Unlocking cancer vaccine potential: What are the key factors?

Cancer is a global health challenge, with changing demographics and lifestyle factors producing an increasing burden worldwide. Screening advancements are enabling earlier diagnoses, but current cancer immunotherapies only induce remission in a small proportion of patients and come at a high cost. Cancer vaccines may offer a solution to these challenges, but they have been mired by poor results in past decades. Greater understanding of tumor biology, coupled with the success of vaccine technologies during the COVID-19 pandemic, has reinvigorated cancer vaccine development. With the first signs of efficacy being reported, cancer vaccines may be beginning to fulfill their potential. Solid tumors, however, present different hurdles than infectious diseases. Combining insights from previous cancer vaccine clinical development and contemporary knowledge of tumor immunology, we ask: who are the 'right' patients, what are the 'right' targets, and which are the 'right' modalities to maximize the chances of cancer vaccine success?

Intravenous heterologous prime-boost vaccination activates innate and adaptive immunity to promote tumor regression.

Therapeutic neoantigen cancer vaccines have limited clinical efficacy to date. Here, we identify a heterologous prime-boost vaccination strategy using a self-assembling peptide nanoparticle TLR-7/8 agonist (SNP) vaccine prime and a chimp adenovirus (ChAdOx1) vaccine boost that elicits potent CD8 T cells and tumor regression. ChAdOx1 administered intravenously (i.v.) had 4-fold higher antigen-specific CD8 T cell responses than mice boosted by the intramuscular (i.m.) route. In the therapeutic MC38 tumor model, i.v. heterologous prime-boost vaccination enhances regression compared with ChAdOx1 alone. Remarkably, i.v. boosting with a ChAdOx1 vector encoding an irrelevant antigen also mediates tumor regression, which is dependent on type I IFN signaling. Single-cell RNA sequencing of the tumor myeloid compartment shows that i.v. ChAdOx1 reduces the frequency of immunosuppressive Chil3 monocytes and activates cross-presenting type 1 conventional dendritic cells (cDC1s). The dual effect of i.v. ChAdOx1 vaccination enhancing CD8 T cells and modulating the TME represents a translatable paradigm for enhancing anti-tumor immunity in humans.

Human ZBP1 induces cell death-independent inflammatory signaling via RIPK3 and RIPK1.

ZBP1 is an interferon-induced cytosolic nucleic acid sensor that facilitates antiviral responses via RIPK3. Although ZBP1-mediated programmed cell death is widely described, whether and how it promotes inflammatory signaling is unclear. Here, we report a ZBP1-induced inflammatory signaling pathway mediated by K63- and M1-linked ubiquitin chains, which depends on RIPK1 and RIPK3 as scaffolds independently of cell death. In human HT29 cells, ZBP1 associated with RIPK1 and RIPK3 as well as ubiquitin ligases cIAP1 and LUBAC. ZBP1-induced K63- and M1-linked ubiquitination of RIPK1 and ZBP1 to promote TAK1- and IKK-mediated inflammatory signaling and cytokine production. Inhibition of caspase activity suppressed ZBP1-induced cell death but enhanced cytokine production in a RIPK1- and RIPK3 kinase activity-dependent manner. Lastly, we provide evidence that ZBP1 signaling contributes to SARS-CoV-2-induced cytokine production. Taken together, we describe a ZBP1-RIPK3-RIPK1-mediated inflammatory signaling pathway relayed by the scaffolding role of RIPKs and regulated by caspases, which may induce inflammation when ZBP1 is activated below the threshold needed to trigger a cell death response.

Combining personalized neoantigen vaccination with chemotherapy and anti-PD-1 to treat NSCLC.

In this issue of Cancer Cell, Awad et al. report a phase 1b clinical trial combining a personalized vaccine NEO-PV-01 with chemotherapy and anti-PD-1 pembrolizumab in first-line metastatic non-squamous NSCLC. They demonstrate that this treatment regimen was well tolerated and induced neoantigen-specific CD4+ T cell responses with effector phenotype.

Absentee Parents in Disney Feature-length Animated Movies: What are Children Watching?

