RESUMEN
The CSF-470 vaccine (VACCIMEL) plus BCG and GM-CSF as adjuvants has been assayed in cutaneous melanoma patients. In the adjuvant randomized Phase II study CASVAC-0401, vaccinated patients had longer distant metastasis-free survival (DMFS) than those treated with IFNα2b. Five years after locking the data, an actualization was performed. The benefit in DMFS was maintained in the vaccinated group versus the IFNα2b-treated group (p = 0.035), with a median DMFS of 96 months for VACCIMEL and 13 months for IFNα2b. The favorable risk-benefit ratio was maintained. DMFS was also analyzed as a single cohort in all the IIB, IIC, and III patients (n = 30) who had been treated with VACCIMEL. The median DMFS was 169 months, and at 48 months follow-up, it was 71.4%, which was not statistically different from DMFS of previously published results obtained in adjuvancy with ipilimumab, pembrolizumab, nivolumab, or dabrafenib/trametinib. The possible toxicity of combining VACCIMEL with anti-immune checkpoint inhibitors (ICKi) was analyzed, especially since VACCIMEL was co-adjuvated with BCG in every vaccination. A patient with in-transit metastases was studied to produce a proof of concept. During treatment with VACCIMEL, the patient developed T-cell clones reactive towards tumor-associated antigens. Three years after ending the VACCIMEL study, the patient progressed and was treated with ICKi. During ICKi treatment, the patient did not reveal any toxicity due to previous BCG treatment. When she recurred after a 4-year treatment with nivolumab, a biopsy was obtained and immunohistochemistry and RNA-seq were performed. The tumor maintained expression of tumor-associated antigens and HLA-I and immune infiltration, with immunoreactive and immunosuppressive features. VACCIMEL plus BCG and GM-CSF is an effective treatment in adjuvancy for stages IIB, IIC, and III cutaneous melanoma patients, and it is compatible with subsequent treatments with ICKi.
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Vacunas contra el Cáncer , Trasplante de Células Madre Hematopoyéticas , Melanoma , Neoplasias Cutáneas , Adyuvantes Inmunológicos , Antígenos de Neoplasias , Vacuna BCG , Vacunas contra el Cáncer/efectos adversos , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Humanos , Nivolumab/uso terapéutico , Melanoma Cutáneo MalignoRESUMEN
Introduction: Animal studies and preclinical studies in cancer patients suggest that the induction of immunogenic cell death (ICD) by neoadjuvant chemotherapy with doxorubicin and cyclophosphamide (NAC-AC) recovers the functional performance of the immune system. This could favor immunotherapy schemes such as the administration of antigen-free autologous dendritic cells (DCs) in combination with NAC-AC to profit as cryptic vaccine immunogenicity of treated tumors. Objective: To explore the safety and immunogenicity of autologous antigen-free DCs administered to breast cancer patients (BCPs) in combination with NAC-AC. Materials and Methods: A phase I/II cohort clinical trial was performed with 20 BCPs treated with NAC-AC [nine who received DCs and 11 who did not (control group)]. The occurrence of adverse effects and the functional performance of lymphocytes from BCPs before and after four cycles of NAC-AC receiving DCs or not were assessed using flow cytometry and compared with that from healthy donors (HDs). Flow cytometry analysis using manual and automated algorithms led us to examine functional performance and frequency of different lymphocyte compartments in response to a stimulus in vitro. This study was registered at clinicaltrials.gov (NCT03450044). Results: No grade II or higher adverse effects were observed associated with the transfer of DCs to patients during NAC-AC. Interestingly, in response to the in vitro stimulation, deficient phosphorylation of Zap70 and AKT proteins observed before chemotherapy in most patients' CD4 T cells significantly recovered after NAC-AC only in patients who received DCs. Conclusions: The transfer of autologous DCs in combination with NAC-AC in BCPs is a safe procedure. That, in BCPs, the administration of DCs in combination with NAC-AC favors the recovery of the functional capacity of T cells suggests that this combination may potentiate the adjuvant effect of ICD induced by NAC-AC on T cells and, hence, potentiate the immunogenicity of tumors as cryptic vaccines.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas/trasplante , Inmunoterapia Adoptiva , Linfocitos Infiltrantes de Tumor/inmunología , Terapia Neoadyuvante , Linfocitos T/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Quimioterapia Adyuvante , Colombia , Ciclofosfamida/uso terapéutico , Células Dendríticas/inmunología , Doxorrubicina/uso terapéutico , Femenino , Humanos , Inmunoterapia Adoptiva/efectos adversos , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , Microambiente TumoralRESUMEN
Purpose: A vaccine composition based on the extracellular domain of the human epidermal growth factor receptor 1 (HER1-ECD) and the combination of VSSP (very small size proteoliposomes) and Montanide ISA 51 adjuvants when used by intramuscular route, demonstrated promising results in preclinical studies. However, in order to avoid potential adverse events due to the use of Montanide, it is proposed to modify the vaccine formulation by using VSSP (very small size proteoliposomes) adjuvant alone, and to evaluate the quality of subcutaneously induced immune response. This study aimed to assess the immunotoxicological effects of HER1 vaccine in Cercopithecus aethiops.Materials and methods: Fifteen monkeys were randomized into four groups: Negative Control (Tris/NaCl, s.c.), Positive Control (200 µg HER1-ECD/VSSP/Montanide ISA-51 VG, i.m), Low Dose (200 µg HER1-ECD/VSSP/Tris NaCl, s.c.) and High Dose (800 µg HER1-ECD/VSSP/Tris NaCl, s.c). All monkeys received 7 doses and were daily inspected for clinical signs. Body weight, rectal temperature, cardiac and respiratory rates were measured during the study, and electrocardiographical and ophthalmological studies were performed. Humoral and cellular immune response and clinical pathology parameters were analyzed.Results: Animal's survival in the study was 100% (n = 15). Administration site reactions were observed in the Positive Control animals (n = 4). HER1 vaccine administered subcutaneously (High Dose Group) achieved good IgG antibody titers although lower than the Positive Control group, but with higher ability to inhibit HER1 phosphorylation. Conclusions: This suggests that the alternative of eliminating the use of Montanide in the HER1 vaccine preparation and the using subcutaneous route is feasible.
