy-induced immunologic selection against antigen-expressing clones. These results demonstrated that autologous lymphocyte infusion augmentation of autoSCT confers a favorable milieu for immunotherapies such as tumor vaccines. This strategy does not require ex vivo manipulation of autologous lymphocyte products and is an applicable platform for further investigation into combination immunotherapies to treat multiple myeloma.
Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Transfusão de Linfócitos , Mieloma Múltiplo/terapia , Proteínas de Neoplasias/imunologia , Transplante de Células-Tronco , Adulto , Idoso , Feminino , Humanos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Transplante AutólogoRESUMO
This study evaluated the safety and clinical benefit of ecromeximab (KW2871) combined with high-dose interferon-α2b (HDI) in patients with metastatic melanoma. We also carried out pharmacokinetic and immune monitoring studies of this combination. This was an open-label, phase 1/2 study of ecromeximab plus HDI in patients with measurable metastatic melanoma. Eligible patients received ecromeximab-HDI combination therapy: ecromeximab administered intravenously once every 2 weeks and HDI at a dose of 20 million units (MU)/m administered intravenously for 5 consecutive days per week for the first 4 weeks (induction phase) and then at 10 MU/m subcutaneously thrice weekly through week 14 (maintenance phase). Patients were treated with combination therapy until disease progression or limiting toxicity. Three dose-escalation cohorts (5, 10, and 20 mg/m) of ecromeximab were planned. Thirty-six evaluable patients were enrolled including six in each of cohorts 1 and 2, and 24 in cohort 3. Median progression-free survival was 2.53 months [95% confidence interval (CI):1.93-3.83] and it was 1.93 months (95% CI: 1.00-3.80) in cohort 3. The median overall survival was 10.28 months (95% CI: 6.93-16.77) and 7.78 months (95% CI: 6.03-13.97) in cohort 3. There was no significant difference in progression-free survival or overall survival by BRAF mutation status. The response rate was 5.6% (95% CI: 0.68-18.7), with two patients showing an objective response (one complete response and one partial response), and the clinical benefit rate was 78% (95% CI: 61-90). Stable disease as best response was observed in 26 (72%) patients including five in each of cohorts 1 and 2, and 16 in cohort 3. Treatment-emergent adverse events considered related to ecromeximab treatment occurred in four (66.7%) patients in cohort 1, five (83.3%) patients in cohort 2, and seven (29.2%) patients in cohort 3. Among TEAEs with a maximum severity of grade 3 or 4, those that occurred only in cohort 3 were related to pain, electrolyte imbalance, blood cell decreases, and allergic reaction. Safety and efficacies considered related to ecromeximab occurred in cohort 3 and included grade 3 hypersensitivity [one (4.2%)] and grade 2 hypotension [one (4.2%)]. Regimen-limiting toxicities occurred in two (8.3%) patients in cohort 3: hypersensitivity (with hypertension, supraventricular tachycardia, bronchospasm, chills, and dyspnea) and hypotension. One patient out of 31 examined showed a low-level transient positivity for human antichimeric antibodies against ecromeximab. Pharmacokinetic measurements by enzyme-linked immunosorbent assay determined that administration of HDI does not influence serum levels of ecromeximab at 5, 10, and 20 mg/m dose levels. Ecromeximab in combination with HDI was generally well tolerated in patients with metastatic melanoma and has shown low immunogenicity. However, the clinical activity was limited, suggesting that future development of this combination should be deprioritized and that other combinations, such as with immune checkpoint inhibitors, should be considered.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
We conducted a clinical trial of a cancer vaccine using NY-ESO-1 protein with polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) and/or OK-432 against solid tumors. A total of 15 patients were sequentially enrolled in 4 cohorts. Patients in cohort 1 received NY-ESO-1 protein; cohort 2a received NY-ESO-1 protein+OK-432; cohort 2b received NY-ESO-1 protein+poly-ICLC; cohort 3 received NY-ESO-1 protein+OK-432+poly-ICLC with Montanide ISA-51. The endpoints of this trial were safety, NY-ESO-1 immune responses, and clinical response. Vaccine-related adverse events observed were fever and injection-site reaction (grade 1). Two patients showed stable disease after vaccination. NY-ESO-1 antibodies were observed in 4 patients at the baseline (sero-positive) and augmented in all patients after vaccination. Eleven patients showed a conversion of negative antibody responses at baseline to positive after vaccination (seroconversion). The seroconversions were observed in all 11 sero-negative patients by the fourth immunization; in particular, it was observed by the second immunization in patients with poly-ICLC, and these induced antibody responses were stronger than those in patients immunized without poly-ICLC. The number of NY-ESO-1-specific interferon (IFN)γ-producing T cells was increased in patients immunized with poly-ICLC and/or OK-432, and furthermore, the increase of IFNγ-producing CD8 T cells in patients immunized with poly-ICLC was significantly higher than that in patients without poly-ICLC. Nonspecific activations of T-cell or antigen presenting cells were not observed. Our present study showed that poly-ICLC is a promising adjuvant for cancer vaccines.
