RESUMO
Key Clinical Message: To overcome patient-initiated treatment refusal because of fear of experiencing severe negative adverse events, mild immunotherapy using a cancer vaccine such as the autologous formalin-fixed tumor vaccine should be considered. Abstract: A patient who refused chemotherapy and immune checkpoint inhibitor treatment for Stage IV uterine cancer after displaying circulating tumor cells and high microsatellite instability received monotherapy with autologous formalin-fixed tumor vaccine (AFTV). Following treatment, we observed regression of multiple lung metastases, suggesting that AFTV is an attractive treatment option.
RESUMO
OBJECTIVE: An autologous formalin-fixed tumor vaccine (AFTV) derived from resected glioblastoma (GBM) tissue can be used against unidentified tumor antigens. Thus, the authors conducted a multicenter double-blind phase IIb trial to investigate the efficacy of an AFTV. METHODS: Eligible patients were adults with supratentorial GBMs, 16-75 years of age, with Karnofsky Performance Scale (KPS) scores ≥ 60%, and no long-term steroid administration. An AFTV comprising fixed paraffin-embedded tumor tissue with immune adjuvants or an identical placebo without fixed tumor tissue was injected intradermally over three courses before and after chemoradiotherapy. The primary and secondary end points were overall survival (OS), progression-free survival (PFS), and 3-year survival rate. RESULTS: Sixty-three patients were enrolled. The average patient age was 61 years. The median KPS score was 80%, and the median resection rate was 95%. The full analysis set of 57 patients indicated no significant difference in OS (p = 0.64) for the AFTV group (median OS 25.6 months, 3-year OS rate 38%) compared with the placebo group (31.5 months and 41%, respectively) and no difference in PFS (median PFS 13.3 months in both groups, p = 0.98). For patients with imaging-based total tumor removal, the 3-year PFS rate was 81% in the AFTV group versus 46% in the placebo group (p = 0.067), whereas the 3-year OS rate was 80% versus 54% (p = 0.16), respectively. Similar results were obtained in the p53-negative subgroups. Severe adverse effects were not observed. CONCLUSIONS: The AFTV may have potential effects in certain patient subgroups. A phase III study for patients with total tumor removal remains warranted to confirm these findings. Clinical trial registration no.: UMIN000010602 (UMIN Clinical Trials Registry).
RESUMO
Immune checkpoint inhibitors elicit durable tumor regression in multiple types of tumor, but may induce potential side effects with low response rates in many tumors. Herein, to increase the therapeutic efficacy of immune checkpoint inhibitors, a hollow mesoporous silica (HMS) nanosphere-based cancer vaccine was combined with an immune checkpoint inhibitor, anti-programmed death-ligand 1 (anti-PD-L1) antibody. The HMS nanospheres function as adjuvants that promote dendritic cell activation and antigen cross-presentation. Mice immunized with the HMS-based cancer vaccine show suppressed tumor growth with increased tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-2 (IL-2) levels in their spleens compared with those without HMS-based cancer vaccine. Moreover, the HMS-based cancer vaccine synergistically acts with the anti-PD-L1 antibody on the tumor. The combination of an HMS-based cancer vaccine and an antibody markedly decreases the required dose of the immune checkpoint inhibitor. Mice locally administered with the HMS-based cancer vaccine and 1/8 dose of a standard anti-PD-L1 antibody (25 µg/mouse) show comparable anti-tumor effect and significantly increased CD4+ and CD8+ T cell populations, compared with those systemically immunized with the standard anti-PD-L1 antibody done at 200 µg/mouse. Our work presents a promising cancer treatment strategy of combining an immune checkpoint inhibitor with an HMS-based cancer vaccine. STATEMENT OF SIGNIFICANCE: The clinical benefits of checkpoint blockade therapy rekindle the hope of cancer immunotherapy. However, objective response rates in checkpoint blockade therapy remain at about 10-40% owing to multiple immunosuppressive factors. To solve these problems, herein, a hollow mesoporous silica (HMS) nanosphere-based cancer vaccine was combined with an immune checkpoint inhibitor, anti-PD-L1 antibody. The HMS-based cancer vaccine synergistically acts with the anti-PD-L1 antibody on the tumor. Mice locally administered with the HMS-based cancer vaccine and 1/8 dose of a standard anti-PD-L1 antibody (25 µg/mouse) show comparable anti-tumor effect and significantly increased CD4+ and CD8+ T cell populations, compared with those systemically immunized with the standard anti-PD-L1 antibody done at 200 µg/mouse. Our work presents a promising cancer treatment strategy of combining an immune checkpoint inhibitor with an HMS-based cancer vaccine.
