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.
Asunto(s)
Vacunas contra el Cáncer , Neoplasias , Humanos , Linfocitos Infiltrantes de Tumor , Vacunas contra el Cáncer/uso terapéutico , Neoplasias/terapia , Neoplasias/patología , Inmunoterapia , Microambiente TumoralRESUMEN
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.
Asunto(s)
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
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.
Asunto(s)
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: 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.
Asunto(s)
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
OBJECTIVE: To evaluate outcomes of systemic to pulmonary artery shunts (SPS) in patients weighing less than 3 kg with regard to shunt type, shunt size, and surgical approach. METHODS: Patients weighing less than 3 kg who underwent modified Blalock-Taussig or central shunts with polytetrafluoroethylene grafts at our institution from January 1, 2000, to May 31, 2011, were reviewed. Patients who had undergone other major concomitant procedures were excluded from the analysis. Primary outcomes included mortality (discharge mortality and mortality before next planned palliative procedure or definitive repair), cardiac arrest and/or extracorporeal membrane oxygenation (ECMO), and shunt reintervention. RESULTS: In this cohort of 80 patients, discharge survival was 96% (77/80). Postoperative cardiac arrest or ECMO occurred in 6/80 (7.5%), and shunt reintervention was required in 14/80 (17%). On univariate analysis, shunt reintervention was more common in patients with 3-mm shunts (11/30, 37%) compared with 3.5-mm (2/36, 6%) or 4-mm shunts (1/14, 7%) (P < .003). There were no statistically significant associations between shunt type, shunt size, or surgical approach and cardiac arrest/ECMO or mortality. Multiple logistic regression demonstrated that a shunt size of 3 mm (P = .019) and extracardiac anomaly (P = .047) were associated with shunt reintervention, whereas no variable was associated with cardiac arrest/ECMO or mortality. CONCLUSIONS: In this high-risk group of neonates weighing less than 3 kg at the time of SPS, survival to discharge and the next planned surgical procedure was high. Outcomes were good with the 3.5- and 4-mm shunts; however, shunt reintervention was common with 3-mm shunts.
Asunto(s)
Procedimiento de Blalock-Taussing , Peso Corporal , Cardiopatías Congénitas/cirugía , Arteria Pulmonar/cirugía , Circulación Pulmonar , Procedimiento de Blalock-Taussing/efectos adversos , Procedimiento de Blalock-Taussing/instrumentación , Procedimiento de Blalock-Taussing/mortalidad , Prótesis Vascular , Distribución de Chi-Cuadrado , Oxigenación por Membrana Extracorpórea , Cardiopatías Congénitas/mortalidad , Cardiopatías Congénitas/fisiopatología , Mortalidad Hospitalaria , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Modelos Logísticos , Politetrafluoroetileno , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/terapia , Diseño de Prótesis , Arteria Pulmonar/fisiopatología , Reoperación , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
The objective of this study was to detect and classify the number and size of gaseous microemboli in a simulated pediatric model of cardiopulmonary bypass. Tests were conducted at five different flow rates (400-1,200 ml/min in 200 ml/min increments), pulsatile versus nonpulsatile perfusion modes, and under normothermic, hypothermic, and deep hypothermic (35 degrees C, 25 degrees C, and 15 degrees C) conditions, yielding 180 total experiments. The circuit was primed with lactated Ringer's solution and filled with heparinized bovine blood. At the beginning of each experiment, 5 ml of air were injected into the venous line via the luer port of the oxygenator. Microemboli were quantified and classified by size for 5 minute segments at three transducer sites: postpump, postoxygenator, and postarterial filter. The purge line of the arterial filter was closed during all experiments. In all but one experiment, 90% of emboli at the postpump site were found to be smaller than 40 microm. At the postarterial filter site, nearly 99% of the emboli were smaller than 40 microm. Additionally, increasing microemboli counts were observed when the flow rate was increased and when the temperature was decreased. Lower temperatures, higher flow rates, and pulsatile perfusion were all associated with higher emboli counts. The majority of gaseous microemboli found in the simulated circuit was significantly below 40 microm; the smallest level detectable by traditional Doppler devices.