RESUMO
INTRODUCTION: Adjuvant (A) multiagent chemotherapy (MC) is the standard of care for patients with pancreatic adenocarcinoma (PDAC). Tolerating MC following a morbid operation may be difficult, thus neoadjuvant (NA) treatment is preferable. This study examined how the timing of chemotherapy was related to the regimen given and ultimately the overall survival (OS). METHODS: The National Cancer Database was queried from 2006 to 2017 for nonmetastatic PDAC patients who underwent surgical resection and received MC or single-agent chemotherapy (SC) pre- or postresection. Predictors of receiving MC were determined using multivariable logistic regression. Five-year OS was evaluated using the Kaplan-Meier and Cox proportional hazards model. RESULTS: A total of 12,440 patients (NA SC, n = 663; NA MC, n = 2313; A SC, n = 6152; A MC, n = 3312) were included. MC utilization increased from 2006-2010 to 2011-2017 (33.1%-49.7%; odds ratio [OR]: 0.59; p < 0.001). Younger age, fewer comorbidities, higher clinical stage, and larger tumor size were all associated with receipt of MC (all p < 0.001), but NA treatment was the greatest predictor (OR 5.18; 95% confidence interval [CI]: 4.63-5.80; p < 0.001). MC was associated with increased median 5-year OS (26.0 vs. 23.9 months; hazard ratio [HR]: 0.92; 95% CI: 0.88-0.96) and NA MC was associated with the highest survival (28.2 months) compared to NA SC (23.3 months), A SC (24.0 months), and A MC (24.6 months; p < 0.001). CONCLUSION: Use and timing of MC contribute to OS in PDAC with an improved 5-year OS compared to SC. The greatest predictor of receiving MC was being given as NA therapy and the greatest survival benefit was the NA MC subgroup. Randomized studies evaluating the timing of effective MC in PDAC are needed.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Adenocarcinoma/patologia , Quimioterapia Adjuvante , Terapia Neoadjuvante , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
BACKGROUND: The benefit of adjuvant therapy (AT) remains unclear in pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT) and surgical resection. METHODS: The 2019 National Cancer Database was queried for patients with non-metastatic PDAC who received NAT followed by pancreaticoduodenectomy. Only patients with data regarding receipt of AT were included. Patients were classified if they had nodal down-staging specifically, or any downstaging (Tumor, Nodal, or overall). Propensity score matching (PSM) adjusted for pretreatment covariate imbalance between groups. The weighted Kaplan-Meier method and log-rank test were used to estimate the cumulative survival. RESULTS: After exclusion criteria and PSM, a total of 2784 patients remained; 1689 (60.7%) received AT and 1095 (39.3%) did not receive AT. Among all, those with additional AT had a significantly improved overall survival (OS) (p < 0.001). Upon evaluation of patients without downstaging after NAT, those who received AT had improved OS (no nodal downstaging or any downstaging; p = 0.002; p = 0.001). When evaluating patients with downstaging after NAT, those receiving AT did not have improved OS (nodal downstaging or any downstaging: p = 0.352; p = 0.99). CONCLUSION: Response to NAT appears to correlate with the benefit of AT following pancreaticoduodenectomy; patients who have a favorable response to NAT may not benefit from AT.