Globally, Disney animated films integrate education into entertainment for families with children. This study uses the Social Capital Theory as the framework to support its focus on parental attention to children's developmental learning needs. This exploratory study examines how Disney animated movies over the last eight decades portraited parents in the life of the leading child characters. With three inclusion criteria (figure-length, animated, and at least one child being the protagonist), we found 155 films for the general audience released between 1937 and 2020. We read relevant website-posted plots and themes of each selected movie from three major informational websites. Data included the leading child, parents or parental figures, and the central theme of the movie. Most of these 155 stories (n = 97, 61.3%) did not mention the child's biological parents. Half of the 48 parental-presence films projected life in a single-headed family and the main characters' heroic image. The movies released during 2000-2020 showed a higher parental presence than the previous seven vicennial periods. Findings show that families could use Disney animated movies illustrating fantasy and reality. Parents can engage children in discussions about friendship and family relationships after watching a movie. If children continue consuming Disney movies, parental involvement is needed to facilitate discussions of real-life learning to help children develop communication skills.

Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy.

BACKGROUND: The clinical benefit of immune checkpoint blockade (ICB) therapy is often limited by the lack of pre-existing CD8+ T cells infiltrating the tumor. In principle, CD8+ T-cell infiltration could be promoted by therapeutic vaccination. However, this remains challenging given the paucity of vaccine platforms able to induce the strong cytotoxic CD8+ T-cell response required to reject tumors. A therapeutic cancer vaccine that induces a robust cytotoxic CD8+ T-cell response against shared tumor antigens and can be combined with ICB could improve the outcome of cancer immunotherapy. METHODS: Here, we developed a heterologous prime-boost vaccine based on a chimpanzee adenovirus (ChAdOx1) and a modified vaccinia Ankara (MVA) encoding MAGE-type antigens, which are tumor-specific shared antigens expressed in different tumor types. The mouse MAGE-type antigen P1A was used as a surrogate to study the efficacy of the vaccine in combination with ICB in murine tumor models expressing the P1A antigen. To characterize the vaccine-induced immune response, we performed flow cytometry and transcriptomic analyses. RESULTS: The ChAdOx1/MVA vaccine displayed strong immunogenicity with potent induction of CD8+ T cells. When combined with anti-Programmed Cell Death Protein 1 (PD-1), the vaccine induced superior tumor clearance and survival in murine tumor models expressing P1A compared with anti-PD-1 alone. Remarkably, ChAdOx1/MVA P1A vaccination promoted CD8+ T-cell infiltration in the tumors, and drove inflammation in the tumor microenvironment, turning 'cold' tumors into 'hot' tumors. Single-cell transcriptomic analysis of the P1A-specific CD8+ T cells revealed an expanded population of stem-like T cells in the spleen after the combination treatment as compared with vaccine alone, and a reduced PD-1 expression in the tumor CD8+ T cells. CONCLUSIONS: These findings highlight the synergistic potency of ChAdOx1/MVA MAGE vaccines combined with anti-PD-1 for cancer therapy, and establish the foundation for clinical translation of this approach. A clinical trial of ChadOx1/MVA MAGE-A3/NY-ESO-1 combined with anti-PD-1 will commence shortly.

Vaccination against the Epstein-Barr virus.

Epstein-Barr virus (EBV) was the first human tumor virus being discovered and remains to date the only human pathogen that can transform cells in vitro. 55 years of EBV research have now brought us to the brink of an EBV vaccine. For this purpose, recombinant viral vectors and their heterologous prime-boost vaccinations, EBV-derived virus-like particles and viral envelope glycoprotein formulations are explored and are discussed in this review. Even so, cell-mediated immune control by cytotoxic lymphocytes protects healthy virus carriers from EBV-associated malignancies, antibodies might be able to prevent symptomatic primary infection, the most likely EBV-associated pathology against which EBV vaccines will be initially tested. Thus, the variety of EBV vaccines reflects the sophisticated life cycle of this human tumor virus and only vaccination in humans will finally be able to reveal the efficacy of these candidates. Nevertheless, the recently renewed efforts to develop an EBV vaccine and the long history of safe adoptive T cell transfer to treat EBV-associated malignancies suggest that this oncogenic γ-herpesvirus can be targeted by immunotherapies. Such vaccination should ideally implement the very same immune control that protects healthy EBV carriers.

