Breast Cancer Vaccines: Disappointing or Promising?

Breast cancer has become the most commonly diagnosed cancer globally. The relapse and metastasis of breast cancer remain a great challenge despite advances in chemotherapy, endocrine therapy, and HER2 targeted therapy in the past decades. Innovative therapeutic strategies are still critically in need. Cancer vaccine is an attractive option as it aims to induce a durable immunologic response to eradicate tumor cells. Different types of breast cancer vaccines have been evaluated in clinical trials, but none has led to significant benefits. Despite the disappointing results at present, new promise from the latest study indicates the possibility of applying vaccines in combination with anti-HER2 monoclonal antibodies or immune checkpoint blockade. This review summarizes the principles and mechanisms underlying breast cancer vaccines, recapitulates the type and administration routes of vaccine, reviews the current results of relevant clinical trials, and addresses the potential reasons for the setbacks and future directions to explore.

Cancer Vaccines: Toward the Next Breakthrough in Cancer Immunotherapy.

Until now, three types of well-recognized cancer treatments have been developed, i.e., surgery, chemotherapy, and radiotherapy; these either remove or directly attack the cancer cells. These treatments can cure cancer at earlier stages but are frequently ineffective for treating cancer in the advanced or recurrent stages. Basic and clinical research on the tumor microenvironment, which consists of cancerous, stromal, and immune cells, demonstrates the critical role of antitumor immunity in cancer development and progression. Cancer immunotherapies have been proposed as the fourth cancer treatment. In particular, clinical application of immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1/PD-L1 antibodies, in various cancer types represents a major breakthrough in cancer therapy. Nevertheless, accumulating data regarding immune checkpoint inhibitors demonstrate that these are not always effective but are instead only effective in limited cancer populations. Indeed, several issues remain to be solved to improve their clinical efficacy; these include low cancer cell antigenicity and poor infiltration and/or accumulation of immune cells in the cancer microenvironment. Therefore, to accelerate the further development of cancer immunotherapies, more studies are necessary. In this review, we will summarize the current status of cancer immunotherapies, especially cancer vaccines, and discuss the potential problems and solutions for the next breakthrough in cancer immunotherapy.

Induced pluripotent stem cells as a novel cancer vaccine.

Introduction: Although many current cancer therapies are effective, the mortality rate globally is unacceptably high. Cancer remains the second leading cause of death worldwide after heart disease and has caused nearly 10 million deaths in 2018. Additionally, current preventive therapies for cancer are underdeveloped, undermining the quality of life of high-risk individuals. Therefore, new treatment options for targeting cancer are urgently needed. In a recent study, researchers adopted an autologous iPSC-based vaccine to present a broad spectrum of tumor antigens to the immune system and succeeded in orchestrating a strong prophylactic immunity towards multiple types of cancer in mice. Areas covered: In this review, we provide an overview of how cancer develops, the role of immune surveillance in cancer progression, the current status and challenges of cancer immunotherapy as well as the genetic overlap between pluripotent stem cells and cancer cells. Finally, we discuss the rationale for an autologous iPSC-based vaccine and its applications in murine cancer models. Expert opinion: The autologous iPSC-based vaccine is a promising preventive and therapeutic strategy for fighting various types of cancers. Continuing efforts and clinical/translational follow-up studies may bring an autologous iPSC-based cancer vaccination approach from bench to bedside.

The use of the EVITA algorithm for clinical assessment of novel agents used in prostate cancer, metastatic melanoma, and systemic lupus erythematosus.

