RESUMO
Memory T cells play a key role in immune protection against cancer. Vaccine-induced tissue-resident memory T (TRM) cells in the lung have been shown to protect against lung metastasis. Identifying the source of lung TRM cells can help to improve strategies, preventing tumor metastasis. Here, we found that a prime-boost vaccination approach using intramuscular DNA vaccine priming, followed by intranasal live-attenuated influenza-vectored vaccine (LAIV) boosting induced higher frequencies of lung CD8+ TRM cells compared with other vaccination regimens. Vaccine-induced lung CD8+ TRM cells, but not circulating memory T cells, conferred significant protection against metastatic melanoma and mesothelioma. Central memory T (TCM) cells induced by the DNA vaccination were major precursors of lung TRM cells established after the intranasal LAIV boost. Single-cell RNA sequencing analysis indicated that transcriptional reprogramming of TCM cells for differentiation into TRM cells in the lungs started as early as day 2 post the LAIV boost. Intranasal LAIV altered the mucosal microenvironment to recruit TCM cells via CXCR3-dependent chemotaxis and induced CD8+ TRM-associated transcriptional programs. These results identified TCM cells as the source of vaccine-induced CD8+ TRM cells that protect against lung metastasis. Significance: Prime-boost vaccination shapes the mucosal microenvironment and reprograms central memory T cells to generate lung resident memory T cells that protect against lung metastasis, providing insights for the optimization of vaccine strategies.
Assuntos
Linfócitos T CD8-Positivos , Vacinas Anticâncer , Memória Imunológica , Neoplasias Pulmonares , Células T de Memória , Animais , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/patologia , Camundongos , Células T de Memória/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Camundongos Endogâmicos C57BL , Vacinas de DNA/imunologia , Vacinas de DNA/administração & dosagem , Imunização Secundária/métodos , Vacinação/métodos , Feminino , Humanos , Administração Intranasal , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Pulmão/imunologia , Pulmão/patologiaRESUMO
Subunit vaccines have emerged as a promising strategy in immunotherapy for combating viral infections and cancer. Nevertheless, the clinical application of subunit vaccines is hindered by limitations in antigen delivery efficiency, characterized by rapid clearance and inadequate cellular uptake. Here, a novel subunit vaccine delivery system utilizing ovalbumin@magnetic nanoparticles (OVA@MNPs) encapsulated within biodegradable gelatin methacryloyl (GelMA) microspheres was proposed to enhance the efficacy of antigen delivery. OVA@MNPs-loaded GelMA microspheres, denoted as OMGMs, can be navigated through magnetic fields to deliver subunit vaccines into the lymphatic system efficiently. Moreover, the biodegradable OMGMs enabled the sustained release of subunit vaccines, concentrating OVA around lymph nodes and enhancing the efficacy of induced immune response. OMGMs were produced through a microfluidic droplet generation technique, enabling mass production. In murine models, OMGMs successfully accumulated antigens in lymph nodes abundant in antigen-presenting cells, leading to enhanced cellular and humoral immunity and pronounced antitumor effects with a single booster immunization. In conclusion, these findings highlight the promise of OMGMs as a practical subunit vaccination approach, thus addressing the limitations associated with antigen delivery efficiency and paving the way for advanced immunotherapeutic strategies.
Assuntos
Imunoterapia , Microesferas , Ovalbumina , Vacinas de Subunidades Antigênicas , Animais , Camundongos , Ovalbumina/química , Ovalbumina/imunologia , Ovalbumina/administração & dosagem , Vacinas de Subunidades Antigênicas/química , Vacinas de Subunidades Antigênicas/imunologia , Nanopartículas de Magnetita/química , Camundongos Endogâmicos C57BL , Feminino , Gelatina/química , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Sistemas de Liberação de Medicamentos/métodosRESUMO
ABSTRACT: The immune revolution that swept the field of oncology in the mid-2010s with the advent of checkpoint inhibitors has led to a paradigm shift in approaches toward adapting new cancer prevention modalities. Cancer vaccines have emerged from this era with astounding potential as a durable intervention to prevent cancers especially for patients with hereditary susceptibilities such as Lynch syndrome carriers. This review covers new insights in the immunoprevention landscape for patients living with Lynch syndrome including highlights ranging from clinical trials exploring the use of chemoprevention agents to boost immune cellularity to investigative studies using novel vaccine approaches to induce long-term antitumor immunity.
