RESUMEN
Checkpoint inhibitors have invigorated cancer immunotherapy research, including cancer vaccination. Classic early phase trial design and endpoints used in developing chemotherapy are not suited for evaluating all forms of cancer treatment. Peripheral T cell response dynamics have demonstrated inconsistency in assessing the efficacy of cancer vaccination. Tumor infiltrating lymphocytes (TILs), reflect the local tumor microenvironment and may prove a superior endpoint in cancer vaccination trials. Cancer vaccines may also promote success in combination immunotherapy treatment of weakly immunogenic tumors. This review explores the impact of TILs as an endpoint for cancer vaccination in multiple malignancies, summarizes the current literature regarding TILs analysis, and discusses the challenges of providing validity and a standardized implementation of this approach.
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Vacunas contra el Cáncer , Neoplasias , Humanos , Linfocitos Infiltrantes de Tumor , Vacunas contra el Cáncer/uso terapéutico , Neoplasias/terapia , Neoplasias/patología , Inmunoterapia , Microambiente TumoralRESUMEN
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.
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Vacunas contra el Cáncer , Melanoma , Humanos , Células Dendríticas , Factor Estimulante de Colonias de Granulocitos , Melanoma Cutáneo MalignoRESUMEN
Which clinical findings most reliably point to appendicitis? How do the 3 primary clinical scoring systems compare? When is it time to order imaging studies?
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Apendicitis , Apendicitis/diagnóstico , Apendicitis/cirugía , Humanos , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: The coronavirus disease 2019 pandemic has profoundly impacted surgical education. We assessed resident perceptions of our virtual academic program, which consists of daily lectures or case conferences held via a videoconferencing platform. METHODS: A survey evaluating attitudes and practices for virtual academics was administered to general surgery residents. A focus group was conducted to identify benefits, barriers to engagement, and opportunities for improvement for virtual education. A total of 19 residents completed the education survey, and seven residents participated in the focus group. RESULTS: While expressing preference toward in-person academics (84.2%), residents felt the virtual academics were of good quality (median rating 4/5) and preferred virtual academics to no academic sessions (94.7%). Of respondents, 57.9% believe that the coronavirus pandemic negatively impacted their surgical education. They believe their American Board of Surgery In-Training Examination preparation was not impacted. Residents preferred using a computer over a phone for academics (79% versus 16%). The focus group identified the benefits of virtual academics, including the ability to participate while away and having recordings available. Areas for improvement included reinforcement of protected time for academics, requiring cameras be on, increasing in-lecture polls, and creation of an online repository of recordings for review. Residents hoped a virtual component of academics and recordings would continue past the pandemic. CONCLUSIONS: Although virtual academics are not the preferred mode of learning in our residency, there are multiple unintended benefits. We recommend a hybrid academic model with in-person didactics and recorded video for later review.
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COVID-19 , Educación a Distancia , Internado y Residencia , Curriculum , Humanos , Pandemias/prevención & controlRESUMEN
Immunotherapy has revolutionized the treatment of melanoma, yet survival remains poor for patients with metastatic disease. The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine has been shown to be safe adjuvant therapy for patients with resected stage III/IV melanoma who complete the primary vaccine series. Here, we describe an open-label trial of patients with metastatic melanoma treated with TLPLDC vaccine in addition to standard of care (SoC) therapies. The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles, which are phagocytosed by autologous dendritic cells ex vivo. Patients who recurred while enrolled in a phase IIb trial of adjuvant TLPLDC vaccine (crossover cohort) and patients with measurable metastatic melanoma cohort were offered TLPLDC vaccine along with SoC therapies. Tumor response was measured by RECIST 1.1 criteria. Overall survival (OS) and progression-free survival (PFS) were estimated by intention-to-treat analysis. Fifty-four patients were enrolled (28 in crossover cohort; 26 in metastatic melanoma cohort). The vaccine was well-tolerated with no grade ≥3 adverse events when given with SoC therapies to include checkpoint inhibitors, BRAF/MEK inhibitors, tyrosine kinase inhibitors, intralesional therapy and/or radiation. In the crossover arm, OS was 76.5% and PFS was 57.1% (median follow-up of 13.9 months). In the metastatic melanoma arm, OS was 85.7% and PFS was 52.2% (median follow-up 8.5 months). The TLPLDC vaccine is well-tolerated and safe in combination with SoC therapies. Future trials will determine the efficacy of TLPLDC in combination with SoC therapies in metastatic melanoma.