PURPOSE: Existing health technology assessment methods can be time-consuming and complicated to use in practice. EValuation of pharmaceutical Innovations with regard to Therapeutic Advantage (EVITA) is a recently developed drug assessment strategy that provides a detailed and clinically relevant evaluation of new agents compared to standard therapies. We therefore sought to use EVITA to evaluate eight novel agents recently introduced to clinical practice or in late-stage trials for the treatment of prostate cancer, metastatic melanoma, or systemic lupus erythematosus (SLE). METHODS: Eight agents (abiraterone, enzalutamide, sipuleucel-T, Prostvac, radium 223, ipilimumab, vemurafenib, and belimumab) were selected for study using the EVITA algorithm. A comprehensive literature search was performed to find clinical trial data, which were then classified using the EVITA protocol. EVITA was also compared to results from health technology assessments (HTAs) or reimbursement decisions. RESULTS: The EVITA scores for the eight drugs ranged from 5.5 to 9: all the selected agents are therefore classed as 'recommended' and are likely to produce a therapeutic advantage. In particular, vemurafenib is likely to be highly beneficial to patients with metastatic melanoma and radium 223 to patients with metastatic prostate cancer affecting the bone. The EVITA results were generally concordant with HTAs. CONCLUSIONS: All the agents show favourable EVITA scores and are therefore recommended for clinical practice. EVITA is an easy-to-use tool that provides clinical context to the assessment of newly introduced agents and can be easily used by non-specialists.

Exploiting the mutanome for tumor vaccination.

Multiple genetic events and subsequent clonal evolution drive carcinogenesis, making disease elimination with single-targeted drugs difficult. The multiplicity of gene mutations derived from clonal heterogeneity therefore represents an ideal setting for multiepitope tumor vaccination. Here, we used next generation sequencing exome resequencing to identify 962 nonsynonymous somatic point mutations in B16F10 murine melanoma cells, with 563 of those mutations in expressed genes. Potential driver mutations occurred in classical tumor suppressor genes and genes involved in proto-oncogenic signaling pathways that control cell proliferation, adhesion, migration, and apoptosis. Aim1 and Trrap mutations known to be altered in human melanoma were included among those found. The immunogenicity and specificity of 50 validated mutations was determined by immunizing mice with long peptides encoding the mutated epitopes. One-third of these peptides were found to be immunogenic, with 60% in this group eliciting immune responses directed preferentially against the mutated sequence as compared with the wild-type sequence. In tumor transplant models, peptide immunization conferred in vivo tumor control in protective and therapeutic settings, thereby qualifying mutated epitopes that include single amino acid substitutions as effective vaccines. Together, our findings provide a comprehensive picture of the mutanome of B16F10 melanoma which is used widely in immunotherapy studies. In addition, they offer insight into the extent of the immunogenicity of nonsynonymous base substitution mutations. Lastly, they argue that the use of deep sequencing to systematically analyze immunogenicity mutations may pave the way for individualized immunotherapy of cancer patients.

Potential targets for pancreatic cancer immunotherapeutics.

Pancreatic adenocarcinoma is the fourth leading cause of cancer death with an overall 5-year survival of less than 5%. As there is ample evidence that pancreatic adenocarcinomas elicit antitumor immune responses, identification of pancreatic cancer-associated antigens has spurred the development of vaccination-based strategies for treatment. While promising results have been observed in animal tumor models, most clinical studies have found only limited success. As most trials were performed in patients with advanced pancreatic cancer, the contribution of immune suppressor mechanisms should be taken into account. In this article, we detail recent work in tumor antigen vaccination and the recently identified mechanisms of immune suppression in pancreatic cancer. We offer our perspective on how to increase the clinical efficacy of vaccines for pancreatic cancer.

[Anti-HER2 vaccines: The HER2 immunotargeting future?]. / Vaccination anti-HER2 : l'avenir du ciblage immunologique de HER2 ?

Breast cancer is a widely spread women's disease. In spite of progress in the field of surgery and adjuvant therapies, the risk of breast cancer metastatic relapses remains high especially in those overexpressing HER2. Different studies have shown cellular and/or humoral immune responses against HER2 in patients with HER2-overexpressing tumors. This immune response is associated with a lower tumor development at early stages of the disease. These observations, associated with the efficiency today demonstrated by a trastuzumab-based anti-HER2 immunotherapy, allowed to envisage various vaccinal strategies against HER2. These findings have so led to the hypothesis that the generation of an anti-HER2 immune response should protect patients from HER2-overexpressing tumor growth, and induction of a stable and strong immunity by cancer vaccines is expected to lead to establishment of immune memory, thereby preventing tumor recurrence. However, an immunological tolerance against HER2 antigen exists representing a barrier to effective vaccination against this oncoprotein. As a consequence, the current challenge for vaccines is to find the best conditions to break this immunological tolerance. In this review, we will discuss the different anti-HER2 vaccine strategies currently developed; considering the strategies having reached the clinical phases as well as those still in preclinical development. The used antigen can be composed of tumoral allogenic cells or autologous cells or be specific of HER2. It can be delivered by denditric cells or in a DNA, peptidic or proteic form. Another area of the research concerns the use of anti-idiotypic antibodies mimicking HER2.