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Vacunas contra el Cáncer/farmacología , Animales , Vacunas contra el Cáncer/efectos adversos , Chlorocebus aethiops , Evaluación Preclínica de Medicamentos , Receptores ErbB/efectos adversos , Receptores ErbB/farmacología , Femenino , Inyecciones Subcutáneas , MasculinoRESUMEN
Hepatocellular carcinoma (HCC) is considered an immunogenic tumor that arises in chronically inflamed livers due to underlying chronic liver disease caused by viral and non-viral pathogenesis. This inflammation leads to tumor development and is associated to higher tumor immunogenicity. For this reason immunotherapeutic approaches may be suitable therapeutic strategies for HCC. Indeed, several preclinical and clinical data support this hypothesis showing that immunotherapy and even more their combination may be a good alternative candidate for the treatment of HCC patients. However, considering that the liver plays a central role in host defense as well as in the maintenance of self-tolerance, it is characterized by a strong intrinsic immune suppressive microenvironment as well as by a high immune evasion, which may represent a major impediment for an effective immune response against tumor. Furthermore, the low expression of tumor antigens on liver cancer cells leads to a lower T-cell activation and tumor infiltration, resulting in a less efficient control of the tumor growth and, consequently, in a worse clinical outcome. For this reason, strategies should be developed to counteract the different factors in the HCC tumor microenvironment playing a major role in reducing the effects of immunotherapy.
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Antineoplásicos Inmunológicos/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Carcinoma Hepatocelular/terapia , Inmunoterapia/métodos , Neoplasias Hepáticas/terapia , Animales , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Antineoplásicos Inmunológicos/efectos adversos , Vacunas contra el Cáncer/efectos adversos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Humanos , Inmunoterapia/efectos adversos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Mutación , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Escape del Tumor/efectos de los fármacos , Microambiente TumoralRESUMEN
The allogeneic therapeutic vaccine CSF-470 has demonstrated a significant benefit over medium-dose IFNα2b in the distant metastasis-free survival for stages IIB-IIC-III cutaneous melanoma patients in a randomized phase II/III clinical trial (CASVAC-0401, NCT01729663). At the end of the 2-year CSF-470 immunization protocol, patient #006 developed several lung and one subcutaneous melanoma metastases; this later was excised. In this report, we analyzed the changes throughout vaccination of immune populations in blood and in the tumor tissue, with special focus on the T-cell repertoire. Immunohistochemistry revealed a marked increase in CD8+, CD4+, and CD20+ lymphocytes infiltrating the metastasis relative to the primary tumor. Lymphocytes were firmly attached to dying-tumor cells containing Granzyme-B granules. Whole-exon sequencing assessment indicated a moderate-to-high tumor mutational burden, with BRAFV600E as the main oncogenic driver. Mutational signature presented large numbers of mutations at dipyrimidines, typical of melanoma. Relevant tumor and immune-related genes from the subcutaneous metastasis were addressed by RNA-Seq analysis, revealing expression of typical melanoma antigens and proliferative tumor-related genes. Stimulatory and inhibitory immune transcripts were detected as well as evidence of active T-cell effector function. Peripheral blood monitoring revealed an increase in CD4+ and CD8+ cells by the end of the immunization protocol. By CDR3-T-cell receptor ß (TCRß) sequencing, generation of new clones and an increase in oligoclonality was observed in the peripheral T-cells immune repertoire throughout immunization. A shift, with the expansion of selected preexisting and newly arising clones with reduction of others, was detected in blood. In tumor-infiltrating lymphocytes, prevalent clones (50%) were both new and preexisting that were expanded in blood following CSF-470 immunization. These clones persisted in time, since 2 years after completing the immunization, 51% of the clones present in the metastasis were still detected in blood. This is the first report of the modulation of the TCRß repertoire from a melanoma patient immunized with the CSF-470 vaccine. After immunization, the changes observed in peripheral immune populations as well as in the tumor compartment suggest that the vaccine can induce an antitumor adaptive immune repertoire that can reach tumor lesions and persists in blood for at least 2 years.