RESUMO
PURPOSE: CS-1008 (tigatuzumab) is a humanized, monoclonal immunoglobulin G1 (IgG1) agonistic antibody to human death receptor 5. The purpose of this study was to investigate the impact of CS-1008 dose on the biodistribution, quantitative tumor uptake, and antitumor response in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with mCRC who had received at least one course of chemotherapy were assigned to one of five dosage cohorts and infused with a weekly dose of CS-1008. Day 1 and day 36 doses were trace-labeled with indium-111 ((111)In), followed by whole-body planar and regional single-photon emission computed tomography (SPECT) imaging at several time points over the course of 10 days. RESULTS: Nineteen patients were enrolled. (111)In-CS-1008 uptake in tumor was observed in only 12 patients (63%). (111)In-CS-1008 uptake and pharmacokinetics were not affected by dose or repeated drug administration. (111)In-CS-1008 biodistribution showed gradual blood-pool clearance and no abnormal uptake in normal tissue. No anti-CS-1008 antibody development was detected. One patient achieved partial response (3.7 months duration), eight patients had stable disease, and 10 patients had progressive disease. Clinical benefit rate (stable disease + partial response) in patients with (111)In-CS-1008 uptake in tumor was 58% versus 28% in patients with no uptake. An analysis of individual lesions showed that lesions with antibody uptake were one third as likely to progress as those without antibody uptake (P = .07). Death-receptor-5 expression in archived tumor samples did not correlate with (111)In-CS-1008 uptake (P = .5) or tumor response (P = .6). CONCLUSION: Death-receptor-5 imaging with (111)In-CS-1008 reveals interpatient and intrapatient heterogeneity of uptake in tumor, is not dose dependent, and is predictive of clinical benefit in the treatment of patients who have mCRC.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Radioisótopos de Índio , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Cintilografia , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
The Toll-like receptor (TLR) 7/8 agonist resiquimod has been used as an immune adjuvant in cancer vaccines. We evaluated the safety and immunogenicity of the cancer testis antigen NY-ESO-1 given in combination with Montanide (Seppic) with or without resiquimod in patients with high-risk melanoma. In part I of the study, patients received 100 µg of full-length NY-ESO-1 protein emulsified in 1.25 mL of Montanide (day 1) followed by topical application of 1,000 mg of 0.2% resiquimod gel on days 1 and 3 (cohort 1) versus days 1, 3, and 5 (cohort 2) of a 21-day cycle. In part II, patients were randomized to receive 100-µg NY-ESO-1 protein plus Montanide (day 1) followed by topical application of placebo gel [(arm A; n = 8) or 1,000 mg of 0.2% resiquimod gel (arm B; n = 12)] using the dosing regimen established in part I. The vaccine regimens were generally well tolerated. NY-ESO-1-specific humoral responses were induced or boosted in all patients, many of whom had high titer antibodies. In part II, 16 of 20 patients in both arms had NY-ESO-1-specific CD4⺠T-cell responses. CD8⺠T-cell responses were only seen in 3 of 12 patients in arm B. Patients with TLR7 SNP rs179008 had a greater likelihood of developing NY-ESO-1-specific CD8⺠responses. In conclusion, NY-ESO-1 protein in combination with Montanide with or without topical resiquimod is safe and induces both antibody and CD4⺠T-cell responses in the majority of patients; the small proportion of CD8⺠T-cell responses suggests that the addition of topical resiquimod to Montanide is not sufficient to induce consistent NY-ESO-1-specific CD8⺠T-cell responses.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Imidazóis/imunologia , Melanoma/terapia , Proteínas de Membrana/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antineoplásicos/uso terapêutico , Formação de Anticorpos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunidade Celular , Masculino , Manitol/administração & dosagem , Manitol/análogos & derivados , Pessoa de Meia-Idade , Ácidos Oleicos/administração & dosagem , Fragmentos de Peptídeos/imunologia , VacinaçãoRESUMO
