mRNA COVID-19 vaccine: A future hope for cancer treatment

Background: mRNA vaccines have a strong potential for a possible cancer therapy platform. They express tumor antigens in antigen-presenting cells (APCs) after immunization, facilitating innate/adaptive immune stimulation. Because of its high effectiveness, safe administration, rapid development potential, and cost-efficient manufacturing, the mRNA cancer vaccine surpasses other traditional vaccination platforms. Conclusion: Careful evaluation of promising mRNA vaccines to supervise as carriers of lipids for cancer patients needs to be done. In addition, a possible revaluation for optimal protection is required. However, the extent to which solid tumours might take a significant part of the vaccine doses is still unknown.

Protein-Based Nanoparticle Vaccines for SARS-CoV-2

The pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has upended healthcare systems and economies around the world. Rapid understanding of the structural biology and pathogenesis of SARS-CoV-2 has allowed the development of emergency use or FDA-approved vaccines and various candidate vaccines. Among the recently developed SARS-CoV-2 candidate vaccines, natural protein-based nanoparticles well suited for multivalent antigen presentation and enhanced immune stimulation to elicit potent humoral and cellular immune responses are currently being investigated. This mini-review presents recent innovations in protein-based nanoparticle vaccines against SARS-CoV-2. The design and strategy of displaying antigenic domains, including spike protein, receptor-binding domain (RBD), and other domains on the surface of various protein-based nanoparticles and the performance of the developed nanoparticle-based vaccines are highlighted. In the final part of this review, we summarize and discuss recent advances in clinical trials and provide an outlook on protein-based nanoparticle vaccines.

Serum Proteomic Analyses Suggest That the HMGB1 and Other Inflammatory Pathways Are Operational in MBL and Are Less in Overt CLL