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Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas/trasplante , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Checkpoint inhibitors (CPI) in combination with cell-based vaccines may produce synergistic antitumor immunity. The primary analysis of the randomized and blinded phase IIb trial in resected stage III/IV melanoma demonstrated TLPLDC is safe and improved 24-month disease-free survival (DFS) in the per treatment (PT) analysis. Here, we examine efficacy within pre-specified and exploratory subgroups. METHODS: Stage III/IV patients rendered disease-free by surgery were randomized 2:1 to TLPLDC vaccine versus placebo. The pre-specified PT analysis included only patients completing the primary vaccine/placebo series at 6 months. Kaplan-Meier analysis was used to compare 24-month DFS among subgroups. RESULTS: There were no clinicopathologic differences between subgroups except stage IV patients were more likely to receive CPI. In stage IV patients, 24-month DFS was 43% for vaccine versus 0% for placebo (p = 0.098) in the ITT analysis and 73% versus 0% (p = 0.002) in the PT analysis. There was no significant difference in 24-month DFS when stratified by use of immunotherapy or CPI. For patients with resected recurrent disease, 24-month DFS was 88.9% versus 33.3% (p = 0.013) in the PT analysis. All benefit from vaccination was in the PT analysis; no benefit was found in patients receiving up to three doses. CONCLUSION: The TLPLDC vaccine improved DFS in patients completing the primary vaccine series, particularly in the resected stage IV patients. The efficacy of the TLPLDC vaccine will be confirmed in a phase III study evaluating adjuvant TLPLDC + CPI versus Placebo + CPI in resected stage IV melanoma patients.
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Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas/inmunología , Melanoma/terapia , Recurrencia Local de Neoplasia/prevención & control , Medicina de Precisión , Neoplasias Cutáneas/terapia , Anciano , Supervivencia sin Enfermedad , Método Doble Ciego , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia Adoptiva/métodos , Melanoma/mortalidad , Melanoma/patología , Melanoma/cirugía , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Placebos/uso terapéutico , Estudios Prospectivos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugíaRESUMEN
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.
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Vacunas contra el Cáncer , Melanoma , Neoplasias Cutáneas , Vacunas contra el Cáncer/uso terapéutico , Humanos , Melanoma/patología , Melanoma/terapia , Estadificación de Neoplasias , Estudios Prospectivos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapiaRESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Vacunas contra el Cáncer/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Inmunoterapia/métodos , Fragmentos de Péptidos/inmunología , Receptor ErbB-2/inmunología , Trastuzumab/uso terapéutico , Neoplasias de la Mama Triple Negativas/terapia , Adulto , Estudios de Cohortes , Femenino , Regulación Neoplásica de la Expresión Génica , Antígeno HLA-A24/metabolismo , Humanos , Análisis de Intención de Tratar , Recurrencia Local de Neoplasia , Efecto Placebo , Medicina de Precisión , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Riesgo , Análisis de Supervivencia , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/mortalidadRESUMEN
Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome characterized by colorectal adenomas and a near 100% lifetime risk of colorectal cancer (CRC). Prophylactic colectomy, usually by age 40, is the gold-standard therapy to mitigate this risk. However, colectomy is associated with morbidity and fails to prevent extra-colonic disease manifestations, including gastric polyposis, duodenal polyposis and cancer, thyroid cancer, and desmoid disease. Substantial research has investigated chemoprevention medications in an aim to prevent disease progression, postponing the need for colectomy and temporizing the development of extracolonic disease. An ideal chemoprevention agent should have a biologically plausible mechanism of action, be safe and easily tolerated over a prolonged treatment period, and produce a durable and clinically meaningful effect. To date, no chemoprevention agent tested has fulfilled these criteria. New agents targeting novel pathways in FAP are needed. Substantial preclinical literature exists linking the molecular target of rapamycin (mTOR) pathway to FAP. A single case report of rapamycin, an mTOR inhibitor, used as chemoprevention in FAP patients exists, but no formal clinical studies have been conducted. Here, we review the prior literature on chemoprevention in FAP, discuss the rationale for rapamycin in FAP, and outline a proposed clinical trial testing rapamycin as a chemoprevention agent in patients with FAP.
