RESUMO
BACKGROUND: Cancer-related disturbances in myeloid lineage development, marked by high levels of myeloid-derived suppressor cells (MDSC) and impaired dendritic cell (DC) development, are associated with poor clinical outcome due to immune escape and therapy resistance. Redressing this balance may therefore be of clinical benefit. Here we investigated the effects of combined Prostate GVAX/ipilimumab immunotherapy on myeloid subsets in peripheral blood of castration-resistant prostate cancer (CRPC) patients as well as the putative predictive value of baseline and on-treatment myeloid parameters on clinical outcome. METHODS: Patients with CRPC (n = 28) received thirteen intradermal administrations of Prostate GVAX, consisting of two allogeneic GM-CSF-transduced and irradiated prostate cancer cell lines (LN-CaP and PC3) and six infusions of escalating doses of anti-CTLA4/ipilimumab. Frequencies and activation status of peripheral blood DC (PBDC) and MDSC were determined before, during and after treatment by flowcytometric analysis and related to clinical benefit. RESULTS: Significant treatment-induced activation of conventional and plasmacytoid DC subsets (cDC and pDC) was observed, which in the case of BDCA1/CD1c(+) cDC1 and MDC8(+)/6-sulfoLacNAc(+) inflammatory cDC3 was associated with significantly prolonged overall survival (OS), but also with the development of autoimmune-related adverse events. High pre-treatment levels of CD14(+)HLA-DR(-)monocytic MDSC (mMDSC) were associated with reduced OS. Unsupervised clustering of these myeloid biomarkers revealed particular survival advantage in a group of patients with high treatment-induced PBDC activation and low pretreatment frequencies of suppressive mMDSC in conjunction with our previously identified lymphoid biomarker of high pretreatment CD4(+)CTLA4(+) T cell frequencies. CONCLUSIONS: Our data demonstrate that DC and MDSC subsets are affected by prostate GVAX/ipilimumab therapy and that myeloid profiling may contribute to the identification of patients with possible clinical benefit of Prostate GVAX/ipilimumab treatment.
RESUMO
Immune checkpoint blockade enhances antitumor responses, but can also lead to severe immune-related adverse events (IRAE). To avoid unnecessary exposure to these potentially hazardous agents, it is important to identify biomarkers that correlate with clinical activity and can be used to select patients that will benefit from immune checkpoint blockade. To understand the consequences of CTLA-4 blockade and identify biomarkers for clinical efficacy and/or survival, an exploratory T cell monitoring study was performed in a phase I/II dose escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed striking differences between patients who benefited from therapy and patients that did not. Treatment-induced rises in absolute lymphocyte counts, CD4(+) T cell differentiation, and CD4(+) and CD8(+) T cell activation were all associated with clinical benefit. Moreover, significantly prolonged overall survival (OS) was observed for patients with high pre-treatment frequencies of CD4(+)CTLA-4(+), CD4(+)PD-1(+), or differentiated (i.e., non-naive) CD8(+) T cells or low pre-treatment frequencies of differentiated CD4(+) or regulatory T cells. Unsupervised clustering of these immune biomarkers revealed cancer-related expression of CTLA-4(+) in CD4(+) T cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab therapy and to thus provide a putative and much-needed biomarker for patient selection prior to therapeutic CTLA4 blockade.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Vacinas Anticâncer/uso terapêutico , Neoplasias da Próstata/terapia , Idoso , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/análise , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Ipilimumab , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/mortalidadeRESUMO
BACKGROUND: The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×10(8) cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×10(8) cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288. FINDINGS: We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis--all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1-2 events seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab. INTERPRETATION: GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted. FUNDING: Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Neoplasias da Próstata/terapia , Adulto , Idoso , Terapia Combinada , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Imunoterapia , Ipilimumab , Masculino , Pessoa de Meia-Idade , Orquiectomia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/secundário , Transplante Homólogo , Células Tumorais CultivadasRESUMO
BACKGROUND: This open-label, multicenter, dose-escalation study evaluated multiple dose levels of immunotherapy in patients with metastatic hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, consisted of 2 allogeneic prostate-carcinoma cell lines modified to secrete granulocyte-macrophage-colony-stimulating factor (GM-CSF). METHODS: Dose levels ranged from 100 x 10(6) cells q28d x 6 to 500 x 10(6) cells prime/300 x 10(6) cells boost q14d x 11. Endpoints included safety, immunogenicity, overall survival, radiologic response, prostate-specific antigen (PSA) kinetics, and serum GM-CSF pharmacokinetics. RESULTS: Eighty men, median age 69 years (range, 49-90 years), were treated. The most common adverse effect was injection-site erythema. Overall, the immunotherapy was well tolerated. A maximal tolerated dose was not established. The median survival time was 35.0 months in the high-dose group, 20.0 months in the mid-dose, group, and 23.1 months in the low-dose group. PSA stabilization occurred in 15 (19%) patients, and a >50% decline in PSA was seen in 1 patient. The proportion of patients who generated an antibody response to 1 or both cell lines increased with dose and included 10 of 23 (43%) in the low-dose group, 13 of 18 (72%) in the mid-dose group, and 16 of 18 (89%) in the high-dose group (P = .002; Cochran-Armitage trend test). CONCLUSIONS: This immunotherapy was well tolerated. Immunogenicity and overall survival varied by dose. Two phase 3 trials in patients with metastatic HRPC are underway.