Assuntos
Vacinas Anticâncer , Neoplasias Colorretais Hereditárias sem Polipose , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/imunologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Quimioprevenção/métodos , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/prevenção & controle , Neoplasias Colorretais/etiologiaRESUMO
INTRODUCTION: Targeted liposomal systems for cancer intention have been recognized as a specific and robust approach compared to conventional liposomal delivery systems. Cancer cells have a unique microenvironment with special over-expressed receptors on their surface, providing opportunities for discovering novel and effective drug delivery systems using active targeting. AREAS COVERED: Smartly targeted liposomes, responsive to internal or external stimulations, enhance the delivery efficiency by increasing accumulation of the encapsulated anti-cancer agent in the tumor site. The application of antibodies and aptamers against the prevalent cell surface receptors is a potent and ever-growing field. Moreover, immuno-liposomes and cancer vaccines as adjuvant chemotherapy are also amenable to favorable immune modulation. Combinational and multi-functional systems are also attractive in this regard. However, potentially active targeted liposomal drug delivery systems have a long path to clinical acceptance, chiefly due to cross-interference and biocompatibility affairs of the functionalized moieties. EXPERT OPINION: Engineered liposomal formulations have to be designed based on tissue properties, including surface chemistry, charge, and microvasculature. In this paper, we aimed to investigate the updated targeted liposomal systems for common cancer therapy worldwide.
Assuntos
Antineoplásicos , Sistemas de Liberação de Medicamentos , Lipossomos , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Animais , Vacinas Anticâncer/administração & dosagem , Microambiente Tumoral , Especificidade de ÓrgãosRESUMO
Tumor neoantigen peptide vaccines hold potential for boosting cancer immunotherapy, yet efficiently co-delivering peptides and adjuvants to antigen-presenting cells in vivo remains challenging. Virus-like particle (VLP), which is a kind of multiprotein structure organized as virus, can deliver therapeutic substances into cells and stimulate immune response. However, the weak targeted delivery of VLP in vivo and its susceptibility to neutralization by antibodies hinder their clinical applications. Here, we first designed a novel protein carrier using the mammalian-derived capsid protein PEG10, which can self-assemble into endogenous VLP (eVLP) with high protein loading and transfection efficiency. Then, an engineered tumor vaccine, named ePAC, was developed by packaging genetically encoded neoantigen into eVLP with further modification of CpG-ODN on its surface to serve as an adjuvant and targeting unit to dendritic cells (DCs). Significantly, ePAC can efficiently target and transport neoantigens to DCs, and promote DCs maturation to induce neoantigen-specific T cells. Moreover, in mouse orthotopic liver cancer and humanized mouse tumor models, ePAC combined with anti-TIM-3 exhibited remarkable antitumor efficacy. Overall, these results support that ePAC could be safely utilized as cancer vaccines for antitumor therapy, showing significant potential for clinical translation.
Assuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Células Dendríticas , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/administração & dosagem , Camundongos , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/genética , Humanos , Células Dendríticas/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Vacinas de Partículas Semelhantes a Vírus/genética , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/genética , Peptídeos/imunologia , Feminino , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , VacinaçãoRESUMO
Inducing high levels of antigen-specific CD8α+ T cells in the tumor is beneficial for cancer immunotherapy, but achieving this in a safe and effective manner remains challenging. Here, we have developed a designer liposomal nanovaccine containing a sonosensitizer (LNVS) to efficiently program T cell immunity in mice. Following intravenous injection, LNVS accumulates in the spleen in a protein corona and fluidity-dependent manner, leading to greater frequencies of antigen-specific CD8α+ T cells than soluble vaccines (the mixture of antigens and adjuvants). Meanwhile, some LNVS passively accumulates in the tumor, where it responds to ultrasound (US) to increase the levels of chemokines and adhesion molecules that are beneficial for recruiting CD8α+ T cells to the tumor. LNVS + US induces higher levels of intratumoral antitumor T cells than traditional sonodynamic therapy, regresses established mouse MC38 tumors and orthotopic cervical cancer, and protects cured mice from relapse. Our platform sheds light on the importance of tuning the fluidity and protein corona of naovaccines to program T cell immunity in mice and may inspire new strategies for cancer immunotherapy.
Assuntos
Linfócitos T CD8-Positivos , Vacinas Anticâncer , Imunoterapia , Lipossomos , Camundongos Endogâmicos C57BL , Animais , Lipossomos/química , Camundongos , Feminino , Imunoterapia/métodos , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Linhagem Celular Tumoral , Nanopartículas/química , Neoplasias/imunologia , Neoplasias/terapia , Humanos , NanovacinasRESUMO
Background: Tumor vaccines have achieved remarkable progress in treating patients with various tumors in clinical studies. Nevertheless, extensive research has also revealed that tumor vaccines are not up to expectations for the treatment of solid tumors due to their low immunogenicity. Therefore, there is an urgent need to design a tumor vaccine that can stimulate a broad anti-tumor immune response. Methods: In this work, we developed a nanovaccine (NP-TCL@APS), which includes nanoparticles loaded with colorectal cancer tumor cell lysates (TCL) and Astragalus polysaccharides (APS) into poly (lactic-co-glycolic acid) to induce a robust innate immune response. The NP-TCL@APS was identified by transmission electron microscopy and Malvern laser particle size analyzer. The killing and immune activation effects of NP-TCL@APS were evaluated in vitro. Finally, safety and anti-tumor efficacy were evaluated in the colorectal cancer tumor-bearing mouse model. Results: We found that NP-TCL@APS was preferentially uptaken by DC and further promoted the activation of DC in vitro. Additionally, nanoparticles codelivery of TCL and APS enhanced the antigen-specific CD8+ T cell response and suppressed the growth of tumors in mouse models with good biocompatibility. Conclusion: We successfully prepared a nanovaccine termed NP-TCL@APS, which can promote the maturation of DC and induce strong responses by T lymphocytes to exert anti-tumor effects. The strategy proposed here is promising for generating a tumor vaccine and can be extended to various types of cancers.
Assuntos
Vacinas Anticâncer , Neoplasias Colorretais , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Polissacarídeos , Neoplasias Colorretais/terapia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/tratamento farmacológico , Animais , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Polissacarídeos/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Humanos , Camundongos , Nanopartículas/química , Linhagem Celular Tumoral , Astrágalo/química , Camundongos Endogâmicos BALB C , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Feminino , NanovacinasRESUMO
The immunosuppressive tumor microenvironment (TME) remains a major obstacle to tumor control and causes suboptimal responses to immune checkpoint blockade (ICB) therapy. Thus, developing feasible therapeutic strategies that trigger inflammatory responses in the TME could improve the ICB efficacy. Mitochondria play an essential role in inflammation regulation and tumor immunogenicity induction. Herein, we report the discovery and characterization of a class of small molecules that can recapitulate aqueous self-assembly behavior, specifically target cellular organelles (e.g., mitochondria), and invigorate tumor cell immunogenicity. Mechanistically, this nanoassembly platform dynamically rewires mitochondria, induces endoplasmic reticulum stress, and causes apoptosis/paraptosis-associated immunogenic cell death. After treatment, stressed and dying tumor cells can act as prophylactic or therapeutic cancer vaccines. In preclinical mouse models of cancers with intrinsic or acquired resistance to PD-1 blockade, the local administration of nanoassemblies inflames the immunologically silent TME and synergizes with ICB therapy, generating potent antitumor immunity. This chemically programmed small-molecule immune enhancer acts distinctly from regular cytotoxic therapeutics and offers a promising strategy for synchronous and dynamic tailoring of innate immunity to achieve traceless cancer therapy and overcome immunosuppression in cancers.