Concerns about Suicide among Asian Americans: The Need for Outreach?

Suicide was the ninth leading cause of death for Asian Americans in 2017. The growth of Asian American populations has led to more discussions about suicide prevention efforts. A 128-item needs assessment survey was administered at cultural events in 10 predominantly immigrant Asian communities. In five years, 1,840 respondents (61 percent response rate) filled out the survey anonymously to express their health and mental health concerns. This study aims to identify factors and help-seeking behaviors associated with having suicidal concerns among Asian Americans in various subgroups. Among the respondents, 1,314 rated the intensity of their concerns about suicide with an average of 0.74 (SD = 1.11) on a four-point rating scale in that 13.7 percent rated their concerns as severe. Taiwanese respondents expressed the highest intensity score (1.09) compared with other ethnic groups (from 0.29 to 1.04). A logistic regression analysis found that each unit of health concerns on a four-point rating scale significantly increases the likelihood of suicide concerns by 46 times among Asian Americans. Consistent with previous studies, immigrants were likely to share mental health problems with friends and physicians. Effective suicide prevention requires mental health awareness programming for the Asian American community.

The Association between Firearm Control Policies and Firearm Suicide among Men: A State-Level Age-Stratified Analysis.

This study examined the association between state-specific firearm control policies and firearm suicide rates among men after adjusting for state-level demographics. This cross-sectional study used state-level mortality data from the Centers for Disease Control and Prevention's Web-based Injury Statistics Query and Reporting System and the Brady Campaign State Scorecard in 2017. An age-stratified (15-24 years, 25-44 years, 45-64 years, and ≥ 65 years) multivariable analysis was conducted to identify gun control policies that are associated with firearm suicide rates among men in each age group. Results indicate that the associations of specific firearm control policies and firearm suicide rates differ across the age span. In particular, more policies (for example, dealer regulations and waiting periods) are negatively associated with firearm suicide rate among men 15 to 24 years of age. The findings underscore the importance of designing gender- and age-specific policy advocacy programs directed at lowering the rate of firearm suicide. This study also suggests that California, known for its innovative gun safety legislation efforts, could serve as a model for other states starting preventive programs to reduce the firearm suicide rate. Implications of the findings for social work practice are discussed.

Heterologous prime-boost vaccination protects against EBV antigen-expressing lymphomas.

The Epstein-Barr virus (EBV) is one of the predominant tumor viruses in humans, but so far no therapeutic or prophylactic vaccination against this transforming pathogen is available. We demonstrated that heterologous prime-boost vaccination with the nuclear antigen 1 of EBV (EBNA1), either targeted to the DEC205 receptor on DCs or expressed from a recombinant modified vaccinia virus Ankara (MVA) vector, improved priming of antigen-specific CD4+ T cell help. This help supported the expansion and maintenance of EBNA1-specific CD8+ T cells that are most efficiently primed by recombinant adenoviruses that encode EBNA1. These combined CD4+ and CD8+ T cell responses protected against EBNA1-expressing T and B cell lymphomas, including lymphoproliferations that emerged spontaneously after EBNA1 expression. In particular, the heterologous EBNA1-expressing adenovirus, boosted by EBNA1-encoding MVA vaccination, demonstrated protection as a prophylactic and therapeutic treatment for the respective lymphoma challenges. Our study shows that such heterologous prime-boost vaccinations against EBV-associated malignancies as well as symptomatic primary EBV infection should be further explored for clinical development.

Analysis of ROR1 Protein Expression in Mice with Reconstituted Human Immune System Components.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal antigen expressed on multiple tumors and has no significant expression on normal human tissues. ROR1 is highly upregulated in chronic lymphocytic leukemia (CLL) B cells. NOD-scid IL2rg-/- (NSG) mice engrafted with human CD34+ hematopoietic progenitor cells (huNSG) achieved multilineage human immune cell reconstitution including B cells, T cells, NK cells, and DCs. Like the CLL patients, huNSG mice have abnormally high percentage of CD5-expressing B cells in the periphery. In light of this, we aim to determine whether ROR1 is expressed on huNSG B cells. Using flow cytometry analysis, we found that ROR1 was highly expressed in a proportion of bone marrow, spleen, and blood B cells, which were mostly immature B cells. Transplantation of the oncogene TCL-1-transduced CD34+ cells in neonatal NSG mice did not increase the frequency of ROR1-expressing B cells, but the mouse with the highest engraftment of transduced cells developed a tumor-like lump consisting of a high percentage of ROR1-expressing B cells. This study highlights the potential use of huNSG mice to study B cell malignant diseases and to evaluate immunotherapeutics targeting ROR1.