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Poliposis Adenomatosa del Colon/prevención & control , Poliposis Adenomatosa del Colon/tratamiento farmacológico , Antiinflamatorios no Esteroideos/uso terapéutico , Antibióticos Antineoplásicos/uso terapéutico , Ácido Ascórbico/uso terapéutico , Aspirina/uso terapéutico , Cápsulas , Celecoxib/uso terapéutico , Quimioprevención/métodos , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Quimioterapia Combinada/métodos , Eflornitina/uso terapéutico , Clorhidrato de Erlotinib/uso terapéutico , Ácidos Grasos no Esterificados/uso terapéutico , Genes APC , Humanos , Sirolimus/uso terapéutico , Sulindac/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismo , Vitaminas/uso terapéuticoRESUMEN
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.
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Analgésicos Opioides/uso terapéutico , Cirugía General/educación , Internado y Residencia/estadística & datos numéricos , Dolor Postoperatorio/prevención & control , Pautas de la Práctica en Medicina/estadística & datos numéricos , Femenino , Cirugía General/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
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.
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Adenocarcinoma/diagnóstico , Biopsia/métodos , Linfocitos T CD4-Positivos/inmunología , Colon/patología , Neoplasias Colorrectales/diagnóstico , Linfocitos Infiltrantes de Tumor/inmunología , Anciano , Antígeno B7-H1/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Sensibilidad y Especificidad , Microambiente TumoralRESUMEN
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.
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Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Lobular/tratamiento farmacológico , Recurrencia Local de Neoplasia/prevención & control , Receptor ErbB-2/inmunología , Vacunas de Subunidad/administración & dosificación , Adulto , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/inmunología , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patología , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Fragmentos de Péptidos , Pronóstico , Estudios Prospectivos , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Método Simple Ciego , Tasa de Supervivencia , Vacunas de Subunidad/inmunologíaRESUMEN
BACKGROUND: The COVID-19 pandemic presents a unique challenge to surgical residency programs. Due to the restrictions recommended by the Centers for Disease Control and Prevention and other organizations, the educational landscape for surgical residents is rapidly changing. In addition, the time course of these changes is undefined. METHODS: We attempt to define the scope of the problem of maintaining surgical resident education while maintaining the safety of residents, educators, and patients. Within the basic framework of limiting in-person gatherings, postponing or canceling elective operations in hospitals, and limiting rotations between sites, we propose innovative solutions to maintain rigorous education. RESULTS: We propose several innovative solutions including the flipped classroom model, online practice questions, teleconferencing in place of in-person lectures, involving residents in telemedicine clinics, procedural simulation, and the facilitated use of surgical videos. Although there is no substitute for hands-on learning through operative experience and direct patient care, these may be ways to mitigate the loss of learning exposure during this time. CONCLUSIONS: These innovative solutions utilizing technology may help to bridge the educational gap for surgical residents during this unprecedented circumstance. The support of national organizations may be beneficial in maintaining rigorous surgical education.