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Adenocarcinoma/terapia , Vacinas Anticâncer/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Imunoterapia/métodos , Neoplasias da Próstata/terapia , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/administração & dosagem , Linhagem Celular Tumoral , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Hormônio-DependentesRESUMO
PURPOSE: This trial evaluated the safety, clinical activity, and immunogenicity of an allogeneic cellular immunotherapy in 55 chemotherapy-naïve patients with hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, is a combination of two prostate carcinoma cell lines modified with the granulocyte macrophage colony-stimulating factor (GM-CSF) gene. EXPERIMENTAL DESIGN: HRPC patients with radiologic metastases (n = 34) or rising prostate-specific antigen (PSA) only (n = 21) received a prime dose of 500 million cells and 12 boost doses of either 100 million cells (low dose) or 300 million cells (high dose) biweekly for 6 months. End points were changes in PSA, time to progression, and survival. RESULTS: Median survival was 26.2 months (95% confidence interval, 17, 36) in the radiologic group: 34.9 months (8, 57) after treatment with the high dose (n = 10) of immunotherapy and 24.0 months (11, 35) with the low dose (n = 24). The median time to bone scan progression in the radiologic group was 5.0 months (2.6, 11.6) with the high dose and 2.8 months (2.8, 5.7) with the low dose. In the rising-PSA group (n = 21) receiving the low dose, the median time to bone scan progression was 5.9 months (5.6, not reached), and median survival was 37.5 months (29, 56). No dose-limiting or autoimmune toxicities were seen; the most common adverse events were injection site reaction and fatigue. CONCLUSIONS: These results suggest that this GM-CSF-secreting, allogeneic cellular immunotherapy is well tolerated and may have clinical activity in patients with metastatic HRPC. Phase 3 trials to confirm these results are under way.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Imunoterapia/métodos , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Antígeno Prostático Específico/biossíntese , Fatores de Tempo , Resultado do TratamentoRESUMO
Therapeutic cancer vaccines are a heterogeneous group of complex biologics with distinctly different clinical characteristics than cytotoxic agents. The current clinical development paradigm used for oncology drug development is based on criteria developed for cytotoxic agents. More flexible and focused developmental guidelines are needed to address the unique characteristics of therapeutic cancer vaccines. Over the course of 1 year, the Cancer Vaccine Clinical Trial Working Group, representing academia and the pharmaceutical and biotechnology industries with participation from the US Food and Drug Administration, defined in a consensus process the cornerstones of a new clinical development paradigm for cancer vaccines and related biologics. Four major topics were addressed: (1) end points for clinical trials, (2) trial designs and statistical methods, (3) technical and developmental challenges, and (4) combination therapy. The proposed paradigm suggests therapeutic cancer vaccines to be investigated in 2 general types of clinical studies: proof-of-principle trials and efficacy trials. Proof-of-principle trials, which introduce a novel cancer vaccine into humans, should include a minimum of 20 or more patients in a homogenous, well-defined population in an adjuvant setting or without rapidly progressive disease in a metastatic setting to allow vaccines adequate time to induce biologic activity and should incorporate immune and molecular markers. Objectives should include initiation of a safety database, determination of dose and schedule, and demonstration of biologic activity as proof-of-principle. Biologic activity is defined as any effect of the vaccine on the target disease or host immune system using biologic markers as study end points, for example, clinical, molecular, or immune response. Immune response is demonstrated if determined in 2 separate, established and reproducible assays at 2 consecutive follow-up time points after the baseline assessment. If proof-of-principle trials show such immune response, or other biologic or clinical activity, efficacy trials may be initiated. If none of these end points is met, the clinical development plan should be reevaluated to decide if further development is warranted. Efficacy trials formally establish clinical benefit either directly or through a surrogate and are encouraged to be randomized studies. This is in contrast to single-arm phase 2 trials used for cytotoxic agents, which often use tumor response rate as the primary end point and historical controls as a comparator. Efficacy trials may use prospectively planned adaptive designs to expand from randomized phase 2 into phase 3 studies if well-defined trigger-point criteria are met, but the cost of incorporating such design elements should be carefully evaluated. Efficacy trials can also be exploratory randomized phase 2 trials or conventional phase 3 trials. In addition, conventional clinical end points can be adjusted to account for biologic features of cancer vaccines. The concept of efficacy trials allows for an early assessment of vaccine efficacy based on credible prospective data. This 2-phase developmental paradigm supports a more flexible, expeditious, and focused clinical developmental process with early and informed decision making. In addition, this report addresses clinical development challenges and issues for combination therapies.
Assuntos
Vacinas Anticâncer/uso terapêutico , Neoplasias/terapia , Ensaios Clínicos como Assunto , Humanos , Neoplasias/imunologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
New approaches to therapeutics of advanced prostate cancer are urgently needed. GVAX (granulocyte-macrophage colony-stimulating factor [GM-CSF] gene transduced irradiated prostate cancer vaccine cells) offers the possibility that "host versus prostate cancer" immune responses can be generated in prostate cancer patients. Critical components involve the dendritic cell loading of candidate prostate cancer lymph node metastasis and candidate bone metastasis antigens derived from irradiated prostate cancer whole cells. GM-CSF acts at the vaccination site to enhance activation dendritic cells and antigen presentation to both the B-cell and T-cell arms of the immune system. GVAX preclinically-in both rat and transgenic prostate cancer models-has antitumor activity which has informed early clinical trial designs. Clinical investigations reviewed in this report suggest that vaccination is safe and immune tolerance can be broken against prostate cancer. Multi-institutional phase III investigation is currently underway to evaluate the impact of allogeneic prostate GVAX cellular immunotherapy on time to progression and overall survival in hormone refractory prostate cancer.