Assuntos
Carcinoma Ductal Pancreático , Terapia Neoadjuvante , Neoplasias Pancreáticas , Pancreaticoduodenectomia , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/tratamento farmacológico , Masculino , Feminino , Terapia Neoadjuvante/mortalidade , Quimioterapia Adjuvante , Idoso , Pessoa de Meia-Idade , Taxa de Sobrevida , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adenocarcinoma/tratamento farmacológico , Estudos Retrospectivos , Seguimentos , PrognósticoRESUMO
BACKGROUND: A randomized, double-blind, placebo-controlled phase 2b trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine was conducted in patients with resected stage III/IV melanoma. Dendritic cells (DCs) were harvested with and without granulocyte-colony stimulating factor (G-CSF). This analysis investigates differences in clinical outcomes and RNA gene expression between DC harvest methods. METHODS: The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles (YCWPs) and exposing them to phagocytosis by DCs. For DC harvest, patients had a direct blood draw or were pretreated with G-CSF before blood draw. Patients were randomized 2:1 to receive TLPLDC or placebo. Differences in disease-free survival (DFS) and overall survival (OS) were evaluated. RNA-seq analysis was performed on the total RNA of TLPLDC + G and TLPLDC vaccines to compare gene expression between groups. RESULTS: 144 patients were randomized: 103 TLPLDC (47 TLPLDC/56 TLPLDC + G) and 41 placebo (19 placebo/22 placebo + G). Median follow-up was 27.0 months. Both 36-month DFS (55.8% vs. 24.4% vs. 30.0%, p = 0.010) and OS (94.2% vs. 69.8% vs. 70.9%, p = 0.024) were improved in TLPLDC compared to TLPLDC + G or placebo, respectively. When compared to TLPLDC + G vaccine, RNA-seq from TLPLDC vaccine showed upregulation of genes associated with DC maturation and downregulation of genes associated with DC suppression or immaturity. CONCLUSIONS: Patients receiving TLPLDC vaccine without G-CSF had improved OS and DFS. Outcomes remained similar between patients receiving TLPLDC + G and placebo. Direct DC harvest without G-CSF had higher expression of genes linked to DC maturation, likely improving clinical efficacy.
Assuntos
Vacinas Anticâncer , Melanoma , Humanos , Células Dendríticas , Fator Estimulador de Colônias de Granulócitos , Melanoma Maligno CutâneoRESUMO
Rapamycin inhibits the mechanistic (formally mammalian) target of rapamycin (mTOR), an evolutionarily conserved intracellular kinase that influences activation of growth signaling pathways and immune responses to malignancy. Rapamycin has been found to have both immunosuppressant and immunostimulatory effects throughout the innate and adaptive responses based on the inhibition of mTOR signaling. While the immunosuppressant properties of rapamycin and mTOR inhibition explain rapamycin's success in the prevention of transplant rejection, the immunostimulatory characteristics are likely partially responsible for rapamycin's anti-neoplastic effects. The immunologic response to rapamycin is at least partially dependent on the dose and administration schedule, with lower doses inducing immunostimulation and intermittent dosing promoting immune function while limiting metabolic and immunosuppressant toxicities. In addition to its FDA-approved application in advanced malignancies, rapamycin may be effective as a chemopreventive agent, suspending progression of low-grade cancers, preventing invasive conversion of in situ malignancy, or delaying malignant transformation of established pre-malignant conditions.
Assuntos
Neoplasias , Sirolimo , Humanos , Quimioprevenção , Imunossupressores/farmacologia , Neoplasias/prevenção & controle , Neoplasias/tratamento farmacológico , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: Neoadjuvant chemotherapy (NAC) or chemoradiation (NAC+XRT) is incorporated into the treatment of localized pancreatic adenocarcinoma (PDAC), often with the goal of downstaging before resection. However, the effect of downstaging on overall survival, particularly the differential effects of NAC and NAC+XRT, remains undefined. This study examined the impact of downstaging from NAC and NAC+XRT on overall survival. METHODS: The National Cancer Data Base (NCDB) was queried from 2006 to 2015 for patients with non-metastatic PDAC who received NAC or NAC+XRT. Rates of overall and nodal downstaging, and pathologic complete response (pCR) were assessed. Predictors of downstaging were evaluated using multivariable logistic regression. Overall survival (OS) was assessed with Kaplan-Meier and Cox proportional hazards modeling. RESULTS: The study enrolled 2475 