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Vacunas contra el Cáncer/inmunología , Melanoma/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Neoplasias Cutáneas/genética , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/efectos adversos , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/genética , Melanoma/terapia , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Secuencia de ARN , Neoplasias Cutáneas/inmunología , Vacunación , Melanoma Cutáneo MalignoRESUMEN
Immunotherapy based on checkpoint blockers has proven survival benefits in patients with melanoma and other malignancies. Nevertheless, a significant proportion of treated patients remains refractory, suggesting that in combination with active immunizations, such as cancer vaccines, they could be helpful to improve response rates. During the last decade, we have used dendritic cell (DC) based vaccines where DCs loaded with an allogeneic heat-conditioned melanoma cell lysate were tested in a series of clinical trials. In these studies, 60% of stage IV melanoma DC-treated patients showed immunological responses correlating with improved survival. Further studies showed that an essential part of the clinical efficacy was associated with the use of conditioned lysates. Gallbladder cancer (GBC) is a high-incidence malignancy in South America. Here, we evaluated the feasibility of producing effective DCs using heat-conditioned cell lysates derived from gallbladder cancer cell lines (GBCCL). By characterizing nine different GBCCLs and several fresh tumor tissues, we found that they expressed some tumor-associated antigens such as CEA, MUC-1, CA19-9, Erb2, Survivin, and several carcinoembryonic antigens. Moreover, heat-shock treatment of GBCCLs induced calreticulin translocation and release of HMGB1 and ATP, both known to act as danger signals. Monocytes stimulated with combinations of conditioned lysates exhibited a potent increase of DC-maturation markers. Furthermore, conditioned lysate-matured DCs were capable of strongly inducing CD4+ and CD8+ T cell activation, in both allogeneic and autologous cell co-cultures. Finally, in vitro stimulated CD8+ T cells recognize HLA-matched GBCCLs. In summary, GBC cell lysate-loaded DCs may be considered for future immunotherapy approaches.
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Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Neoplasias de la Vesícula Biliar/terapia , Animales , Antígenos de Neoplasias/inmunología , Biomarcadores , Vacunas contra el Cáncer/efectos adversos , Línea Celular Tumoral , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/inmunología , Neoplasias de la Vesícula Biliar/metabolismo , Regulación de la Expresión Génica , Respuesta al Choque Térmico , Humanos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
PURPOSE: EGFR is a well-validated target for patients with non-small cell lung cancer (NSCLC). CIMAvax-EGF is a therapeutic cancer vaccine composed of human recombinant EGF conjugated to a carrier protein and Montanide ISA51 as adjuvant. The vaccine is intended to induce antibodies against self EGFs that block EGF-EGFR interaction. EXPERIMENTAL DESIGN: To evaluate overall survival, safety, immunogenicity, and EGF concentration in serum after CIMAvax-EGF, a randomized phase III trial was done in patients with advanced NSCLC. Four to 6 weeks after first-line chemotherapy, 405 patients with stage IIIB/IV NSCLC were randomly assigned to a vaccine group, which received CIMAvax-EGF or a control group, treated with best supportive care. RESULTS: Long-term vaccination was very safe. Most frequent adverse reactions were grade 1 or 2 injection-site pain, fever, vomiting, and headache. Vaccination induced anti-EGF antibodies and decreased serum EGF concentration. In the safety population, median survival time (MST) was 10.83 months in the vaccine arm versus 8.86 months in the control arm. These differences were not significant according the standard log rank (HR, 0.82; P = 0.100), but according a weighted log rank (P = 0.04) that was applied once the nonproportionality of the HR was verified. Survival benefit was significant (HR, 0.77; P = 0.036) in the per-protocol setting (patients receiving at least four vaccine doses): MST was 12.43 months for the vaccine arm versus 9.43 months for the control arm. MST was higher (14.66 months) for vaccinated patients with high EGF concentration at baseline. CONCLUSIONS: Switch maintenance with CIMAvax-EGF was well tolerated and significantly increased MST of patients that completed induction vaccination. Baseline EGF concentration predicted survival benefit. Clin Cancer Res; 22(15); 3782-90. ©2016 AACR.