[Cancer vaccine].

Cancer vaccine is an intervention for therapeutic or prophylactic option by activating antitumor immune responses in vivo. Vaccine to human papillomavirus is clinically available, which prevents women from developing cervical cancer. Therapeutic cancer vaccines have been studied in randomized clinical trials. Melanoma vaccine using a gpl00 -peptide has been analyzed in recurrent disease patients. Patients treated with peptide vaccine with high-dose IL-2 lived longer than those with IL-2 alone. Another clinical trial covered hormone-resistant prostate cancer patients who were treated with dendritic cell (DC) vaccine of prostate-acid protein plus GM-CSF. DC-vaccinated patients significantly lived longer than those with placebo, though no difference of disease progression was seen between the two groups. Worldwide phase III study of MAGE-A3 vaccine for non-small cell lung cancer has been initiated. Its analysis on clinical benefits will be expected. Vaccine therapy for cancer would be another option for clinical practice in near

Vaccination therapy in malignant disease.

Improvement in survival among patients with early malignancy is well established in various cancers. However, long-term survival in those with advanced malignancy has changed little and this poses a major therapeutic challenge to clinicians. Anti-cancer immunotherapy is a novel approach, which is still experimental, but offers a new therapeutic strategy. In this review, we discuss the basic immunological interplay between the host immune system and the tumour, mechanisms of anti-tumour immune responses induced by immunotherapy and key in vivo pilot studies of active specific immunotherapy in various sold cancers, carried out during the last five years.

Non-clinical development of cancer vaccines: regulatory considerations.

This paper discusses regulatory requirements essential during the non-clinical development of cancer vaccines. DNA vaccines and vaccines containing monoclonal antibodies are specifically addressed. ICH, CHMP, FDA, and WHO guidance documents in addition to scientific literature are reviewed and the regulatory framework, including respective EMEA and the FDA divisions responsible for review and assessment of cancer vaccines, is described. Selection criteria for an appropriate animal model for efficacy and/or toxicity studies are discussed.

Current status of therapeutic vaccines for non-Hodgkin's lymphoma.

PURPOSE OF REVIEW: Therapeutic vaccines targeting B cell lymphoma idiotype have reached an advanced stage of clinical development, with three multicenter randomized clinical trials ongoing. This review describes the rationale and development of this immunotherapeutic approach, the design of current phase III trials, and other active vaccination approaches likely to move forward into clinical testing for lymphomas. RECENT FINDINGS: Several groups have achieved promising results in phase II trials of patient-specific idiotype vaccines, with very few side effects noted. Anti-idiotype antibodies, in addition to cytotoxic T cells, are now believed to be important effectors of antitumor immunity after idiotype vaccination. The manufacturing of autologous tumor idiotype proteins is being rapidly refined by the use of molecular technologies. Two trials involving more than 1000 patients are now under way, which use idiotype vaccination after induction chemotherapy; one trial completed accrual in early 2004. A third trial opened in 2004, using rituximab followed by idiotype vaccine with maintenance booster vaccines continuing throughout the period of normal B cell recovery. In accordance with the United States Food and Drug Administration, progression-free survival serves as the accepted primary efficacy endpoint in these studies. SUMMARY: Lymphoma idiotype vaccination represents a promising immunotherapeutic approach targeting a patient-specific tumor antigen. The results of pivotal phase III trials for three first-generation idiotype vaccines will become available in the next several years. Advanced manufacturing techniques should permit application of this tailor-made treatment to large numbers of non-Hodgkin's lymphoma patients.

Vaccine strategies for human papillomavirus-associated cancers.