Background. CLL-like monoclonal B-ceII lymphocytosis (MBL) is considered a requisite precursor of CLL, with 1-2% of subjects annually progressing to CLL requiring therapy. The role of immune alterations leading to and operating in MBL and controlling progression to CLL is not well characterized. Since an increased frequency of immune-related conditions associated with immune dysfunction exists prior to CLL diagnosis (Landgren et al, Br J Haematol 2007 and Blood 2007; Andersen et al, Leukemia 2020), immune alterations likely exist in MBL. We have examined the serum protein profiles of MBL and CLL in search of clues linking immune dysfunction with malignant transformation. Objectives. 1. Characterize the serum proteomic profiles of MBL individuals, IGHV-mutated CLL (M-CLL) and IGHV-unmutated CLL (U-CLL) patients, and age-matched healthy controls (HC). 2. Compare the serum proteomic profiles between the groups. 3. Assess the effect of IGHV mutation status on serum proteomic profiles in CLL. Methods. A total of 12 MBL, 12 M-CLL, 12 U-CLL and 12 age-matched HC were studied. Patients were cared for at Northwell Health, New York (n=25) and Hospital del Mar, Barcelona (n=11). All patients were treatment naive except for one U-CLL patient who was treated one year beforehand. Serum samples were collected, and their protein levels measured employing SOMAmers (modified single-stranded DNA aptamers; SomaLogic) to quantify relative levels of 1,310 proteins. P-values <0.05 were used to define significantly different protein levels between groups. Ingenuity Pathway Analysis (IPA; QIAGEN) was employed to evaluate potential protein interactions and pathways. IPA pathways with P-value <0.05 and Z-score ≥2 or ≤-2 were considered to be activated or inhibited, respectively. Results. Overall, the levels of 862 proteins differed significantly between groups: MBL vs. HC: 10 downregulated (d) and 24 upregulated (u); M-CLL vs. HC: 206d and 6u; U-CLL vs. HC: 54d and 40u; M-CLL vs. MBL: 384d and 5u; U-CLL vs. MBL: 74d and 24u; and M-CLL vs. U-CLL: 35d and 0u. IPA highlighted a role for the pro-inflammatory HMGB1 pathway in several comparisons. First, an activated HMGB1 pathway was predicted in MBL compared to HC, together with activation of phagocytes, and an inhibition of the systemic immune suppressor TGF-β. Second and consistent with the former, U-CLL patients displayed an activated HMGB1 pathway compared to HC, along with other signs of immune stimulation (activated NFkB and Th1 pathways, maturation of dendritic cells, and inhibition of TGF-β) and leukemic progression (activated progression of tumor, and leukocyte extravasation). Third and contrary to the above, the HMGB1 pathway was inhibited when comparing M-CLL to HC, in line with a global immune suppression signature (inhibited PRR, GM-CSF, FcεRI, IL1, IL8, TNF, Th1, STAT3 and NFkB pathways, in addition to inhibited cell movement, viability and activation). Notably, inhibition of immune pathways was predicted for both M-CLL and U-CLL compared to MBL (diminished TNF and IL6 signaling, and reduced cell movement), although the greatest differences were seen for M-CLL vs. MBL comparison, including blockade of the HMGB1 pathway in M-CLL. Finally, the M-CLL vs. U-CLL comparison suggested inhibited INFγ, IL2, IL3, IL4, NFkB, and decreased T lymphocyte stimulation and movement of tumor cells in M-CLL patients. Conclusions. An increased pro-inflammatory signature with involvement of the HMGB1 pathway was identified in MBL and U-CLL compared with HC, whereas the opposite was seen for M-CLL. Since MBL most often exhibit mutated IGHV (91% of cases in our cohort), these findings suggest immune stimulation as a characteristic feature in the pre-leukemic and U-CLL leukemic stage that surprisingly is not operative in M-CLL. Consistent with this, M-CLL displayed a global immune suppression (HMGB1 pathway inhibition), whereas U-CLL exhibited signs of immune stimulation (HMGB1 pathway activation) compared to HC which may relate to distinct capabilities of the two subtypes to interact with the microenvironment. Lastly, the increased inflammatory signature identified in MBL, which are mainly IGHV-mutated, was lessened in CLL, mainly in M-CLL patients. This is consistent with a decreased influence of immune imbalance and the HMGB1 pathway associated with IGHV-mutated clonal expansions. Acknowledgments. GB is supported by a grant from Fundación Alfonso Martín Escudero. Disclosures Allen: Alexon: Research Funding; Bristol Myers Squibb: Other: Equity Ownership; C4 Therapeutics: Other: Equity Ownership; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees. Rhodes: Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support; AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant.

The viral expression and immune status in human cancers and insights into novel biomarkers of immunotherapy

Background Viral infections are prevalent in human cancers and they have great diagnostic and theranostic values in clinical practice. Recently, their potential of shaping the tumor immune microenvironment (TIME) has been related to the immunotherapy of human cancers. However, the landscape of viral expressions and immune status in human cancers remains incompletely understood. Methods We developed a next-generation sequencing (NGS)-based pipeline to detect viral sequences from the whole transcriptome and used machine learning algorithms to classify different TIME subtypes. Results We revealed a pan-cancer landscape of viral expressions in human cancers where 9 types of viruses were detected in 744 tumors of 25 cancer types. Viral infections showed different tissue tendencies and expression levels. Multi-omics analyses further revealed their distinct impacts on genomic, transcriptomic and immune responses. Epstein-Barr virus (EBV)-infected stomach adenocarcinoma (STAD) and Human Papillomavirus (HPV)-infected head and neck squamous cell carcinoma (HNSC) showed decreased genomic variations, significantly altered gene expressions, and effectively triggered anti-viral immune responses. We identified three TIME subtypes, in which the “Immune-Stimulation” subtype might be the promising candidate for immunotherapy. EBV-infected STAD and HPV-infected HNSC showed a higher frequency of the “Immune-Stimulation” subtype. Finally, we constructed the eVIIS pipeline to simultaneously evaluate viral infection and immune status in external datasets. Conclusions Viral infections are prevalent in human cancers and have distinct influences on hosts. EBV and HPV infections combined with the TIME subtype could be promising biomarkers of immunotherapy in STAD and HNSC, respectively. The eVIIS pipeline could be a practical tool to facilitate clinical practice and relevant studies.