Assuntos
Mitocôndrias , Neoplasias , Microambiente Tumoral , Animais , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Humanos , Linhagem Celular Tumoral , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/imunologia , Apoptose/efeitos dos fármacos , Feminino , Morte Celular Imunogênica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodosRESUMO
INTRODUCTION: Polymeric nanoparticles used for antigen delivery against infections and for cancer immunotherapy are an emerging therapeutic strategy in promoting the development of innovative vaccines. Beyond their capability to create targeted delivery systems with controlled release of payloads, biodegradable polymers are utilized for their ability to enhance the immunogenicity and stability of antigens. AREAS COVERED: This review extensively discusses the physicochemical parameters that affect the behavior of nanoparticles as antigen-delivery systems. Additionally, various types of natural and synthetic polymers and recent advancements in nanoparticle-based targeted vaccine production are reviewed. EXPERT OPINION: Biodegradable polymeric nanoparticles have gained major interest in the vaccination filed and have been extensively used to encapsulate antigens against a wide variety of tumors. Moreover, their versatility in terms of tunning their physicochemical characteristics, and their surface, facilitates the targeting to antigen presenting cells and enhances immune response.
Assuntos
Vacinas Anticâncer , Imunoterapia , Nanopartículas , Neoplasias , Polímeros , Humanos , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Imunoterapia/métodos , Animais , Polímeros/química , Vacinas Anticâncer/administração & dosagem , Antígenos/administração & dosagem , Antígenos/imunologia , Sistemas de Liberação de Medicamentos , Preparações de Ação Retardada , Sistemas de Liberação de Fármacos por Nanopartículas/químicaRESUMO
INTRODUCTION: Although meningiomas are the most common primary brain tumor, there are limited treatment options for recurrent or aggressive lesions. Compared to other brain tumors, meningiomas may be uniquely amenable to immunotherapy by virtue of their location outside the blood-brain barrier. AREAS COVERED: This review describes our current understanding of the immunology of the meninges, as well as immune cell infiltration and immune signaling in meningioma. Current literature on meningioma immunology and immunotherapy was comprehensively reviewed and summarized by a comprehensive search of MEDLINE (1/1/1990-6/1/2024). Further, we describe the current state of immunotherapeutic approaches, as well as potential future targets. Potential immunotherapeutic approaches include immune checkpoint inhibition, CAR-T approaches, tumor vaccine therapy, and immunogenic molecular markers. EXPERT OPINION: Meningioma immunotherapy is in early stages, as no immunotherapies are currently included in treatment guidelines. There is substantial heterogeneity in immune cell infiltration, immunogenicity, and immune escape across tumors, even within tumor grade. Furthering our understanding of meningioma immunology and tumor classification will allow for careful selection of tumors and patient populations that may benefit from primary or adjunctive immunotherapy for meningioma.