Advocacy Journey Promoting Child Sexual Abuse Prevention in Hong Kong.

In a country without a mandatory child abuse reporting system, advocacy for child welfare law can be a tedious and difficult process. This article documents a 10-year advocacy journey based on the capacity-building concept in social sustainability theory which aims to: raise public awareness of child sexual abuse, provide an idea for branding an inquiry column, and connect advocacy efforts to law reforms. Over the past decade in Hong Kong, a total of 336 public inquiries were anonymously sent to Wu Miu Column and published in three local major newspapers. Among these inquiries, 131 inquiries involved child sexual abuse that the "affected individuals" were molested in school or at home and knew the abusers but did not report their cases to child protection services. Inquirers reported more male than female abusers. Proportionally and significantly, female abusers tended to abuse younger children, compared to male abusers who tended to abuse older children. Many abusers were minors who abused younger children, which explains people's reluctance to report the abuse to child protection services. The discovery of this underage phenomenon motivated child advocates to challenge the common law presumption that a boy under the age of 14 is incapable of sexual intercourse. Social workers in this advocacy journey must sustain continuous efforts to prevent youth from becoming future perpetrators.

Deploying an Ecological Model to Stem the Rising Tide of Firearm Suicide in Older Age.

A central objective of the Surgeon General's National Strategy for Suicide Prevention is to focus on older adults. We review individual risk-factors for suicide in late life and then introduce an ecological model to expand conceptualization of elder suicide. We first look at the role of firearms, providing evidence that firearm availability increases the means of elder suicide and gun access policies can contribute to reducing risk. Next, we focus on primary care providers, documenting how older adults often come into contact with these professionals before ending their lives and how these providers could take a more active role in mediating individual-level risk factors. We then turn our attention to the intersection between gun access and primary care and consider how advancing standards of care concerning gun access and suicide risk might be an effective policy alternative for blocking the pathway to suicide among older adults.

Endogenous Antigen Presentation of MHC Class II Epitopes through Non-Autophagic Pathways.

Antigenic peptides presented by major histocompatibility complex (MHC) class II molecules are generally derived from exogenous proteins acquired by antigen presenting cells. However, in some circumstances, MHC class II molecules can present intracellular proteins expressed within the antigen-presenting cells. There are several described pathways by which endogenous antigens are degraded and gain access to MHC class II molecules. These include autophagy and other non-autophagic pathways; the latter category includes the MHC class I-like pathways, heat shock protein 90-mediated pathways, and internalization from the plasma membrane. This review will summarize and discuss the non-autophagic pathways.

HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population.

Histone deacetylases (HDACs) are enzymes involved in transcriptional repression. We aimed to examine the significance of HDAC1 and HDAC2 gene expression in the prediction of recurrence and survival in 156 patients with hepatocellular carcinoma (HCC) among a South East Asian population who underwent curative surgical resection in Singapore. We found that HDAC1 and HDAC2 were upregulated in the majority of HCC tissues. The presence of HDAC1 in tumor tissues was correlated with poor tumor differentiation. Notably, HDAC1 expression in adjacent non-tumor hepatic tissues was correlated with the presence of satellite nodules and multiple lesions, suggesting that HDAC1 upregulation within the field of HCC may contribute to tumor spread. Using competing risk regression analysis, we found that increased cancer-specific mortality was significantly associated with HDAC2 expression. Mortality was also increased with high HDAC1 expression. In the liver cancer cell lines, HEP3B, HEPG2, PLC5, and a colorectal cancer cell line, HCT116, the combined knockdown of HDAC1 and HDAC2 increased cell death and reduced cell proliferation as well as colony formation. In contrast, knockdown of either HDAC1 or HDAC2 alone had minimal effects on cell death and proliferation. Taken together, our study suggests that both HDAC1 and HDAC2 exert pro-survival effects in HCC cells, and the combination of isoform-specific HDAC inhibitors against both HDACs may be effective in targeting HCC to reduce mortality.