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Vacunas contra el Cáncer/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Factor de Crecimiento Epidérmico/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Adyuvantes Inmunológicos , Vacunas contra el Cáncer/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Factor de Crecimiento Epidérmico/sangre , Femenino , Humanos , Inmunoterapia Activa , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Estadificación de Neoplasias , Pronóstico , Retratamiento , Resultado del TratamientoRESUMEN
We aimed to evaluate dendritic cell (DC) tumor vaccines for preventing liver cancer recurrence and metastasis. DCs were induced from mononuclear cells in the peripheral blood with recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) and recombinant human interleukin 4 (rhIL-4), followed by sensitization with lysis of autologous liver cancer cells. One hundred and sixty patients with hepatocellular carcinoma were randomly divided into two groups of 80. One group was treated postoperatively with six cycles of the DC tumor vaccine. The other group was treated postoperatively with six cycles of FOLFOX 6, beginning 1 week after surgery. After treatment with DC tumor vaccines, the levels of CD3+, CD4+, and CD8+, the ratio of CD4+ to CD8+ DC, and the serum levels of IL-12 and IFN-γ were significantly increased both in comparison to the pre-treatment levels (P < 0.001) and to the chemotherapy group (P < 0.001). After a postoperative follow-up of 18 months, the metastatic recurrence rate in the DC tumor vaccine group was significantly lower than that in the chemotherapy group (17.50 vs 48.75%, P < 0.005), and the survival rate of the patients in the DC tumor vaccine group was higher than that of the chemotherapy treatment group (86.25 vs 52.50%, P < 0.005). Treatment with DC tumor vaccines was safe and feasible. It can enhance the immunity of the patients, reduce the rates of metastasis and recurrence, and improve survival rates. This is a promising treatment for the prevention of postoperative recurrence in patients with liver cancer.
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Vacunas contra el Cáncer/inmunología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/terapia , Células Dendríticas/inmunología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/terapia , Antígenos de Superficie/metabolismo , Biomarcadores , Vacunas contra el Cáncer/efectos adversos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirugía , Terapia Combinada , Citocinas/sangre , Células Dendríticas/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Inmunofenotipificación , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Resultado del TratamientoRESUMEN
Racotumomab-alum vaccine is an anti-idiotypic vaccine able to mimic the tumor-associated antigen NeuGcGM3. Different Phase I clinical trials and compassionate use studies demonstrated its low toxicity and capacity to induce a strong anti-NeuGcGM3 response, able to bind and directly kill tumor cells expressing the antigen. A Phase II/III randomized double-blind clinical trial in advanced non-small cell lung cancer patients showed a significant improvement in overall survival and progression-free survival for racotumomab-alum versus placebo. Patients who developed anti-NeuGcGM3 antibodies capable of binding and killing NeuGcGM3 expressing tumor cells showed significantly longer median survival times. The impact of using racotumomab-alum as switch maintenance followed by second-line therapy is currently being explored in a new randomized, multinational Phase III study.
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Adyuvantes Inmunológicos/administración & dosificación , Compuestos de Alumbre/administración & dosificación , Vacunas contra el Cáncer/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Adyuvantes Inmunológicos/efectos adversos , Compuestos de Alumbre/efectos adversos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales de Origen Murino , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/efectos adversos , Gangliósido G(M3)/análogos & derivados , Gangliósido G(M3)/antagonistas & inhibidores , Gangliósido G(M3)/inmunología , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Se realiza un estudio con el objetivo de evaluar la seguridad y efectividad de la vacuna terapéutica CIMAvax EGF en pacientes con cáncer de pulmón de células no pequeñas en estadio IIIB ó IV tratados en la Atención Primaria de Salud, en la provincia Guantánamo durante el año 2011. Se incluyen pacientes con confirmación citohistológica de carcinoma de células no pequeñas de pulmón en estadios avanzados que no fueran candidatos a las terapias oncoespecíficas o porque las lesiones progresaron con posterioridad a recibir las mismas y solo estuvieran recibiendo los cuidados de soporte o paliativos. Se evaluaron 35 pacientes, de estos, 11, cumplieron con los criterios de inclusión y exclusión. Los eventos adversos que con mayor frecuencia se registraron fueron: fiebre, dolor en sitio de inyección y vómitos. La tasa de fallecimiento en el estudio fue del 54,5 por ciento. El tiempo global de supervivencia fue de 3,1 meses y la supervivencia a la inclusión, 1,8 meses. La calidad de vida de vida de los pacientes mejoró notablemente, con disminución de la disnea e incorporación de los pacientes a su medio familiar(AU)