patients (975 NAC and 1500 NAC+XRT patients). Compared with NAC, NAC+XRT was associated with higher rates of overall downstaging (38.3 % vs 23.6 %; p ≤ 0.001), nodal downstaging (16.0 % vs 7.8 %; p ≤ 0.001), and pCR (1.7 % vs 0.7 %; p = 0.041). Receipt of NAC+XRT was independently predictive of overall (odds ratio [OR] 2.28; p < 0.001) and nodal (OR 3.09; p < 0.001) downstaging. Downstaging by either method was associated with improved 5-year OS (30.5 vs 25.2 months; p ≤ 0.001). Downstaging with NAC was associated with an 8-month increase in median OS (33.7 vs 25.6 months; p = 0.005), and downstaging by NAC+XRT was associated with a 5-month increase in median OS (30.0 vs 25.0 months; p = 0.008). Cox regression showed an association of overall downstaging with an 18 % reduction in the risk of death (hazard ratio [HR] 0.82; 95 % confidence interval, 0.71-0.95; p = 0.01) CONCLUSION: Downstaging after neoadjuvant therapies improves survival. The addition of radiation therapy may increase the rate of downstaging without affecting overall oncologic outcomes.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Quimiorradioterapia , Quimioterapia Adjuvante , Humanos , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias PancreáticasRESUMO
HER2-targeted therapy has not benefited patients with low levels of HER2 expression; however, combination therapy may be effective. Primary analysis of a phase IIb trial investigating the HER2-derived vaccine nelipepimut-S (NPS) did not benefit the intention-to-treat population, but subset analysis showed a benefit in triple-negative breast cancer (TNBC) patients. The subset analysis of this multicenter, randomized, single-blind, phase IIb trial identified significant improvement in 36-month disease-free survival (DFS) between NPS (n = 55) and placebo (n = 44) in TNBC (HR 0.25, p = 0.01) and those who express HLA-A24 (HR 0.41, p = 0.05). The TNBC cohort demonstrated improved 36-month DFS in those with HER2 1+ expression (HR 0.17, p = 0.01), HLA-A24 positivity (HR 0.08, p < 0.01), or in those who received neoadjuvant chemotherapy (HR 0.21, p < 0.01). NPS vaccination with trastuzumab was associated with improved 36-month DFS among patients with TNBC. The observed benefit to this high-risk subgroup warrants confirmation in a phase III trial.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Imunoterapia/métodos , Fragmentos de Peptídeos/imunologia , Receptor ErbB-2/imunologia , Trastuzumab/uso terapêutico , Neoplasias de Mama Triplo Negativas/terapia , Adulto , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Antígeno HLA-A24/metabolismo , Humanos , Análise de Intenção de Tratamento , Recidiva Local de Neoplasia , Efeito Placebo , Medicina de Precisão , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Risco , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/mortalidadeRESUMO
BACKGROUND: Colorectal cancer (CRC) tumor microenvironment (TME) characteristics, such as tumor infiltrating lymphocyte (TIL) densities and PD-L1 status, are predictive of recurrence, disease-free survival, and overall survival. In many malignancies, TME characteristics are also predictive of response to immunotherapy. As window of opportunity studies using neoadjuvant immunotherapy become more common and treatment guidelines incorporate TME features, accurate assessment of the pre-treatment TME using the biopsy specimen is critical. However, no study has thoroughly evaluated the correlation between the TMEs of the biopsy and resection specimens. METHODS: We conducted a retrospective analysis of patients with stage I-III CRC with matched biopsy and resection specimens. CD3+, CD4+, CD8+, and FoxP3+ lymphocyte populations at the center of tumor (CT) and invasive margin (IM) and tumor PD-L1 status in the biopsy and resection specimens were evaluated. TIL populations were compared using Mann-Whitney U tests or Student's t tests and correlated using Pearson r. RESULTS: CD3+ and CD4+ densities were significantly higher in the CT of the biopsy relative to the resection specimen Comparing biopsy and resection specimens, no TIL population at either the CT or IM had a correlation coefficient > 0.5. Determining PD-L1 status based on biopsy tissue resulted in a sensitivity of 37.1%, specificity of 81.4%, and accuracy of 61.5%. CONCLUSIONS: These findings demonstrate significant discordance between the TME of the biopsy and resection specimens. Caution should be used when basing treatment decisions on pre-treatment endoscopic biopsy findings and when interpreting changes in the TME between pre-treatment biopsy and resection specimens after neoadjuvant therapy.