Animal models of Epstein Barr virus infection.

Epstein Barr virus (EBV) was the first human tumor virus to be identified. Despite 50years of research on this oncogenic virus, no therapeutic or prophylactic vaccine is available against this pathogen. In part, the development of such a vaccine is hampered by the lack of in vivo models for EBV infection and immune control. However, with the advent of mice with reconstituted human immune system components (HIS mice), certain aspects of EBV associated diseases and immune responses can be modeled in vivo. In this review, we will discuss the insights that can be gained from these experiments, and how immune system components can be manipulated to interrogate their function during EBV infection. Finally, we will compare EBV immunobiology in HIS mice to infection by EBV-related viruses in monkeys, and we will outline the strengths and weaknesses of these two in vivo models of EBV infection. Both of these models show great promise as a platform for preclinical EBV vaccine testing.

Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection.

Primary infection with the human oncogenic Epstein-Barr virus (EBV) can result in infectious mononucleosis (IM), a self-limiting disease caused by massive lymphocyte expansion that predisposes for the development of distinct EBV-associated lymphomas. Why some individuals experience this symptomatic primary EBV infection, whereas the majority acquires the virus asymptomatically, remains unclear. Using a mouse model with reconstituted human immune system components, we show that depletion of human natural killer (NK) cells enhances IM symptoms and promotes EBV-associated tumorigenesis mainly because of a loss of immune control over lytic EBV infection. These data suggest that failure of innate immune control by human NK cells augments symptomatic lytic EBV infection, which drives lymphocyte expansion and predisposes for EBV-associated malignancies.

Spontaneous lytic replication and epitheliotropism define an Epstein-Barr virus strain found in carcinomas.

The Epstein-Barr virus (EBV) is found in a variety of tumors whose incidence greatly varies around the world. A poorly explored hypothesis is that particular EBV strains account for this phenomenon. We report that M81, a virus isolated from a Chinese patient with nasopharyngeal carcinoma (NPC), shows remarkable similarity to other NPC viruses but is divergent from all other known strains. M81 exhibited a reversed tropism relative to common strains with a reduced ability to infect B cells and a high propensity to infect epithelial cells, which is in agreement with its isolation from carcinomas. M81 spontaneously replicated in B cells in vitro and in vivo at unusually high levels, in line with the enhanced viral replication observed in NPC patients. Spontaneous replication and epitheliotropism could be partly ascribed to polymorphisms within viral proteins. We suggest considering M81 and its closely related isolates as an EBV subtype with enhanced pathogenic potential.

Cross-validation of a non-exercise measure for cardiorespiratory fitness in Singaporean adults.

INTRODUCTION: Cardiorespiratory fitness (CRF) is an independent predictor of voluminous health outcomes and can be measured using non-exercise fitness assessment (NEFA) equations. However, the accuracy of such equations in Asian populations is unknown. The objective of this study was to cross-validate the NEFA equation, developed by Jurca et al in 2005, in the adult Singaporean population. METHODS: A total of 100 participants (57 men, 43 women; aged 18-65 years) were recruited, and their maximal oxygen consumption (VO2 max) was measured in the laboratory by indirect calorimetry. The participants also completed the NEFA questionnaire, which helps to predict VO2 max with the NEFA equation. The relationship between NEFA-predicted and laboratory-measured VO2 max values was analysed. RESULTS: Overall, our study demonstrated a high correlation between the NEFA-predicted and laboratory-measured VO2 max values (r = 0.83). The Pearson's correlation coefficient values for the men and women in the study were 0.61 and 0.77, respectively. To improve the accuracy of the predictive equation, we transformed the original equation developed by Jurca et al into new equations that would allow estimation of VO2 max with and without resting heart rate as a variable. CONCLUSION: The modified NEFA equations accurately estimated CRF and may be applied to the majority of adult Singaporeans. With this, health practitioners and researchers are now able to assess CRF levels at both the individual and population levels in either the primary care, fitness or research setting.