A study to evaluate the safety and effectiveness of CIMAvax EGF therapeutic vaccine in patients with lung cancer non-small cell stage IIIB or IV treated in primary health care in the province is done during the year Guantánamo, 2011. It was important the insertion of patients with cytohistological confirmation of non-small cell carcinoma of lung in advanced stages who were not candidates for oncospecific therapies because lesions were progressing after receiving supportive care or palliative. 35 patients were evaluated, only 11 of these completed the inclusion and exclusion criteria. Adverse events were registered such as: fever, injection site pain and vomiting. The death rate in the study was 54, 5 percent. The survival time was 3, 1 month and survival at inclusion, 1,8 months. The quality of life the patients improved significantly, with low dyspnea and incorporation of patients to their families
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Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Vacunas contra el Cáncer/efectos adversos , Neoplasias Pulmonares/mortalidad , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológicoRESUMEN
AIM: The aim of the study is to explore the safety of cytotoxic T lymphocytes (CTLs) infusion by transfected dendritic cells (DCs) with recombinant adeno-associated virus vector (rAAV) carrying CEA cDNA among advanced cancer patients. PATIENTS AND METHODS: A total of 27 cancer patients with tumor tissue expression positivity and/or sera-elevated level of CEA were subsequently divided into cohort A and B resulted from the ex vivo expansion number of CTLs generated from co-culture of specific transfected DCs with autologous T lymphocytes. Based on the variations of infused number of specific CTL derived from different yields of individualized patients who had experienced various anti-cancer treatments, we compared the patients of low number of CTL cells (2-8 × 10(8) infused, cohort A, 6 cases) with those of higher number (above 8 × 10(8) infused, cohort B, 21 cases) to testify the possible adverse reactions caused by amount of infused CTLs. This study resembled a phase I study aiming for setting up clinical trial of adoptive cellular therapy that conceptually comes from conventional cytotoxic drugs. RESULTS: The results showed that one case from the each cohort had experienced moderate fever, and four cases with fatigue were seen in cohort B. The symptoms were transient without serious adverse events. For the consideration of clinical response 2 partial remission (8.0 %, 2/25), 1 minor remission, and 9 stable disease (40 %, 10/25) were observed in 25 patients eligible for evaluation. Sera levels of CEA assay were lowered in six patients. During a median follow-up of 8.1 months, we could not observe severe or chronic adverse reactions related to rAAV-DC infusions. Meanwhile, the variation of number of CTLs infused in this setting did not alter the status of peripheral lymphocyte population. CONCLUSIONS: These preliminary data suggest that the rAAV-DC immunotherapy is well-tolerated and showed no severe adverse reactions in cancer patients.
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Vacunas contra el Cáncer/efectos adversos , Células Dendríticas/trasplante , Dependovirus/genética , Neoplasias/terapia , Linfocitos T Citotóxicos/trasplante , Adulto , Anciano , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Vectores Genéticos , Humanos , Inmunoterapia , Masculino , Persona de Mediana Edad , Neoplasias/inmunología , Neoplasias/metabolismo , Fenotipo , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , TransfecciónRESUMEN
CIMAvax-EGF consists of a human recombinant epidermal growth factor (EGF), coupled to P64k, a recombinant carrier protein from N. meningitis, and Montanide ISA 51 as adjuvant. The vaccine immunization induces a specific antibody production, inhibiting the EGF/EGF-R interaction through EGF deprivation. The objective of this study was to assess the CIMAvax-EGF toxicity in Sprague Dawley rats after intramuscular administration of repeated doses (6 months) and at the same time to determine if rat is a relevant species for studying CIMAvax-EGF vaccine. Rats were randomly distributed into four groups: control, Montanide ISA 51, treated with 1× and 15× of human total dose of the antigen. Animals were immunized weekly during 9 weeks, plus 9 immunizations every 14 days. Rats were inspected daily for clinical signs. Body weight, food consumption, and rectal temperature were measured during the administration of doses. Blood samples were collected for hematological, serum biochemical determinations and EGF titles at the beginning, three months and at the end of experimentation. Gross necropsy and histological examination of tissues were performed on animals at the end of the assay. Vaccine provoked the apparition of antibodies against EGF in the rats, demonstrating rat species relevance in these studies. Body weight gain, food and water consumption were not affected. CIMAvax-EGF and Montanide ISA 51 produced local damage at the administration site, showing multiple cysts and granulomas. Both vaccine-treated groups showed neutrophil elevation, besides an AST increase probably related to the damage at the administration site. Rectal temperature was found to be significantly higher in 15× treated group after immunizations, probably induced by the inflammatory process at the injection site. In summary, the clinical pathology findings together with the body temperature results, appear to be caused by the inflammatory reaction at the administration site of the vaccine, mainly mediated by the oil-based adjuvant Montanide ISA 51, probably enhanced by the immunological properties of the antigen. This study showed evidences that intramuscular administration during 26 weeks of CIMAvax-EGF at doses up to 15× human total dose is well tolerated in rats and it has a clinical importance since this long lasting study in relevant species allows to treat cancer patients with tumors during long periods with relative weight safety margin.