Assuntos
Adenocarcinoma/diagnóstico , Biópsia/métodos , Linfócitos T CD4-Positivos/imunologia , Colo/patologia , Neoplasias Colorretais/diagnóstico , Linfócitos do Interstício Tumoral/imunologia , Idoso , Antígeno B7-H1/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Sensibilidade e Especificidade , Microambiente TumoralRESUMO
BACKGROUND: Melanoma therapy has changed dramatically over the last decade with improvements in immunotherapy, yet many patients do not respond to current therapies. This novel vaccine strategy may prime a patient's immune system against their tumor and work synergistically with immunotherapy against advanced-stage melanoma. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine administered to prevent recurrence in patients with resected stage III/IV melanoma. Patients were enrolled and randomized 2:1 to the TLPLDC vaccine or placebo (empty yeast cell wall particles and autologous dendritic cells). Both intention-to-treat (ITT) and per treatment (PT) analyses were predefined, with PT analysis including patients who remained disease-free through the primary vaccine/placebo series (6 months). RESULTS: A total of 144 patients were randomized (103 vaccine, 41 control). Therapy was well-tolerated with similar toxicity between treatment arms; one patient in each group experienced related serious adverse events. While disease-free survival (DFS) was not different between groups in ITT analysis, in PT analysis the vaccine group showed improved 24-month DFS (62.9% vs. 34.8%, p = 0.041). CONCLUSIONS: This phase IIb trial of TLPLDC vaccine administered to patients with resected stage III/IV melanoma shows TLPLDC is well-tolerated and improves DFS in patients who complete the primary vaccine series. This suggests patients who do not recur early benefit from TLPLDC in preventing future recurrence from melanoma. A phase III trial of TLPLDC + checkpoint inhibitor versus checkpoint inhibitor alone in patients with advanced, surgically resected melanoma is under development. TRIAL REGISTRATION: NCT02301611.
Assuntos
Vacinas Anticâncer , Melanoma , Neoplasias Cutâneas , Vacinas Anticâncer/uso terapêutico , Humanos , Melanoma/patologia , Melanoma/terapia , Estadiamento de Neoplasias , Estudos Prospectivos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapiaRESUMO
BACKGROUND: Variability exists in opioid prescribing practices among surgeons, frequently resulting in the prescription of excessive opioids. This study evaluated the ability of a single educational intervention targeted toward general surgery residents to reduce the quantity of postoperative opioids prescribed. MATERIALS AND METHODS: This retrospective cohort study evaluated opioid prescribing practices 12 mo prior to and 6 mo following a 30-min lecture for general surgery residents that discussed prescribing guidelines and multimodal analgesia. Opioid volumes (normalized to oral morphine equivalents, OME), opioid type, nonopioid pain medications, and refills requested were analyzed for opioid-naïve adult patients undergoing excisional breast biopsy (EB), mastectomy (M), laparoscopic appendectomy (LA), laparoscopic cholecystectomy (LC), open umbilical hernia repair (OUHR), open inguinal hernia repair (OIHR), or laparoscopic inguinal hernia repair (LIHR). RESULTS: 695 and 376 patients preintervention and postintervention were included, respectively. Median OME prescribed decreased for EB (150 mg to 75 mg, P < 0.001), M (225 mg to 150 mg, P = 0.85), LA (150 mg to 94 mg, P < 0.001), LC (150 mg to 82 mg, P < 0.001), OUHR (150 mg to 103 mg, P < 0.001), OIHR (175 mg to 100 mg, P = 0.001), and LIHR (200 mg to 113 mg, P < 0.001). Fewer patients received opioids alone and more patients received an opioid with two nonopioid adjuncts (P < 0.001). More patients received oxycodone as fewer received acetaminophen-containing opioid combinations (P < 0.001). Patients requiring refills decreased (11.9% to 7.2%) (P = 0.014). CONCLUSIONS: Following this targeted intervention, patients were discharged with fewer OME and more nonopioid analgesics, even as refill requests decreased. Educating residents on opioid prescription guidelines and multimodal therapy is effective and should be part of the annual didactic curriculum.