Vaccination strategies based on repeated injections of NY-ESO-1 protein formulated in ISCOMATRIX particles (NY-ESO-1 ISCOMATRIX) have shown to elicit combined NY-ESO-1 specific antibody and T cell responses. However, it remains unclear whether heterologous prime-boost strategies based on the combination with NY-ESO-1 ISCOMATRIX with different NY-ESO-1 boosting reagents could be used to increase NY-ESO-1 CD8(+) or CD4(+) T cell responses. To address this question, we carried out a randomized clinical trial in 39 high-risk, resected melanoma patients vaccinated with NY-ESO-1 ISCOMATRIX, and then boosted with repeated injections of either recombinant fowlpox virus encoding full length NY-ESO-1 (rF-NY-ESO-1) (Arm A) or NY-ESO-1 ISCOMATRIX alone (Arm B). We have comprehensively analyzed NY-ESO-1 specific T cells and B cells response in all patients before and after vaccination for a total of seven time points per patient. NY-ESO-1 ISCOMATRIX alone elicited a strong NY-ESO-1 specific CD4(+) T cell and antibody response, which was maintained by both regiments at similar levels. However, CD8(+) T cell responses were significantly boosted in 3 out of 18 patients in Arm A after the first rF-NY-ESO-1 injection and such responses were maintained until the end of the trial, while no patients in Arm B showed similar CD8(+) T cell responses. In addition, our results clearly identified immunodominant regions in the NY-ESO-1 protein: NY-ESO-179-102 and NY-ESO-1115-138 for CD4+ T cells and NY-ESO-185-108 for CD8+ T cells in a large proportion of vaccinated patients. These regions of NY-ESO-1 protein should be considered in future clinical trials as immunodominant epitopes.
Assuntos
Adjuvantes Imunológicos/farmacologia , Antígenos de Neoplasias/imunologia , Colesterol/farmacologia , Melanoma/terapia , Proteínas de Membrana/imunologia , Fosfolipídeos/farmacologia , Saponinas/farmacologia , Formação de Anticorpos , Antígenos de Neoplasias/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Combinação de Medicamentos , Vírus da Varíola das Aves Domésticas/genética , Humanos , Melanoma/imunologia , Proteínas de Membrana/genética , Vacinação , Vacinas Sintéticas/imunologiaRESUMO
We conducted a clinical trial of an NY-ESO-1 cancer vaccine using 4 synthetic overlapping long peptides (OLP; peptides #1, 79-108; #2, 100-129; #3, 121-150; and #4, 142-173) that include a highly immunogenic region of the NY-ESO-1 molecule. Nine patients were immunized with 0.25 mg each of three 30-mer and a 32-mer long NY-ESO-1 OLP mixed with 0.2 KE Picibanil OK-432 and 1.25 mL Montanide ISA-51. The primary endpoints of this study were safety and NY-ESO-1 immune responses. Five to 18 injections of the NY-ESO-1 OLP vaccine were well tolerated. Vaccine-related adverse events observed were fever and injection site reaction (grade 1 and 2). Two patients showed stable disease after vaccination. An NY-ESO-1-specific humoral immune response was observed in all patients and an antibody against peptide #3 (121-150) was detected firstly and strongly after vaccination. NY-ESO-1 CD4 and CD8 T-cell responses were elicited in these patients and their epitopes were identified. Using a multifunctional cytokine assay, the number of single or double cytokine-producing cells was increased in NY-ESO-1-specific CD4 and CD8 T cells after vaccination. Multiple cytokine-producing cells were observed in PD-1 (-) and PD-1 (+) CD4 T cells. In conclusion, our study indicated that the NY-ESO-1 OLP vaccine mixed with Picibanil OK-432 and Montanide ISA-51 was well tolerated and elicited NY-ESO-1-specific humoral and CD4 and CD8 T-cell responses in immunized patients.