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Competencia Clínica , Infecciones por Coronavirus/epidemiología , Educación a Distancia/métodos , Educación de Postgrado en Medicina/organización & administración , Cirugía General/educación , Pandemias/estadística & datos numéricos , Neumonía Viral/epidemiología , Telecomunicaciones/organización & administración , COVID-19 , Centers for Disease Control and Prevention, U.S. , Infecciones por Coronavirus/prevención & control , Curriculum , Femenino , Humanos , Internado y Residencia/organización & administración , Masculino , Pandemias/prevención & control , Neumonía Viral/prevención & control , Medición de Riesgo , Estados Unidos , Realidad VirtualRESUMEN
BACKGROUND: E39, an HLA-A2-restricted, immunogenic peptide derived from the folate-binding protein (FBP), is overexpressed in multiple malignancies. We conducted a phase I/IIa trial of the E39 + GM-CSF vaccine with booster inoculations of either E39 or E39' (an attenuated version of E39) to prevent recurrences in disease-free endometrial and ovarian cancer patients(pts). Here, we present the final 24-month landmark analysis. PATIENTS AND METHODS: HLA-A2 + patients receiving E39 + GM-CSF were included in the vaccine group (VG), and HLA-A2- pts (or HLA-A2 + patients refusing vaccine) were followed as the control group (CG). VG group received 6 monthly inoculations as the primary vaccine series (PVS) and were randomized to receive either E39 or E39' booster inoculations. Demographic, safety, immunologic, and disease-free survival (DFS) data were collected and evaluated. RESULTS: Fifty-one patients were enrolled; 29 in the VG and 22 in the CG. Fourteen patients received <1000 µg and 15 received 1000 µg of E39. There were no clinicopathologic differences between VG and CG or between dose groups. E39 was well tolerated. At the 24 months landmark, DFS was 55.5% (VG) vs 40.0% (CG), P = 0.339. Patients receiving 1000 µg and boosted patients also showed improved DFS (P < 0.03). DFS was improved in the 1000 µg group after treatment of primary disease (90.0% vs CG:42.9%, P = 0.007), but not in recurrent patients. In low-FBP expressing patients, DFS was 100.0% (1000 µg), 50.0% (<1000 µg), and 25.0% (CG), P = 0.029. CONCLUSIONS: This phase I/IIa trial reveals that E39 + GM-CSF is safe and may be effective in preventing recurrence in high-risk ovarian and endometrial cancer when optimally dosed (1000 µg) to FBP low patients being treated for primary disease.
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Vacunas contra el Cáncer/administración & dosificación , Neoplasias Endometriales/prevención & control , Receptores de Folato Anclados a GPI/química , Recurrencia Local de Neoplasia/prevención & control , Neoplasias Ováricas/prevención & control , Vacunas de Subunidad/administración & dosificación , Anciano , Vacunas contra el Cáncer/inmunología , Relación Dosis-Respuesta a Droga , Neoplasias Endometriales/inmunología , Femenino , Receptores de Folato Anclados a GPI/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Antígeno HLA-A2/metabolismo , Humanos , Inmunización Secundaria , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Neoplasias Ováricas/inmunología , Estudios Prospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Vacunas de Subunidad/inmunologíaRESUMEN
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.
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Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Factores Inmunológicos/efectos adversos , Fragmentos de Péptidos/efectos adversos , Trastuzumab/efectos adversos , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Receptor ErbB-2 , Volumen Sistólico/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/inmunología , Vacunas contra el Cáncer/inmunología , Antígeno HLA-A2/genética , Inmunoterapia/métodos , Receptor ErbB-2/genética , Adulto , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Femenino , Estudios de Seguimiento , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Persona de Mediana Edad , Mutación/genética , Recurrencia Local de Neoplasia , Receptor ErbB-2/inmunología , Proyectos de Investigación , Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Vacunación , Vacunas de SubunidadRESUMEN
INTRODUCTION: Tumor vaccines use various strategies to generate immune responses, commonly targeting generic tumor-associated antigens. The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is produced from DC loaded with autologous tumor antigens, creating a patient-specific vaccine. Here, we describe initial phase I/IIa trial results. METHODS: This trial includes patients with any stage solid tumors, ECOG ≤1, and >4â¯months life-expectancy. A personalized vaccine is created using 1â¯mg of tumor and 120â¯ml blood (to isolate DC). Primary vaccination series (PVS) is four monthly inoculations. Patients are followed per standard of care (SOC). Endpoints include safety and tumor response (RECIST v1.1). RESULTS: 44 patients were enrolled and vaccinated consisting of 31 late stage patients with residual/measurable disease, and 13 disease-free patients after SOC therapies. While 4 patients progressed before completing the PVS, 12/31 (39%) demonstrated clinical benefit (2 complete responses, 4 partial responses, 6 stable disease). In the adjuvant setting, 46% of late stage patients remain disease free at a median of 22.5â¯months. CONCLUSIONS: The TLPLDC vaccine is scalable, generates a personalized DC vaccine, and requires little autologous tumor tissue and few DC. The vaccine is safe, with primarily grade 0-2 toxicities, and nearly 40% clinical benefit rate in varied tumors, warranting further study. TRIAL REGISTRATION: ISRCTN81339386, Registered 2/17/2016.