Assuntos
Analgésicos Opioides/uso terapêutico , Cirurgia Geral/educação , Internato e Residência/estatística & dados numéricos , Dor Pós-Operatória/prevenção & controle , Padrões de Prática Médica/estatística & dados numéricos , Feminino , Cirurgia Geral/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
PURPOSE: AE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis. METHODS: In this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated. RESULTS: 456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573 CI 0.275-1.193), HER2 under-expression (p = 0.181, HR 0.756 CI 0.499-1.145), and triple-negative breast cancer (p = 0.266, HR 0.443 CI 0.114-1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375 CI 0.142-0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG. CONCLUSIONS: This phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Recidiva Local de Neoplasia/prevenção & controle , Receptor ErbB-2/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Adulto , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/imunologia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Fragmentos de Peptídeos , Prognóstico , Estudos Prospectivos , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Método Simples-Cego , Taxa de Sobrevida , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
The development of HER2-targeted therapy has decreased recurrence rates and improved survival, transforming the natural history of HER2-positive breast cancer. However only a minority of breast cancer patients benefit as these agents are not used in patients with tumors expressing low levels of HER2. Preclinical data suggests a synergistic action of HER2-targeted vaccination with trastuzumab. We report the initial safety interim analysis of a phase II trial that enrolled patients with HER2 low-expressing (IHC 1+/2+) breast cancer who were clinically disease-free after standard therapy. Patients were randomized to receive the HER2-peptide vaccine nelipepimut-Sâ¯+â¯GM-CSF with trastuzumab (vaccine arm) or trastuzumab + GM-CSF (control arm) and were followed for recurrence. A planned analysis that occurred after enrollment of 150 patients showed no significant differences in toxicity between the two arms, including cardiac toxicity. The clinical efficacy of this combination will be reported 6â¯months after the final patient was enrolled.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Fatores Imunológicos/efeitos adversos , Fragmentos de Peptídeos/efeitos adversos , Trastuzumab/efeitos adversos , Neoplasias da Mama/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Receptor ErbB-2 , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
In this randomized phase Ib trial, we tested combining the E39 peptide vaccine with a vaccine created from E39', an attenuated version of E39. Patients with breast or ovarian cancer, who were disease-free after standard of care therapy, were enrolled and randomized to one of three arms. Arm EE received six E39 inoculations; arm EE' received three E39 inoculations followed by three E39'; and arm E'E received three E39' inoculations, followed by three E39. Within each arm, the first five patients received 500⯵g of peptide and the remainder received 1000⯵g. Patients were followed for toxicity, and immune responses were measured. This initial analysis after completion of the primary vaccination series has confirmed the safety of both vaccines. Immune analyses suggest incorporating the attenuated version of the peptide improves immune responses and that sequencing of E39 followed by E39' might produce the optimal immune response. TRIAL REGISTRATION: NCT02019524.
Assuntos
Neoplasias da Mama/imunologia , Vacinas Anticâncer/imunologia , Receptores de Folato com Âncoras de GPI/imunologia , Neoplasias Ovarianas/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/terapia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Feminino , Humanos , Hipersensibilidade Tardia/etiologia , Hipersensibilidade Tardia/imunologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/terapia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Vacinação/métodos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversosRESUMO
Immunotherapy, using peptide-based cancer vaccines is being studied to assess its potential in breast cancer. Trials of HLA-restricted peptide vaccines have been difficult to enroll given HLA subtype restrictions. It is necessary to determine the prognostic significance of HLA-status in breast cancer if patients who are ineligible to receive a vaccine due to their HLA-status are used as controls. The impact of targeted tumor associated antigen expression, when it effects eligibility is also important. We examined control patients from two randomized phase II trials that tested HER2-peptide vaccines to determine the effect of HLA-A2 status and HER2 expression on disease-free survival. The analysis showed that HLA-A2-status does not affect disease-free survival, regardless of HER2 expression suggesting that HLA-A2 negative patients can be used as control patients. Additionally, HER2 over-expression was associated with a better disease-free survival in this population, underscoring the need for additional therapies in HER2 low-expressing breast cancer. ClinicalTrials.gov Identifier: NCT00524277.