Assuntos
Antígenos de Neoplasias/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer , Epitopos de Linfócito T/metabolismo , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/terapia , Proteínas de Membrana/metabolismo , Fragmentos de Peptídeos/metabolismo , Vacinas de Subunidades Antigênicas/administração & dosagem , Idoso , Sequência de Aminoácidos , Antígenos de Neoplasias/genética , Células Cultivadas , Citocinas/metabolismo , Feminino , Humanos , Imunidade Humoral/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Manitol/administração & dosagem , Manitol/análogos & derivados , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Ácidos Oleicos/administração & dosagem , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/genética , Picibanil/administração & dosagem , Resultado do Tratamento , Vacinação , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/síntese químicaRESUMO
Background Arginine deiminase (ADI) is an enzyme that degrades arginine, an amino acid that is important for growth and development of normal and neoplastic cells. Melanoma cells are auxotrophic for arginine, because they lack argininosuccinatesynthetase (ASS), a key enzyme required for the synthesis of arginine. Patients and methods Patients with advanced melanoma were treated with 40, 80 or 160 IU/m(2) ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by (18)FDG-PET, pharmacodynamic (PD) effects upon circulating arginine levels, and argininosuccinate synthetase tumor expression by immunohistochemistry. Results 31 previously treated patients were enrolled. The main toxicities were grade 1 and 2 adverse events including injection site pain, rash, and fatigue. No objective responses were seen. Nine patients achieved stable disease (SD), with 2 of these durable for >6 months. Four of the 9 patients with SD had uveal melanoma. PD analysis showed complete plasma arginine depletion in 30/31 patients by day 8. Mean plasma levels of ADI-PEG 20 correlated inversely with ADI-PEG 20 antibody levels. Immunohistochemical ASS expression analysis in tumor tissue was negative in 24 patients, whereas 5 patients had <5 % cells positive. Conclusions ADI-PEG 20 is well tolerated in advanced melanoma patients and leads to consistent, but transient, arginine depletion. Although no RECIST responses were observed, the encouraging rate of SD in uveal melanoma patients indicates that it may be worthwhile to evaluate ADI-PEG 20 in this melanoma subgroup.
Assuntos
Hidrolases/uso terapêutico , Melanoma/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Uveais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Hidrolases/farmacocinética , Técnicas Imunoenzimáticas , Masculino , Dose Máxima Tolerável , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polietilenoglicóis/farmacocinética , Prognóstico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/secundário , Taxa de Sobrevida , Distribuição Tecidual , Neoplasias Uveais/metabolismo , Neoplasias Uveais/secundárioRESUMO
PURPOSE: Long peptides are efficiently presented to both CD4(+) and CD8(+) T cells after intracellular processing by antigen-presenting cells. To investigate the safety and in vivo immunogenicity of synthetic overlapping long peptides (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations. EXPERIMENTAL DESIGN: Twenty-eight patients with advanced ovarian cancer in second or third remission were enrolled sequentially in three cohorts and received at least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2 (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP + 1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and cellular responses were evaluated by standardized immunomonitoring techniques (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining). RESULTS: The vaccine was generally well tolerated with injection site reactions and fatigue that resolved. NY-ESO-1-specific antibody and CD8(+) T cells were undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%) and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide, and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4(+) T cells were detected in all patients with greater frequency and polyclonality when Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant further accelerated the induction of NY-ESO-1-specific immune responses. CONCLUSIONS: The current study shows that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8(+) and CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants.