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Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/efectos adversos , Vacunación/efectos adversos , Vacunación/métodos , Animales , Anticuerpos/sangre , Aspartato Aminotransferasas/sangre , Recuento de Células Sanguíneas , Temperatura Corporal , Peso Corporal , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Conducta Alimentaria , Femenino , Histocitoquímica , Inyecciones Intramusculares , Masculino , Músculos/patología , Ratas , Ratas Sprague-Dawley , Suero/químicaRESUMEN
CIGB-247 is a cancer therapeutic, based on recombinant modified human vascular endothelial growth factor (VEGF) as antigen, in combination with the oil free adjuvant VSSP (very small sized proteoliposomes of Neisseria meningitidis outer membrane). Our previous experimental studies in mice with CIGB-247 have shown that the vaccine has both anti-tumoral and anti-metastatic activity, and produces both antibodies that block VEGF-VEGF receptor interaction, and a specific T-cell cytotoxic response against tumor cells. CIGB-247, with an antigen dose of 100 µg, has been characterized by an excellent safety profile in mice, rats, rabbits, and non human primates. In this article we extend the immunogenicity and safety studies of CIGB-247 in non human primates, scaling the antigen dose from 100 µg to 200 and 400 µg/vaccination. Our results indicate that such dose escalation did not affect animal behavior, clinical status, and blood parameters and biochemistry. Also, vaccination did not interfere with skin deep skin wound healing. Anti-VEGF IgG antibodies and specific T-cell mediated responses were documented at all three studied doses. Antigen dose apparently did not determine differences in maximum antibody titer during the 8 weekly immunization induction phase, or the subsequent increase in antibodies seen for monthly boosters delivered afterwards. Higher antigen doses had a positive influence in antibody titer maintenance, after cessation of immunizations. Boosters were important to achieve maximum antibody VEGF blocking activity, and specific T-cell responses in all individuals. Purified IgG from CIGB-247 immunized monkey sera was able to impair proliferation and formation of capillary-like structures in Matrigel, for HMEC cells in culture. Altogether, these results support the further clinical development of the CIGB-247 therapeutic cancer vaccine, and inform on the potential mechanisms involved in its effect.
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Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Inmunoterapia/métodos , Neoplasias/terapia , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/efectos adversos , Animales , Vacunas contra el Cáncer/efectos adversos , Chlorocebus aethiops , Modelos Animales de Enfermedad , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoterapia/efectos adversos , Masculino , Linfocitos T/inmunologíaRESUMEN
The trend of increased survival in advanced tumors suggests the possibility of the transformation of cancer into a chronic disease. That goal will require therapeutic weapons with low toxicity that can be used chronically. Here we summarize the development of a therapeutic vaccine consisting in recombinant EGF chemically linked to a protein from Neisseria meningitides. In mice, the vaccine elicited antibodies to self-EGF and had anti-tumor activity. Clinical trials have shown that the vaccine is also immunogenic and well tolerated in humans. The vaccination produced a decrease in plasma EGF concentration. Advanced lung cancer patients eliciting high antibody titers of EGF had better survival. The vaccine can be used long term and integrated with other treatment modalities.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Factor de Crecimiento Epidérmico/uso terapéutico , Neoplasias Pulmonares/terapia , Neisseria meningitidis/inmunología , Animales , Autoanticuerpos/sangre , Proteínas de la Membrana Bacteriana Externa/efectos adversos , Proteínas de la Membrana Bacteriana Externa/inmunología , Vacunas contra el Cáncer/efectos adversos , Enfermedad Crónica , Factor de Crecimiento Epidérmico/efectos adversos , Factor de Crecimiento Epidérmico/sangre , Factor de Crecimiento Epidérmico/inmunología , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Resultado del Tratamiento , Vacunas Sintéticas/uso terapéuticoRESUMEN