Assuntos
Vacinas Anticâncer , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias Meníngeas , Meningioma , Meningioma/terapia , Meningioma/imunologia , Meningioma/patologia , Humanos , Neoplasias Meníngeas/terapia , Neoplasias Meníngeas/imunologia , Neoplasias Meníngeas/patologia , Imunoterapia/métodos , Vacinas Anticâncer/administração & dosagem , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/administração & dosagem , Biomarcadores Tumorais , Animais , Evasão Tumoral , Seleção de Pacientes , Recidiva Local de NeoplasiaRESUMO
Adoptive cell therapy (ACT) has shown great success in the clinic for treating hematologic malignancies. However, solid tumor treatment with ACT monotherapy is still challenging, owing to insufficient expansion and rapid exhaustion of adoptive cells, tumor antigen downregulation/loss, and dense tumor extracellular matrix. Delivery strategies for combination cell therapy have great potential to overcome these hurdles. The delivery of vaccines, immune checkpoint inhibitors, cytokines, chemotherapeutics, and photothermal reagents in combination with adoptive cells, have been shown to improve the expansion/activation, decrease exhaustion, and promote the penetration of adoptive cells in solid tumors. Moreover, the delivery of nucleic acids to engineer immune cells directly in vivo holds promise to overcome many of the hurdles associated with the complex ex vivo cell engineering strategies. Here, these research advance, as well as the opportunities and challenges for integrating delivery technologies into cell therapy s are discussed, and the outlook for these emerging areas are criticlly analyzed.
Assuntos
Imunoterapia Adotiva , Neoplasias , Humanos , Animais , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Sistemas de Liberação de Medicamentos/métodos , Vacinas Anticâncer/administração & dosagem , Inibidores de Checkpoint Imunológico/química , Inibidores de Checkpoint Imunológico/farmacologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Citocinas/metabolismo , Terapia CombinadaRESUMO
Hematological malignancies (HM) like acute myeloid leukemia (AML) are often intractable. Cancer vaccines possibly inducing robust and broad anti-tumor immune responses may be a promising treatment option for HM. Few effective vaccines against blood cancers are, however, developed to date partly owing to insufficient stimulation of dendritic cells (DCs) in the body and lacking appropriate tumor antigens (Ags). Here it is found that systemic multifunctional nanovaccines consisting of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and Toll-like receptor 9 (TLR9) agonists - muramyl dipeptide (MDP) and CpG, and tumor cell lysate (TCL) as Ags (MCA-NV) induce potent and broad immunity against AML. MCA-NV show complementary stimulation of DCs and prime homing to lymphoid organs following systemic administration. Of note, in orthotopic AML mouse models, intravenous infusion of different vaccine formulations elicits substantially higher anti-AML efficacies than subcutaneous administration. Systemic MCA-NV cure 78% of AML mice and elicit long-term immune memory with 100% protection from rechallenging AML cells. Systemic MCA-NV can also serve as prophylactic vaccines against the same AML. These systemic nanovaccines utilizing patient TCL as Ags and dual adjuvants to elicit strong, durable, and broad immune responses can provide a personalized immunotherapeutic strategy against AML and other HM.
Assuntos
Vacinas Anticâncer , Imunoterapia , Leucemia Mieloide Aguda , Medicina de Precisão , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/imunologia , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Camundongos , Humanos , Nanopartículas/química , Células Dendríticas/imunologia , Linhagem Celular Tumoral , Antígenos de Neoplasias/imunologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , NanovacinasRESUMO
Background: Glioblastoma (GBM) is a poor prognosis grade 4 glioma. After surgical resection, the standard therapy consists of concurrent radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. Our previous data on melanoma patients showed that Dendritic Cell vaccination (DCvax) could increase the amount of intratumoral-activated cytotoxic T lymphocytes. Methods: This is a single-arm, monocentric, phase II trial in two steps according to Simon's design. The trial aims to evaluate progression-free survival (PFS) at three months and the safety of a DCvax integrated with standard therapy in resected GBM patients. DCvax administration begins after completion of RT-CTwith weekly administrations for 4 weeks, then is alternated monthly with TMZ cycles. The primary endpoints are PFS at three months and safety. One of the secondary objectives is to evaluate the immune response both in vitro and in vivo (DTH skin test). Results: By December 2022, the first pre-planned step of the study was concluded with the enrollment, treatment and follow up of 9 evaluable patients. Two patients had progressed within three months after leukapheresis, but none had experienced DCvax-related G3-4 toxicities Five patients experienced a positive DTH test towards KLH and one of these also towards autologous tumor homogenate. The median PFS from leukapheresis was 11.3 months and 12.2 months from surgery. Conclusions: This combination therapy is well-tolerated, and the two endpoints required for the first step have been achieved. Therefore, the study will proceed to enroll the remaining 19 patients. (Eudract number: 2020-003755-15 https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-003755-15/IT).