Assuntos
Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Vacinas Anticâncer/imunologia , Carboximetilcelulose Sódica/análogos & derivados , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Peptídeos/imunologia , Poli I-C/imunologia , Polilisina/análogos & derivados , Adulto , Idoso , Anticorpos/imunologia , Antígenos de Neoplasias/química , Autoantígenos/química , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Feminino , Seguimentos , Humanos , Imunidade Humoral , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Polilisina/imunologia , Linfócitos T Reguladores/imunologia , Resultado do Tratamento , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
NY-ESO-1 is a prototypic cancer/testis antigen. In a recent phase I clinical trial, we vaccinated 13 patients bearing NY-ESO-1-expressing tumors with a complex of cholesterol-bearing hydrophobized pullulan (CHP) and NY-ESO-1 protein (CHP-NY-ESO-1) and showed efficient induction of NY-ESO-1 antibody, and CD4 and CD8 T cell responses using peripheral blood from the patients. In our study, we analyzed heteroclitic serological responses in those patients after vaccination. Serological response against 11 tumor antigens including MAGE-A1, MAGE-A3, MAGE-A4, CT7/MAGEC1, CT10/MAGEC2, CT45, CT46/HORMAD1, SOX2, SSX2, XAGE1B and p53 was examined by enzyme-linked immunosorbent assay (ELISA) using sera from ten vaccinated patients. Expression of tumor antigens was determined by reverse transcription-polymerase chain reaction or immunohistochemistry. Eight of nine patients who showed antibody responses against NY-ESO-1 also showed an antibody response against at least 1 of these 11 tumor antigens after vaccination. In one patient, seven tumor antigens were recognized. Specificity analysis of the antibody response by ELISA using control recombinant proteins and synthetic peptides and by Western blot showed that the response was not against His6-tag and/or bacterial products included in a preparation of CHP-NY-ESO-1 used for vaccination. Thus, heteroclitic serological responses appear to be indicative of the overall immune response against the tumor, and their analysis could be useful for immune monitoring in cancer vaccine.
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Anticorpos Antineoplásicos/sangue , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Neoplasias Esofágicas/imunologia , Proteínas de Membrana/imunologia , Neoplasias da Próstata/imunologia , Animais , Anticorpos Antineoplásicos/imunologia , Antígenos de Neoplasias/metabolismo , Linhagem Celular Tumoral , Neoplasias Esofágicas/sangue , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias da Próstata/sangueRESUMO
BACKGROUND: NY-ESO-1 protein formulated in ISCOMATRIX™ results in CD4+, CD8+ T cell and antibody-mediated immunity. We evaluated persistence of immunity, relapse-free survival and tumour antigen expression upon relapse in patients vaccinated in an earlier trial. METHODS: Immunity was measured in 28 patients with resected NY-ESO-1-expressing tumours (melanoma 25, breast 3) 252-1,155 days (median = 681) after vaccination. In the earlier vaccination, trial patients received NY-ESO-1 with ISCOMATRIX™ adjuvant at three protein doses 10 µg, 30 µg or 100 µg (n = 14); 100 µg NY-ESO-1 protein (n = 8) or placebo (n = 6), together with 1 µg of intradermal (ID) NY-ESO-1 protein twice for DTH skin testing. Immune responses assessed in the current study included antibody titres, circulating NY-ESO-1-specific T cells and DTH reactivity 2 days after DTH skin testing with NY-ESO-1 protein (1 µg) or peptides (10 µg). Relapse-free survival was determined for 42 melanoma patients. On relapse NY-ESO-1 and HLA, class I was assessed by immunohistochemistry in 17. RESULTS: Persisting anti-NY-ESO-1 immunity was detected in 10/14 recipients who had previously received vaccine with ISCOMATRIX™ adjuvant. In contrast, immunity only persisted in 3/14 who received 100 µg un-adjuvanted NY-ESO-1 protein (3/8) or 2 µg DTH protein (0/6) P = 0.02. Hence, persisting NY-ESO-1 immunity was associated with prior adjuvant. Tumour NY-ESO-1 or HLA class I was downregulated in participants who relapsed suggesting immunoediting had occurred. CONCLUSION: Immunoediting suggests that a signal of anti-tumour activity was observed in high-risk resected melanoma patients vaccinated with NY-ESO-1/ISCOMATRIX™. This was associated with measurable persisting immunity in the majority of vaccinated subjects tested. A prospective randomised trial has been undertaken to confirm these results.