BACKGROUND: Overall therapeutic outcomes of advanced non-small-cell lung cancer (NSCLC) are poor. The dendritic cell (DC) immunotherapy has been developed as a new strategy for the treatment of lung cancer. The purpose of this study was to evaluate the feasibility, safety and immunologic responses in use in mature, antigen-pulsed autologous DC vaccine in NSCLC patients. METHODS: Five HLA-A2 patients with inoperable stage III or IV NSCLC were selected to receive two doses of 5 × 107 DC cells administered subcutaneous and intravenously two times at two week intervals. The immunologic response, safety and tolerability to the vaccine were evaluated by the lymphoproliferation assay and clinical and laboratorial evolution, respectively. RESULTS: The dose of the vaccine has shown to be safe and well tolerated. The lymphoproliferation assay showed an improvement in the specific immune response after the immunization, with a significant response after the second dose (p = 0.005). This response was not long lasting and a tendency to reduction two weeks after the second dose of the vaccine was observed. Two patients had a survival almost twice greater than the expected average and were the only ones that expressed HER-2 and CEA together. CONCLUSION: Despite the small sample size, the results on the immune response, safety and tolerability, combined with the results of other studies, are encouraging to the conduction of a large clinical trial with multiples doses in patients with early lung cancer who underwent surgical treatment. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN45563569.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Células Dendríticas/inmunología , Inmunoterapia Adoptiva/métodos , Neoplasias Pulmonares/terapia , Anciano , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Terapia Combinada , Femenino , Humanos , Inmunoterapia Adoptiva/efectos adversos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Proyectos Piloto , Resultado del TratamientoRESUMEN
We have developed a cancer vaccine candidate (hereafter denominated CIGB-247), based on recombinant modified human vascular endothelial growth factor (VEGF) as antigen, and the adjuvant VSSP (very small sized proteoliposomes of Neisseria meningitidis outer membrane). In mice, previous work of our group had shown that vaccination with CIGB-247 extended tumor-take time, slowed tumor growth, and increased animal survival. Immunization elicited anti-human and murine VEGF-neutralizing antibodies, and spleen cells of vaccinated mice are cytotoxic in vitro to tumor cells that produce VEGF. We have now tested the immunogenicity of CIGB-247 in Wistar rats, New Zealand White rabbits and the non-human primate Chlorocebus aethiops sabaeus. Using weekly, biweekly and biweekly plus montanide immunization schemes, all three species develop antigen-specific IgG antibodies that can block the interaction of VEGF and VEGF receptor 2 in an ELISA assay. Antibody titers decline after vaccination stops, but can be boosted with new immunizations. In monkeys, DTH and direct cell cytotoxicity experiments suggest that specific T-cell responses are elicited by vaccination. Immunization with CIGB-247 had no effect on normal behavior, hematology, blood biochemistry and histology of critical organs, in the tested animals. Skin deep wound healing was not affected in vaccinated rats and monkeys.
Asunto(s)
Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Inmunoterapia Activa/métodos , Neoplasias/terapia , Factor A de Crecimiento Endotelial Vascular/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/aislamiento & purificación , Animales , Anticuerpos Antineoplásicos/sangre , Proteínas de la Membrana Bacteriana Externa/administración & dosificación , Proteínas de la Membrana Bacteriana Externa/aislamiento & purificación , Vacunas contra el Cáncer/genética , Cercopithecinae , Femenino , Humanos , Inmunización Secundaria , Inmunoglobulina G/sangre , Liposomas/administración & dosificación , Liposomas/aislamiento & purificación , Ratones , Neisseria meningitidis/química , Ácidos Oléicos/administración & dosificación , Conejos , Ratas , Ratas Wistar , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Linfocitos T/inmunología , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
1E10 mAb is an anti-Id murine mAb (Ab2 mAb) specific for an Ab1 mAb that reacts with NeuGc-containing gangliosides, sulfatides, and Ags expressed in some human tumors. In preclinical studies, this Ab2 Ab was able to mimic NeuGc-containing gangliosides only in animals lacking expression of these Ags in normal tissues. In this study, we report on the immune responses elicited in 20 non-small cell lung cancer patients treated with 1 mg of aluminum hydroxide-precipitated 1E10 mAb. In the hyperimmune sera from 16 of 20 patients, a strong specific Ab response of both IgM and IgG isotypes against NeuGcGM3 ganglioside was observed. Patient immune sera were able to induce complement-independent cell death of NeuGcGM3-expressing X63 murine myeloma target cells. Significant immunoreactivity to NeuGcGM3 was still detected after the complete abrogation of the reactivity against 1E10 mAb by the adsorption of patient sera with this Ab. We hypothesize that Id(-)Ag(+) Abs could reflect the activation of an autologous idiotypic cascade into the patients. Both Id(+)Ag(+) and Id(-)Ag(+) fractions were separated by affinity chromatography and characterized. Although IgG isotype Abs were found in both fractions, IgM isotype Abs were found only in the Id(-)Ag(+) fraction. Both Id(+)Ag(+) and Id(-)Ag(+) Abs were able to specifically recognize and induce cell death in NeuGcGM3-expressing X63 myeloma target cells. Patients that developed IgG and/or IgM Abs against NeuGcGM3 showed longer median survival times.