Assuntos
Vacinas Anticâncer , Neoplasias , Animais , Inibidores de Checkpoint Imunológico , Imunoterapia , Camundongos , Neoplasias/terapia , Dióxido de SilícioRESUMO
Strengthening the antitumor immune response to surpass the activation energy barrier associated with the immunosuppressive tumor microenvironment is an active area of cancer immunotherapy. Emerging evidence suggests that delivery of immunostimulatory molecules with the aid of a carrier system is essential for cancer immunotherapy. However, the size-dependent effect of the delivery system on immune-targeted sites and anticancer immune responses is yet to be comprehensively understood. Herein, to clarify the size-dependent effect of the delivery system on the underlying anticancer immune mechanism, rod-shaped hydroxyapatite (HA) particles with lengths from 100 nm to 10 µm are designed. HA rods stimulate anticancer immunity in a size-dependent manner. Shorter HA rods with lengths ranging from 100 to 500 nm promote antigen cellular uptake, dendritic cell (DC) maturation, and lymph node targeting antigen. In contrast, longer HA rods with lengths ranging from 500 nm to 10 µm prolong antigen retention and increase DC accumulation. Medium-sized HA rods with a length of 500 nm, taking advantage of both short and long rods, show optimized antigen release and uptake, increased DCs accumulation and maturation, highest CD4+ and CD8+ T cell population, and the best anticancer immunity in vivo. The present study provides a rod-scale design strategy for an immune-targeted delivery system toward cancer immunotherapy in the future.
Assuntos
Antineoplásicos/farmacologia , Materiais Biocompatíveis/química , Sistemas de Liberação de Medicamentos , Durapatita/imunologia , Imunoterapia , Neoplasias/terapia , Adsorção , Animais , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/imunologia , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biocompatíveis/síntese química , Células Cultivadas , Durapatita/síntese química , Durapatita/química , Feminino , Injeções Subcutâneas , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Imagem Óptica , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
Multiple phase II clinical trials on the use of tumor vaccines in cases of high-grade gliomas (HGG), in particular autologous formalin-fixed tumor vaccine (AFTV), demonstrated the safety and potential efficacy of such therapy. There is evidence that maximal resection of neoplasm provides optimal conditions for enhancement of the tumor-specific immune reactions induced by vaccine administration, and thus aggressive surgery may be an important prerequisite for treatment success. Irradiation and chemotherapy may also enhance the effectiveness of vaccines, particularly through modulation of the tumor microenvironment. Nevertheless, the most effective combinations of vaccine therapies with surgery, irradiation, chemotherapy, antiangiogenic therapy, or other modes of immunotherapy in cases of HGG are still unclear and likely to be an active area of research in the future.
Assuntos
Neoplasias Encefálicas/terapia , Vacinas Anticâncer/uso terapêutico , Terapia Combinada/métodos , Glioma/terapia , Imunoterapia Ativa/métodos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Glioma/tratamento farmacológico , Glioma/radioterapia , Glioma/cirurgia , HumanosRESUMO
INTRODUCTION: No effective treatment has been developed for bone-metastatic breast cancer. We found 3 cases with clinical complete response (cCR) of the bone metastasis and longer overall survival of the retrospectively examined cohort treated comprehensively including autologous formalin-fixed tumor vaccine (AFTV). PATIENTS AND METHODS: AFTV was prepared individually for each patient from their own formalin-fixed and paraffin-embedded breast cancer tissues. RESULTS: Three patients maintained cCR status of the bone metastasis for 17 months or more. Rate of cCR for 1 year or more appeared to be 15% (3/20) after comprehensive treatments including AFTV. The median overall survival time (60.0 months) and the 3- to 8-year survival rates after diagnosis of bone metastasis were greater than those of historical control cohorts in Japan (1988-2002) and in the nationwide population-based cohort study of Denmark (1999-2007). CONCLUSION: Bone-metastatic breast cancer may be curable after comprehensive treatments including AFTV, although larger scale clinical trial is required.
RESUMO
Stellated fibrous mesoporous silica nanospheres significantly improve the cellular uptake of cancer antigen and the maturation of bone marrow derived dendritic cells in vitro. Moreover, the combination of poly(I:C) with stellated fibrous MS nanospheres markedly decreases the necessary dose of poly(I:C) for anti-tumor immunity, and thus opens new opportunities for the future clinical application of poly(I:C) in cancer immunotherapy.