Assuntos
Neoplasias Encefálicas , Vacinas Anticâncer , Células Dendríticas , Glioblastoma , Humanos , Glioblastoma/terapia , Glioblastoma/imunologia , Glioblastoma/mortalidade , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Células Dendríticas/imunologia , Células Dendríticas/transplante , Pessoa de Meia-Idade , Feminino , Masculino , Adulto , Idoso , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/mortalidade , Temozolomida/uso terapêutico , Temozolomida/administração & dosagem , Intervalo Livre de ProgressãoRESUMO
Personalized cancer vaccines based on tumor cell lysates offer promise for cancer immunotherapy yet fail to elicit a robust therapeutic effect due to the weak immunogenicity of tumor antigens. Autophagosomes, obtained from pleural effusions and ascites of cancer patients, have been identified as abundant reservoirs of tumor neoantigens that exhibit heightened immunogenicity. However, their potential as personalized cancer vaccines have been constrained by suboptimal lymphatic-targeting performances and challenges in antigen-presenting cell endocytosis. Here,a reinforced biomimetic autophagosome-based (BAPs) nanovaccine generated by precisely amalgamating autophagosome-derived neoantigens and two types of adjuvants capable of targeting lymph nodes is developed to potently elicit antitumor immunity. The redox-responsive BAPs facilitate cytosolic vaccine opening within antigen-presenting cells, thereby exposing adjuvants and antigens to stimulate a strong immune response. BAPs evoke broad-spectrum T-cell responses, culminating in the effective eradication of 71.4% of established tumors. Notably, BAPs vaccination triggers enduring T-cell responses that confer robust protection, with 100% of mice shielded against tumor rechallenge and a significant reduction in tumor incidence by 87.5%. Furthermore, BAPs synergize with checkpoint blockade therapy to inhibit tumor growth in the poorly immunogenic breast cancer model. The biomimetic approach presents a powerful nanovaccine formula with high versatility for personalized cancer immunotherapy.
Assuntos
Autofagossomos , Materiais Biomiméticos , Vacinas Anticâncer , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/química , Vacinas Anticâncer/administração & dosagem , Camundongos , Materiais Biomiméticos/química , Autofagossomos/metabolismo , Linhagem Celular Tumoral , Humanos , Imunoterapia , Feminino , Antígenos de Neoplasias/imunologia , Nanopartículas/química , Adjuvantes Imunológicos/química , Biomimética/métodos , NanovacinasRESUMO
We have previously reported two single-agent phase I trials, evaluating the dose or schedule, of a DNA vaccine (pTVG-HP) encoding prostatic acid phosphatase (PAP) administered with GM-CSF as the adjuvant. These were in patients with PSA-recurrent, radiographically non-metastatic, prostate cancer (PCa). We report here the long-term safety and overall survival of these patients. Specifically, 22 patients with non-metastatic, castration-sensitive PCa (nmCSPC) were treated with pTVG-HP, 100-1500 µg, administered over 12 weeks and followed for 15 y. 17 patients with non-metastatic castration-resistant PCa (nmCRPC) were treated with 100 µg pTVG-HP with different schedules of administration over 1 y and followed for 5 y. No adverse events were detected in long-term follow-up from either trial that were deemed possibly related to vaccination. Patients with nmCSPC had a median overall survival of 12.3 y, with 5/22 (23%) alive at 15 y. 8/22 (36%) died due to prostate cancer with a median survival of 11.0 y, and 9/22 (41%) died of other causes. Patients with nmCRPC had a median overall survival of 4.5 y, with 8/17 (47%) alive at 5 y. The presence of T-cells specific for the PAP target antigen was detectable in 6/10 (60%) individuals with nmCSPC, and 3/5 (60%) individuals with nmCRPC, many years after immunization. The detection of immune responses to the vaccine target years after immunization suggests durable immunity can be elicited in patients using a DNA vaccine encoding a tumor-associated antigen.Trial Registration: NCT00582140 and NCT00849121.