Asunto(s)
Anticuerpos Antiidiotipos/biosíntesis , Anticuerpos Monoclonales/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Gangliósido G(M3)/análogos & derivados , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Animales , Anticuerpos Antiidiotipos/administración & dosificación , Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/toxicidad , Especificidad de Anticuerpos , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Muerte Celular/inmunología , Línea Celular Tumoral , Perros , Relación Dosis-Respuesta Inmunológica , Gangliósido G(M3)/biosíntesis , Gangliósido G(M3)/sangre , Gangliósido G(M3)/genética , Gangliósido G(M3)/inmunología , Caballos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Células Tumorales CultivadasRESUMEN
PURPOSE: We show the result of a randomized phase II clinical trial with an epidermal growth factor (EGF)-based cancer vaccine in advanced non-small-cell lung cancer (NSCLC) patients, evaluating immunogenicity, safety, and effect on survival. PATIENTS AND METHODS: Eighty patients with stage IIIB/IV NSCLC after finishing first-line chemotherapy were randomly assigned to receive best supportive care or EGF vaccinations. RESULTS: Vaccination was safe. Adverse events were observed in less than 25% of cases and were grade 1 or 2 according to National Cancer Institute Common Toxicity Criteria. Good anti-EGF antibody response (GAR) was obtained in 51.3% of vaccinated patients and in none of the control group. Serum EGF concentration showed a major decrease in 64.3% of vaccinated patients. GAR patients survived significantly more than those with poor antibody response (PAR). Also, patients whose serum EGF dropped below 168 pg/mL survived significantly more than the rest. There was a trend to an increased survival for vaccinated patients compared with controls. The survival advantage for vaccinated patients compared with controls was statistically significant in the subgroup of patients with age younger than 60 years. CONCLUSION: Vaccination with EGF was safe and provoked an increase in anti-EGF antibody titers and a decrease in serum EGF. There was a direct correlation between antibody response and survival. There was a direct correlation between decrease in serum EGF and survival. In patients younger than 60 years, vaccination was associated with increased survival.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Factor de Crecimiento Epidérmico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/inmunología , Adulto , Anciano , Vacunas contra el Cáncer/efectos adversos , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma de Células Grandes/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/inmunología , Factor de Crecimiento Epidérmico/efectos adversos , Factor de Crecimiento Epidérmico/inmunología , Receptores ErbB/metabolismo , Femenino , Humanos , Inmunoterapia Activa/métodos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
We describe an approach to produce an autologous therapeutic antitumor vaccine using hydroxyapatite (HA) for vaccinating cancer patients. The novel approach involved (1) the purification of part of the self-tumor antigens/ adjuvants using column chromatography with HA, (2) the employ of HA as a medium to attract antigen-presenting cells (APCs) to the vaccination site, and (3) the use of HA as a vector to present in vivo the tumor antigens and adjuvants to the patient's APCs. The vaccine was prepared using and combining HA particles, with at least 3 heat shock proteins (gp96 was one of them possibly with chaperoned proteins/peptides as shown in the slot blots) and with proteins from the cell membrane system (including Hsp70, Hsp27, and membrane proteins). The timing of HA degradation was tested in rats; the HA particles administered under the skin attracted macrophages and were degraded into smaller particles, and they were totally phagocytized within 1 week. In patients (n = 20), the vaccine was then administered weekly and showed very low toxicity, causing minor and tolerable local inflammation (erythema, papule, or local pain); only 1 patient who received a larger dose presented hot flashes, and there were no systemic manifestations of toxicity or autoimmune diseases attributed to the vaccine. Our study suggests that this therapeutic vaccine has shown some efficacy producing a positive response in certain patients. Stable disease was noted in 25% of the patients (renal carcinoma, breast carcinoma, and astrocytoma), and a partial response was noted in 15% of the patients (breast carcinoma and astrocytoma). The most encouraging results were seen in patients with recurrent disease; 4 patients in these conditions (20%) are disease free following the vaccine administration. However, we do not want to overstate the clinical efficacy in this small number of patients. The therapeutic vaccine tested in our study is working by activating the T-cell response as was shown in the comparative histological and immunohistochemical study performed in the pre- and postvaccine biopsy taken from a patient with inflammatory breast carcinoma. However, we cannot ruled out that the vaccine could also be producing an antibody(ies)-mediated response. In conclusion, this therapeutic vaccine based on HA ceramic particles and self-antigens can be safely administered and is showing some encouraging clinical results in cancer patients.
Asunto(s)
Autoantígenos/inmunología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Cerámica , Durapatita/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Adulto , Anciano , Animales , Células Presentadoras de Antígenos/citología , Células Presentadoras de Antígenos/inmunología , Autoantígenos/administración & dosificación , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/síntesis química , Durapatita/administración & dosificación , Femenino , Proteínas de Choque Térmico/administración & dosificación , Proteínas de Choque Térmico/inmunología , Humanos , Macrófagos/inmunología , Masculino , Persona de Mediana Edad , Neoplasias/patología , Fagocitosis , Proyectos Piloto , Ratas , Ratas Sprague-Dawley , Piel/citología , Piel/patologíaRESUMEN
CONTEXT: Sarcomatous differentiation, which represents transformation to high-grade malignancy, can occur in all histological types of renal malignancy. CASE REPORT: The authors report on the case of a 66-year-old woman with a right renal mass that was shown to be a clear cell carcinoma. She underwent radical nephrectomy and dendritic cell vaccination and, 3.5 years later, she developed retroperitoneal pure sarcomatous recurrence of the tumor. The authors speculate that the vaccination could have played some role in this differentiation or selection of the sarcomatous component of the primary tumor.