Assuntos
Neoplasias da Mama/imunologia , Vacinas Anticâncer/imunologia , Antígeno HLA-A2/genética , Imunoterapia/métodos , Receptor ErbB-2/genética , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Pessoa de Meia-Idade , Mutação/genética , Recidiva Local de Neoplasia , Receptor ErbB-2/imunologia , Projetos de Pesquisa , Risco , Análise de Sobrevida , Resultado do Tratamento , Vacinação , Vacinas de Subunidades AntigênicasRESUMO
BACKGROUND: CD8+ T cell-eliciting vaccines are being investigated in breast cancer patients. Preclinical data showed that trastuzumab increases the susceptibility of tumor cells to lysis by vaccine-generated CD8+ T cells, suggesting potential benefit of a combination immunotherapy strategy. The current trial was undertaken to demonstrate the safety of this approach. METHODS: This study was designed as a dose-escalation trial enrolling clinically disease-free, human leukocyte antigen A2+ or A3+ , human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. Patients received 6-monthly inoculations of GP2+ granulocyte-macrophage colony-stimulating factor (GM-CSF) administered concurrently with standard-of-care trastuzumab. Local and systemic toxicity, as well as left ventricular ejection fraction (LVEF) were monitored. Immunologic responses were assessed in vivo by measuring the local reaction and in vitro using an interferon-γ enzyme-linked immunosorbent spot (ELISPOT) assay. RESULTS: Seventeen disease-free breast cancer patients were vaccinated. There were no dose-limiting or grade 3-5 local or systemic toxicities, and the median LVEF was unchanged from baseline after vaccination. Mean local reaction at initial inoculation was 28 ± 10 mm, increasing to 68 ± 8 mm at the final inoculation (p < 0.01). Mean ELISPOT response to GP2 increased from 47 ± 19 at baseline to 144 ± 60 (p = 0.13) after vaccination. Based on safety and immunologic data, the appropriate dose was determined to be 1000 µg of GP2 + 250 µg of GM-CSF. CONCLUSION: The GP2 + GM-CSF vaccine is safe and stimulates an immunologic response when administered concurrently with trastuzumab. An ongoing phase II trial is evaluating the efficacy of combining a CD8 T-cell-eliciting vaccine with trastuzumab in HER2-positive breast cancer patients.
Assuntos
Neoplasias da Mama/prevenção & controle , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/uso terapêutico , Imunoterapia , Fragmentos de Peptídeos/imunologia , Receptor ErbB-2/imunologia , Trastuzumab/uso terapêutico , Adulto , Neoplasias da Mama/imunologia , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Humanos , Pessoa de Meia-Idade , Prognóstico , VacinaçãoRESUMO
BACKGROUND: Stage IV melanoma has high mortality, largely unaffected by traditional therapies. Immunotherapy including cytokine therapies and checkpoint inhibitors improves outcomes, but has significant toxicities. In this phase I/IIa trial, we investigated safety and efficacy of a dendritoma vaccine, an active, specific immunotherapy, in stage IV melanoma patients. METHODS: Autologous tumor lysate and dendritic cells were fused creating dendritoma vaccines for each patient. Phase I patients were vaccinated every 3 months with IL-2 given for 5 days after initial inoculation. Phase IIa patients were vaccinated every 6 weeks with IL-2 given on days 1, 3 and 5 after initial inoculation. Toxicity and clinical outcomes were assessed. RESULTS: Twenty-five patients were enrolled and inoculated. All dendritoma and IL-2 toxicities were Assuntos
Vacinas Anticâncer/imunologia
, Células Dendríticas/imunologia
, Interleucina-2/imunologia
, Melanoma/imunologia
, Melanoma/terapia
, Idoso
, Artralgia/induzido quimicamente
, Vacinas Anticâncer/efeitos adversos
, Vacinas Anticâncer/uso terapêutico
, Calafrios/induzido quimicamente
, Terapia Combinada
, Células Dendríticas/metabolismo
, Relação Dose-Resposta a Droga
, Esquema de Medicação
, Eritema/induzido quimicamente
, Feminino
, Humanos
, Interleucina-2/efeitos adversos
, Interleucina-2/uso terapêutico
, Estimativa de Kaplan-Meier
, Masculino
, Pessoa de Meia-Idade
, Náusea/induzido quimicamente
, Recidiva Local de Neoplasia
, Estadiamento de Neoplasias
, Resultado do Tratamento
Assuntos
Vacinas Anticâncer , Melanoma , Células Dendríticas/imunologia , Humanos , Melanoma/terapia , VacinaçãoRESUMO
There is significant interest in investigating immunotherapeutic strategies to be used for the treatment of breast cancer patients. One form of immunotherapy under active investigation is the cancer vaccine. Vaccines are a form of active immune therapy designed to stimulate the immune system to recognize tumor cells as foreign. Vaccines include an antigen that serves as the target for the immune response, and an immunoadjuvant, which is a nonspecific stimulator of the immune response that promotes an environment conducive to immune stimulation. Vaccines are an appealing therapeutic strategy because they are specific and are associated with minimal toxicity. In addition, they stimulate the adaptive immune system, thereby producing a memory response allowing for sustained effect without repeated therapy. Currently, there are no US Food and Drug Administration-approved breast cancer vaccines; however, there are multiple vaccines and treatment strategies employing these vaccines that are being actively investigated in clinical trials.