Assuntos
Vacinas Anticâncer , Antígeno Prostático Específico , Neoplasias da Próstata , Vacinas de DNA , Humanos , Masculino , Vacinas de DNA/imunologia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/efeitos adversos , Antígeno Prostático Específico/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/administração & dosagem , Idoso , Seguimentos , Neoplasias da Próstata/imunologia , Pessoa de Meia-Idade , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Resultado do Tratamento , Idoso de 80 Anos ou mais , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Recidiva Local de Neoplasia , Análise de Sobrevida , Fosfatase Ácida , Proteínas Tirosina Fosfatases/imunologiaRESUMO
Personalized cancer vaccines targeting specific neoantigens have been envisioned as one of the most promising approaches in cancer immunotherapy. However, the physicochemical variability of the identified neoantigens limits their efficacy as well as vaccine manufacturing in a uniform format. Herein, we developed a uniform nanovaccine platform based on poly(2-oxazoline)s (POx) to chemically conjugate neoantigen peptides, regardless of their physicochemical properties. This vaccine system could self-assemble into nanoparticles with uniform size (around 50 nm) and improve antigen accumulation as well as infiltration in the lymph node to increase antigen presentation. In vivo vaccination using this system conjugated with three predicted peptide neoantigen peptides from the MC38 tumor cell line induced 100% robust CD8+ T cell responses and superior tumor clearance compared to free peptides. This POx-based vaccine carrier represents a generalizable approach to increase the availability and efficacy of screened neoantigen peptides for a personalized cancer vaccine.
Assuntos
Antígenos de Neoplasias , Vacinas Anticâncer , Nanopartículas , Peptídeos , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/química , Peptídeos/química , Peptídeos/imunologia , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/química , Camundongos , Nanopartículas/química , Humanos , Linhagem Celular Tumoral , Linfócitos T CD8-Positivos/imunologia , Oxazóis/química , Polímeros/química , Imunoterapia/métodos , NanovacinasRESUMO
Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints.
Assuntos
Vacinas Anticâncer , Macroglobulinemia de Waldenstrom , Humanos , Masculino , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Pessoa de Meia-Idade , Feminino , Macroglobulinemia de Waldenstrom/imunologia , Macroglobulinemia de Waldenstrom/terapia , Macroglobulinemia de Waldenstrom/genética , Idoso , Microambiente Tumoral/imunologia , Medicina de Precisão/métodos , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico , Antígenos de Neoplasias/imunologia , Linfócitos B/imunologiaRESUMO
Engineering nanovaccines capable of targeting dendritic cells (DCs) is desperately required to maximize antigen cross-presentation to effector immune cells, elicit strong immune responses, and avoid adverse reactions. Here, we showed that glucose transporter 1 (Glut-1) on DCs is a reliable target for delivering antigens to DCs, and thus, a versatile antigen delivery strategy using glucosylated nanovaccines was developed for DC-targeted antigen delivery and tumor immunotherapy. The developed glucosylated ovalbumin-loaded nanovaccines highly accumulated in lymph nodes and efficiently engaged with Glut-1 on DCs to accelerate intracellular antigen delivery and promote DC maturation and antigen presentation, which elicited potent antitumor immunity to prevent and inhibit ovalbumin-expressing melanoma. Moreover, immunotherapeutic experiments in DC- and macrophage-depleted animal models confirmed that the glucosylated nanovaccines functioned mainly through DCs. In addition, the neoantigen-delivering glucosylated nanovaccines were further engineered to elicit tumor-specific immune responses against MC38 tumors. This study offers a DC-targeted antigen delivery strategy for cancer immunotherapy.