PURPOSE OF REVIEW: To review novel immunologic strategies for the prevention and treatment of human papillomavirus infection and associated diseases. Both animal model systems and human protocols are discussed. RECENT FINDINGS: Many vaccine platforms for both prevention of human papillomavirus infection and treatment of associated disease have been developed. Virus-like particle constructs containing human papillomavirus capsid proteins have been shown to protect against human papillomavirus infection. Novel peptide or protein constructs containing modified E6 or E7 proteins, novel adjuvants, fusion proteins such as immunoglobulin-G-heavy chain E7, or heat shock proteins have been made as therapeutic modalities. In addition, many new recombinant vaccine vectors such as vaccinia, Listeria species, adenovirus, Semliki Forest vectors, and others have been developed as carriers of immunotherapeutic agents. Recently, chimeric virus-like particle vaccines have been developed to treat existing human papillomavirus-induced neoplasms. SUMMARY: Immunotherapy protocols using a variety of recombinant vectors and modified human papillomavirus proteins induce in-vitro T cell responses and may lead to tumor regression. Vaccine-induced in-vitro immune reactivity and clinical vaccine effects are often not well associated. Further analysis of ongoing human immunotherapy trials is awaited.

Vacunación en huéspedes inmunocomprometidos / Vaccine in immunocompromiced host

Los lactantes, niños y adolescentes con inmunodeficiencia primaria o secundaria constituyen una población creciente. La adecuada utilización de las vacunas incluídas en el Calendario Nacional y otras son una valiosa herramienta para la calidad de vida. Debe considerarse simultáneamente la vacunación de los convivientes. La indicación de la vacuna es personalizada. Se revisan las indicaciones en los pacientes con tratamiento prolongado con corticoides; inmundeficiencia primaria (humoral, celular/combinada); inmunodeficiencia secundaria (cáncer, transplante médula ósea/órganos sólidos.)

Vacunación en huéspedes inmunocomprometidos / Vaccine in immunocompromiced host

Los lactantes, niños y adolescentes con inmunodeficiencia primaria o secundaria constituyen una población creciente. La adecuada utilización de las vacunas incluídas en el Calendario Nacional y otras son una valiosa herramienta para la calidad de vida. Debe considerarse simultáneamente la vacunación de los convivientes. La indicación de la vacuna es personalizada. Se revisan las indicaciones en los pacientes con tratamiento prolongado con corticoides; inmundeficiencia primaria (humoral, celular/combinada); inmunodeficiencia secundaria (cáncer, transplante médula ósea/órganos sólidos.)

Vacunas en melanoma / Melanoma vaccines

Las vacunas terapéuticas han demostrado ser una de las mejores estrategias de intervención en el sistema inmune para proteger al organismo en contra de la progresión de una amplia variedad de enfermedades, incluyendo el cáncer. En este trabajo ofrecemos una revisión de las principales modalidades de vacunas terapéuticas que se han ensayado clínicamente y han demostrado algún efecto antitumoral. Aunque en la actualidad se están desarrollando varios ensayos clínicos fase III con resultados alentadores, la terapia con vacunas de melanoma es todavía experimental y su efectividad no esta demostrada (AU)

Cancer vaccines.

OBJECTIVE: To provide a review of cancer vaccines, how they work, and the current state of the science underlying these treatments. DATA SOURCES: Research studies, review articles, book chapters, personal communications. CONCLUSION: Vaccines have been studied in a variety of malignancies; however, melanoma has provided the best tumor model for vaccination. Clinical trials continue to investigate the optimal vaccine, route, and immunization schedule. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses must grasp a widening array of therapeutic options for cancer patients. The educational needs of the patient will be better met through a thorough understanding of basic concepts of newer cancer therapies.

Vaccination for melanoma.

Our knowledge of the immune system has grown tremendously in the 50 years since Coley used bacteria in an attempt to create a vaccine for cancer. The strategy for cancer vaccines has developed in that time as well. Both clinical and laboratory evidence suggests that melanoma is the more immunogenic of solid tumors. If treated early, melanoma can be controlled with surgery, but many patients continue to die from it. With our increased understanding of the immune system's interaction with melanoma, many clinical trials of melanoma vaccines are now underway. Vaccines designed to treat metastatic melanoma have shown some evidence of clinical effectiveness. This article outlines the current status of melanoma vaccination.