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas/inmunología , Inmunoterapia/métodos , Neoplasias/terapia , Adulto , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/patología , Medicina de Precisión/métodos , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/inmunología , Vacunas contra el Cáncer/inmunología , Receptores de Folato Anclados a GPI/inmunología , Neoplasias Ováricas/inmunología , Vacunas de Subunidad/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/efectos adversos , Femenino , Humanos , Hipersensibilidad Tardía/etiología , Hipersensibilidad Tardía/inmunología , Persona de Mediana Edad , Neoplasias Ováricas/terapia , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Vacunación/métodos , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/efectos adversosRESUMEN
AIM: We developed a novel approach to efficiently deliver autologous tumor antigens to the cytoplasm of dendritic cells (DC) using yeast cell wall particles (YCWP). MATERIALS AND METHODS: Loading of YCWP, leakage of protein from loaded YCWP and cytoplasmic delivery of YCWP content was assessed using fluorescent-tagged experiments. Spectrophotometric analysis compared the epitope-specific T-cell responses following antigen presentation via YCWP versus exogenous loading. The in vivo effectiveness of tumor lysate (TL) particle loaded DC (TLPLDC) vaccine was assessed using murine melanoma models. RESULTS: In fluorescence-tagged experiments, YCWP efficiently delivered antigen to the cytoplasm of DC. TLPLDC loading was more effective than conventional exogenous loading of DC. Finally, in murine melanoma models, TLPLDC outperformed an analogous dendritoma vaccine. CONCLUSION: The TLPLDC vaccine is commercially scalable and holds the potential of producing personalized vaccines.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Melanoma Experimental/patología , Animales , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Modelos Animales de Enfermedad , Femenino , Inmunoterapia/métodos , Neoplasias Pulmonares/inmunología , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
Introduction: Pre-operative MRI is being used with increasing frequency to evaluate breast cancer patients, but the debate surrounding risks and benefits of this use continues. At our institution, we instituted a standardized protocol for pre-operative MRI. Here, we compare patients seen prior to routine use of MRI to those seen after and examine effects on surgical choices, timing and outcomes. Methods: This is a retrospective review of a prospectively collected database of all new invasive breast cancers seen from January 2007 to December 2012. The control group (CG) did not receive MRI, while the MRI group (MRG) underwent MRI according to our pretreatment protocol. Groups were compared with regards to basic demographics, initial surgical choices, need for re-excision, and surgical timing. The electronic medical records of patients in the MRG who underwent mastectomy as their initial surgery were examined closely to determine the main factors leading to their choice of surgery. Finally, correlation between findings on MRI and final surgical pathology was analyzed. Results: Of 282 patients included, 38 were in the CG and 244 in the MRG; the groups were well matched. The MRG had a significantly higher percentage of patients choosing initial mastectomy (MRG: 47.1% vs CG 21.1%, p=0.003). Patients seen in the first 2 years of the study were less likely to choose mastectomy than those enrolled in the latter years (29.2%vs 48.6%, p=0.004). The MRG had a lower chance of return to the operating room for re-excision (15.2% vs 28.9%, p=0.035). The average time from initial imaging to initial surgery was approximately the same between groups (MRG: 39.7 days vs CG 42.1 days, p=0.45) and the MRG actually had shorter time to definitive (margin-negative) surgical management (MRG: 43.5 days vs CG: 50.3 days, p=0.079). One hundred-fifteen patients in the MRG underwent mastectomy as initial surgery. Of these, 64 (55.7%) had no additional findings on MRI and chose mastectomy based on patient preference; 30 patients (26.1%) (29 unilateral, 1 bilateral) had mastectomy because of MRI findings. Of the 31 breasts removed (29 unilateral and 1 bilateral mastectomies) because of MRI findings, 26 (83.9%) had histologic findings that correlated with the MRI findings, while 5 (16.1%) did not. Conclusion: Patients receiving routine pre-treatment MRI had an increased mastectomy rate, but had a lower re-excision rate. We found no delay to initial surgical therapy and, perhaps more importantly, a slight decrease in time to margin-negative surgical therapy in the MRI group. Women choosing mastectomy after MRI did so because of personal preference over half of the time, while MRI findings influenced this choice in 26% of these women. When MRI findings did lead to mastectomy, these findings were confirmed by pathology results in the vast majority of cases.