Assuntos
Vacinas Anticâncer , Células Dendríticas , Imunoterapia , Camundongos Endogâmicos C57BL , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/química , Vacinas Anticâncer/administração & dosagem , Camundongos , Ovalbumina/imunologia , Ovalbumina/química , Nanopartículas/química , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/química , Feminino , Apresentação de Antígeno/imunologia , Linhagem Celular Tumoral , Humanos , NanovacinasRESUMO
OBJECTIVES: To determine if nutritional status effects response to immunotherapy in women with gynecologic malignancies. METHODS: A retrospective chart review was conducted on gynecologic cancer patients who received immunotherapy at a single institution between 2015 and 2022. Immunotherapy included checkpoint inhibitors and tumor vaccines. The prognostic nutritional index (PNI) was calculated from serum albumin levels and total lymphocyte count. PNI values were determined at the beginning of treatment for each patient and assessed for their association with immunotherapy response. Disease control response (DCR) as an outcome of immunotherapy was defined as complete response, partial response, or stable disease. RESULTS: One hundred and ninety-eight patients received immunotherapy (IT) between 2015 and 2022. The gynecological cancers treated were uterine (38%), cervix (32%), ovarian (25%), and vulvar or vaginal (4%) cancers. The mean PNI for responders was higher than the non-responder group (p < 0.05). The AUC value for PNI as a predictor of response was 49. A PNI value of 49 was 43% sensitive and 85% specific for predicting a DCR. In Cox proportional hazards analysis, after adjusting for ECOG score and the number of prior chemotherapy lines, severe malnutrition was associated with progression-free survival (PFS) (HR = 1.85, p = 0.08) and overall survival (OS) (HR = 3.82, p < 0.001). Patients with PNI < 49 were at a higher risk of IT failure (HR = 2.24, p = 0.0001) and subsequent death (HR = 2.84, p = 9 × 10-5). CONCLUSIONS: PNI can be a prognostic marker to predict response rates of patients with gynecologic cancers treated with immunotherapy. Additional studies needed to understand the mechanistic role of malnutrition in immunotherapy response.
Assuntos
Neoplasias dos Genitais Femininos , Inibidores de Checkpoint Imunológico , Imunoterapia , Estado Nutricional , Humanos , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias dos Genitais Femininos/terapia , Neoplasias dos Genitais Femininos/imunologia , Idoso , Imunoterapia/métodos , Adulto , Avaliação Nutricional , Resultado do Tratamento , Idoso de 80 Anos ou mais , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/administração & dosagemRESUMO
Therapeutic vaccine becomes a promising strategy to fight cancer by enhancing and sustaining specific anti-tumor immune responses. However, its efficacy is often impeded by low immunogenicity, the immunosuppressive tumor microenvironment (TME), and immune-related adverse events. Herein, we introduce 1-tetradecanol (TD)-wrapped, CpG-loaded porous Prussian blue nanoparticles (pPBNPs-CpG@TD) as a nanoimmunomodulator to initiate photothermal-induced immunogenic cell death (ICD) and photothermal-responsive release of CpG for augmenting the ICD effect. It was revealed that the dual-photothermal action significantly potentiated the in situ anti-tumor vaccine-like immunotherapy in terms of enhanced immunogenicity, promoted dendritic cell maturation, and increased T lymphocyte infiltration, consequently eliciting a robust immune response for inhibiting both primary and rechallenge tumors on a subcutaneous 4T1 tumor-bearing mouse model. The development and use of photoactive nanoimmunomodulators represents a novel and effective strategy to boost immunogenicity and counteract immunosuppressive TME, marking a significant advancement in the realm of ICD-driven in situ anti-tumor vaccine-like immunotherapy.