Assuntos
Antígenos de Neoplasias/administração & dosagem , Neoplasias da Mama/terapia , Vacinas Anticâncer/administração & dosagem , Colesterol/administração & dosagem , Melanoma/terapia , Proteínas de Membrana/administração & dosagem , Fosfolipídeos/administração & dosagem , Saponinas/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adulto , Idoso , Sequência de Aminoácidos , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/imunologia , Neoplasias da Mama/imunologia , Vacinas Anticâncer/imunologia , Colesterol/imunologia , Intervalo Livre de Doença , Regulação para Baixo , Combinação de Medicamentos , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/imunologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Melanoma/imunologia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fosfolipídeos/imunologia , Estudos Prospectivos , Saponinas/imunologia , Pele/imunologiaRESUMO
PURPOSE: NY-ESO-1 is a highly immunogenic antigen expressed in a variety of malignancies, making it an excellent target for cancer vaccination. We recently developed a vaccine consisting of full-length recombinant NY-ESO-1 protein formulated with ISCOMATRIX adjuvant, which generated strong humoral and T-cell-mediated immune responses and seemed to reduce the risk of disease relapse in patients with fully resected melanoma. This study examines the clinical and immunologic efficacy of the same vaccine in patients with advanced metastatic melanoma. EXPERIMENTAL DESIGN: Delayed-type hypersensitivity responses, circulating NY-ESO-1-specific CD4(+) and CD8(+) T cells, and proportions of regulatory T cells (Treg) were assessed in patients. RESULTS: In contrast to patients with minimal residual disease, advanced melanoma patients showed no clinical responses to vaccination. Although strong antibody responses were mounted, the generation of delayed-type hypersensitivity responses was significantly impaired. The proportion of patients with circulating NY-ESO-1-specific CD4(+) T cells was also reduced, and although many patients had CD8(+) T cells specific to a broad range of NY-ESO-1 epitopes, the majority of these responses were preexisting. Tregs were enumerated in the blood by flow cytometric detection of cells with a CD4(+)CD25(+)FoxP3(+) and CD4(+)CD25(+)CD127(-) phenotype. Patients with advanced melanoma had a significantly higher proportion of circulating Treg compared with those with minimal residual disease. CONCLUSIONS: Our results point to a tumor-induced systemic immune suppression, showing a clear association between the stage of melanoma progression, the number of Treg in the blood, and the clinical and immunologic efficacy of the NY-ESO-1 ISCOMATRIX cancer vaccine.
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Adjuvantes Imunológicos/administração & dosagem , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Colesterol/administração & dosagem , Melanoma/terapia , Proteínas de Membrana/imunologia , Fosfolipídeos/administração & dosagem , Saponinas/administração & dosagem , Linfócitos T Reguladores/fisiologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Combinação de Medicamentos , Feminino , Humanos , Hipersensibilidade Tardia/etiologia , Masculino , Proteínas de Membrana/administração & dosagem , Pessoa de Meia-Idade , VacinaçãoRESUMO
T cell-mediated immunity to microbes and to cancer can be enhanced by the activation of dendritic cells (DCs) via TLRs. In this study, we evaluated the safety and feasibility of topical imiquimod, a TLR7 agonist, in a series of vaccinations against the cancer/testis Ag NY-ESO-1 in patients with malignant melanoma. Recombinant, full-length NY-ESO-1 protein was administered intradermally into imiquimod preconditioned sites followed by additional topical applications of imiquimod. The regimen was very well tolerated with only mild and transient local reactions and constitutional symptoms. Secondarily, we examined the systemic immune response induced by the imiquimod/NY-ESO-1 combination, and show that it elicited both humoral and cellular responses in a significant fraction of patients. Skin biopsies were assessed for imiquimod's in situ immunomodulatory effects. Compared with untreated skin, topical imiquimod induced dermal mononuclear cell infiltrates in all patients composed primarily of T cells, monocytes, macrophages, myeloid DCs, NK cells, and, to a lesser extent, plasmacytoid DCs. DC activation was evident. This study demonstrates the feasibility and excellent safety profile of a topically applied TLR7 agonist used as a vaccine adjuvant in cancer patients. Imiquimod's adjuvant effects require further evaluation and likely need optimization of parameters such as formulation, dose, and timing relative to Ag exposure for maximal immunogenicity.