Assuntos
Neoplasias da Mama/terapia , Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Imunidade Adaptativa , Adjuvantes Imunológicos/uso terapêutico , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Vacinas Anticâncer/efeitos adversos , Feminino , Humanos , Memória Imunológica , Imunoterapia/efeitos adversos , Resultado do Tratamento , Evasão Tumoral , Microambiente TumoralRESUMO
E75 (nelipepimut-S) is an immunogenic peptide derived from the HER2 protein. When combined with the immunoadjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF), nelipepimut-S has been used as a vaccine that is capable of eliciting a robust anti-HER2 immune response. Early-phase clinical trials that enrolled women with node-positive or high-risk node-negative breast cancer who had been rendered disease free with standard of care therapy but were at risk for recurrence, demonstrated the vaccine to be safe with a suggestion of clinical benefit. Nelipepimut-S is currently being evaluated in a Phase III clinical trial. This article covers the preclinical and clinical development of nelipepimut-S.
Assuntos
Neoplasias da Mama/terapia , Vacinas Anticâncer/farmacologia , Fragmentos de Peptídeos/farmacologia , Receptor ErbB-2/imunologia , Animais , Ensaios Clínicos como Assunto , Desenho de Fármacos , Feminino , Humanos , Receptor ErbB-2/farmacologia , Vacinas de Subunidades Antigênicas/farmacologiaRESUMO
This Phase I/IIa open-label, single-arm clinical trial addressing advanced, refractory, metastatic breast cancer was conducted at six medical centers in the United States. We repeated inoculations with irradiated SV-BR-1-GM, a breast cancer cell line with antigen-presenting activity engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), with pre-dose low-dose cyclophosphamide and post-dose local interferon alpha. Twenty-six patients were enrolled; 23 (88.5%) were inoculated, receiving a total of 79 inoculations. There were six Grade 4 and one Grade 5 adverse events noted (judged unrelated to SV-BR-1-GM). Disease control (stable disease [SD]) occurred in 8 of 16 evaluable patients; 4 showed objective regression of metastases, including 1 patient with near-complete regressions in 20 of 20 pulmonary lesions. All patients with regressions had human leukocyte antigen (HLA) matches with SV-BR-1-GM; non-responders were equally divided between matching and nonmatching (p = .01, Chi-squared), and having ≥2 HLA matches with SV-BR-1-GM (n = 6) correlated with clinical benefit. Delayed-type hypersensitivity (DTH) testing to candida antigen and SV-BR-1-GM generated positive responses (≥5 mm) in 11 (42.3%) and 13 (50%) patients, respectively. Quantifying peripheral circulating tumor cells (CTCs) and cancer-associated macrophage-like cells (CAMLs) showed that a drop in CAMLs was significantly correlated with an improvement in progression-free survival (PFS; 4.1 months vs. 1.8 months, p = .0058). Eight of 10 patients significantly upregulated programmed cell death ligand 1 (PD-L1) on CTCs/CAMLs with treatment (p = .0012). These observations support the safety of the Bria-IMT regimen, demonstrate clinical regressions, imply a role for HLA matching, and identify a possible value for monitoring CAMLs in peripheral blood.