Assuntos
Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Poli I-C/imunologia , RNA de Cadeia Dupla/síntese química , RNA de Cadeia Dupla/imunologia , Dióxido de Silício/química , Células Dendríticas/imunologia , Humanos , Tamanho da Partícula , Poli I-C/administração & dosagem , Poli I-C/química , Porosidade , RNA de Cadeia Dupla/química , Propriedades de SuperfícieRESUMO
Modern vaccines usually require accompanying adjuvants to increase the immune response to antigens. Aluminum (alum) compounds are the most commonly used adjuvants in human vaccinations for infection diseases. However, alum adjuvants are nondegradable, cause side effects due to the persistence of alum at injection sites, and are rather ineffective for cancer immunotherapy, which requires the Th1 immune response. Recently, we have shown that a plain mesoporous silica (MS) adjuvant can stimulate Th1 anticancer immunity for cancer vaccines. Herein, MS nanospheres doped with Ca, Mg, and Zn (MS-Ca, MS-Mg, and MS-Zn) showed significantly higher degradation rates than pure MS. Moreover, MS-Ca, MS-Mg, and MS-Zn nanospheres stimulated anticancer immune response and increased the CD4+ and CD8+ T cell populations in spleen. The MS-Ca, MS-Mg, and MS-Zn nanospheres with improved biodegradability and excellent ability to induce Th1 anticancer immunity show potential for clinical applications as cancer immunoadjuvants.
Assuntos
Nanosferas , Adjuvantes Imunológicos , Animais , Vacinas Anticâncer , Metais , Camundongos Endogâmicos BALB C , Dióxido de Silício , Células Th1RESUMO
A patient with chemo-refractory multiple-metastatic upper tract urothelial carcinoma (UTUC) treated by monotherapy with autologous formalin-fixed tumor vaccine (AFTV) resulted in complete remission of the lung and para-aortic lymph node metastases (ongoing >3 years after AFTV). The tumor was immunohistologically negative for PD-L1. AFTV will be an attractive treatment option.
RESUMO
BACKGROUND: The prognosis of advanced (stage IV) cancer of the digestive organs is very poor. We have previously reported a case of advanced breast cancer with bone metastasis that was successfully treated with combined treatments including autologous formalin-fixed tumor vaccine (AFTV). Herein, we report the success of this approach in advanced stage IV (heavily metastasized) cases of gall bladder cancer and colon cancer. CASE PRESENTATION: Case 1: A 61-year-old woman with stage IV gall bladder cancer (liver metastasis and lymph node metastasis) underwent surgery in May 2011, including partial resection of the liver. She was treated with AFTV as the first-line adjuvant therapy, followed by conventional chemotherapy. This patient is still alive without any recurrence, as confirmed with computed tomography, for more than 5 years. Case 2: A 64-year-old man with stage IV colon cancer (multiple para-aortic lymph node metastases and direct abdominal wall invasion) underwent non-curative surgery in May 2006. Following conventional chemotherapy, two courses of AFTV and radiation therapy were administered sequentially. This patient has had no recurrence for more than 5 years. CONCLUSION: We report the success of combination therapy including AFTV in cases of liver-metastasized gall bladder cancer and abdominal wall-metastasized colon cancer. Both patients experienced long-lasting, complete remission. Therefore, combination therapies including AFTV should be considered in patients with advanced cancer of the digestive organs.
Assuntos
Vacinas Anticâncer/uso terapêutico , Neoplasias do Colo/terapia , Neoplasias da Vesícula Biliar/terapia , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/terapia , Parede Abdominal/patologia , Parede Abdominal/cirurgia , Vacinas Anticâncer/química , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Terapia Combinada/métodos , Feminino , Formaldeído/química , Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Neoplasias da Vesícula Biliar/imunologia , Neoplasias da Vesícula Biliar/patologia , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Uterine cervical small cell carcinoma is rare and aggressive with no standardized therapy. A patient bearing the advanced chemo-refractory carcinoma, treated with a tumor vaccine combined with 1 mg/kg of pembrolizumab, showed a transient increase and subsequent sharp decrease of the liver-metastasized lesion to less than half its maximum diameter.
RESUMO
A plain mesoporous silica (MS) nanoparticle without any immunomodulatory molecules enhances anti-cancer immunity in vivo. On page 1169, X.P. Wang, N. M. Tsuji, A. Ito and co-workers show that a plain MS nanoparticle promotes both Th1 and Th2 immune responses, and enhances the effector memory of CD4(+) and CD8(+) T cell populations in the three most important immune organs (bone marrow, lymph node and spleen) of mice.
RESUMO
Hollow and non-hollow mesoporous silica nanospheres are synthesized and used for cancer vaccine adjuvants. The hollow structure of mesoporous silica nanospheres significantly promote cellular uptake of a model cancer antigen by macrophage-like cells in vitro, improve anti-cancer immunity, CD4(+) and CD8(+) T cell populations in splenocytes of mice in vivo.
Assuntos
Adjuvantes Imunológicos/química , Nanosferas/química , Dióxido de Silício/química , Adjuvantes Imunológicos/efeitos adversos , Animais , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/química , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Microscopia Eletroquímica de Varredura , Microscopia Eletrônica de Transmissão , Células NIH 3T3 , Nanosferas/efeitos adversos , Nanosferas/ultraestrutura , PorosidadeRESUMO
A plain mesoporous silica nanoparticle without any immunomodulatory molecules significantly enhances anticancer immunity in vivo. Comprehensive mechanism of mesoporous-silica-nanoparticle-induced cancer immunotherapy is analyzed in this paper. The mesoporous silica nanoparticle promotes both Th1 and Th2 immune responses, as it accelerates lymphocytes proliferation, stimulates IFN-γ, IL-2, IL-4, and IL-10 cytokine secretion by lymphocytes ex vivo, and increases IgG, IgG1, IgG2a, IgM, and IgA antibody titers in mice serum compared with those of alum and adjuvant-free groups. Moreover, the mesoporous silica nanoparticle enhances effector memory CD4(+) and CD8(+) T cell populations in three most important immune organs (bone marrow, lymph node, and spleen) of mice compared with those of alum and adjuvant-free groups three months after adjuvant injection. The present study paves the way for the application of mesoporous silica nanoparticle as immunoadjuvant for cancer immunotherapy.
Assuntos
Nanopartículas/administração & dosagem , Neoplasias/imunologia , Neoplasias/terapia , Dióxido de Silício/administração & dosagem , Dióxido de Silício/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Feminino , Imunoglobulinas/imunologia , Memória Imunológica/efeitos dos fármacos , Memória Imunológica/imunologia , Imunoterapia/métodos , Interferon gama/imunologia , Interleucinas/imunologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Baço/efeitos dos fármacos , Baço/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologiaRESUMO
The use of appropriate adjuvants that support the generation of robust and long-lasting antitumor immune responses is crucial for tumor immunotherapy owing to the immunosuppressive environment of the growing tumor. However, the most commonly used adjuvant, aluminum hydroxide, is ineffective for generating such immune responses and therefore not suitable for cancer immunotherapy. It is now shown that plain hollow mesoporous silica nanospheres markedly improve the antitumor immunity, the Th1 and Th2 immunity, and the CD4(+) and CD8(+) effector memory Tâ cell population in bone marrow inâ vivo and may thus be used as immunoadjuvants to treat cancer in humans.
Assuntos
Antineoplásicos/farmacologia , Nanosferas , Neoplasias/terapia , Dióxido de Silício/química , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunoterapia , Neoplasias/imunologiaRESUMO
A Th1 immune response is required for modern vaccines as the most commonly used alum adjuvant has weak capacity for inducing Th1 immune response. Herein, rod-shaped hydroxyapatite (HA), magnesium-substituted HA (MgHA) and zinc-substituted HA (ZnHA) nanoparticles with irregular nanopores were synthesized and used as immunoadjuvants. Magnesium and zinc substitution in HA showed no influence on morphology, particle size, zeta potential and surface area of the nanoparticles. The rod-shaped MgHA and ZnHA nanoparticles promoted the cellular uptake of a molecular immunopotentiator, stimulated both type 1 and 2 cytokine secretion in vitro that relate to Th1 and Th2 immunity of bone marrow dentritic cells, respectively. The MgHA and ZnHA nanoparticles may be useful as immunoadjuvants for human.
Assuntos
Células da Medula Óssea/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Durapatita/farmacologia , Interferon gama/metabolismo , Interleucina-4/metabolismo , Nanopartículas/química , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Durapatita/química , Fêmur/citologia , Fêmur/imunologia , Interferon gama/biossíntese , Interleucina-4/biossíntese , Magnésio/química , Camundongos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Cultura Primária de Células , Equilíbrio Th1-Th2/efeitos dos fármacos , Zinco/químicaRESUMO
Paclitaxel-carboplatin therapy (TC) usually controls primary peritoneal serous carcinoma (PPSC) but not recurrent disease. In this case, PPSC recurred after three courses of TC, responded dramatically to additional autologous formalin-fixed tumor vaccine (AFTV), and resulted in prolonged, progression-free survival without visible lesions detected by positron emission tomography-computed tomography.
Assuntos
Neoplasias Encefálicas/terapia , Vacinas Anticâncer/uso terapêutico , Glioblastoma/terapia , Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/imunologia , Vacinas Anticâncer/imunologia , Ensaios Clínicos como Assunto , Formaldeído , Glioblastoma/diagnóstico , Glioblastoma/imunologia , HumanosRESUMO
Autologous formalin-fixed tumor vaccine (AFTV) suppressed re-recurrence for more than 32 months of multiple-recurrent hepatocellular carcinoma based on hepatitis C virus-induced liver cirrhosis in a case with previous recurrence interval, 51-, 28-, 12-, and 4-months. We detected glypican-3-specific cytotoxic T lymphocytes in the peripheral blood at 12 months after AFTV.