Moving towards the Future of Radio-Immunotherapy: Could We “Tailor” the Abscopal Effect on Head and Neck Cancer Patients?

The abscopal effect (AbE) is defined as radiation-induced shrinkage of distant, non-treated, neoplastic lesions and it is considered the best clinical picture of the efficient immune stimulation by irradiation. The first report about abscopal tumor regression upon radiotherapy dates back to the beginning of the 20th century. The growing preclinical and clinical synergism between radiation and immunotherapy gave birth the purpose to more easily reproduce the abscopal effect, nevertheless, it is still rare in clinical practice. In this review we summarize immunological modulation of radiotherapy, focusing on the well-balanced equilibrium of tumor microenvironment and how radio-immunotherapy combinations can perturb it, with particular attention on head and neck squamous cell cancer. Finally, we investigate future perspectives, with the aim to “tailor” the abscopal effect to the patient.

Therapeutic Effect of an Antibody-Derived Peptide in a Galleria mellonella Model of Systemic Candidiasis

The synthetic peptide T11F (TCRVDHRGLTF), with sequence identical to a fragment of the constant region of human IgM, and most of its alanine-substituted derivatives proved to possess a significant candidacidal activity in vitro. In this study, the therapeutic efficacy of T11F, D5A, the derivative most active in vitro, and F11A, characterized by a different conformation, was investigated in Galleria mellonella larvae infected with Candida albicans. A single injection of F11A and D5A derivatives, in contrast with T11F, led to a significant increase in survival of larvae injected with a lethal inoculum of C. albicans cells, in comparison with infected animals treated with saline. Peptide modulation of host immunity upon C. albicans infection was determined by hemocyte analysis and larval histology, highlighting a different immune stimulation by the studied peptides. F11A, particularly, was the most active in eliciting nodule formation, melanization and fat body activation, leading to a better control of yeast infection. Overall, the obtained data suggest a double role for F11A, able to simultaneously target the fungus and the host immune system, resulting in a more efficient pathogen clearance.

NMR Metabolite Profiles of the Bivalve Mollusc Mytilus galloprovincialis Before and After Immune Stimulation With Vibrio splendidus

The hemolymph metabolome of Mytilus galloprovincialis injected with live Vibrio splendidus bacteria was analyzed by 1H-NMR spectrometry. Changes in spectral hemolymph profiles were already detected after mussel acclimation (3 days at 18 or 25 °C). A significant decrease of succinic acid was accompanied by an increase of most free amino acids, mytilitol, and, to a smaller degree, osmolytes. These metabolic changes are consistent with effective osmoregulation, and the restart of aerobic respiration after the functional anaerobiosis occurred during transport. The injection of Vibrio splendidus in mussels acclimated at 18°C caused a significant decrease of several amino acids, sugars, and unassigned chemical species, more pronounced at 24 than at 12 h postinjection. Correlation heatmaps indicated dynamic metabolic adjustments and the relevance of protein turnover in maintaining the homeostasis during the response to stressful stimuli. This study confirms NMR-based metabolomics as a feasible analytical approach complementary to other omics techniques in the investigation of the functional mussel responses to environmental challenges.

TNFα and Immune Checkpoint Inhibition: Friend or Foe for Lung Cancer?

Tumor necrosis factor-alpha (TNFα) can bind two distinct receptors (TNFR1/2). The transmembrane form (tmTNFα) preferentially binds to TNFR2. Upon tmTNFα cleavage by the TNF-alpha-converting enzyme (TACE), its soluble (sTNFα) form is released with higher affinity for TNFR1. This assortment empowers TNFα with a plethora of opposing roles in the processes of tumor cell survival (and apoptosis) and anti-tumor immune stimulation (and suppression), in addition to angiogenesis and metastases. Its functions and biomarker potential to predict cancer progression and response to immunotherapy are reviewed here, with a focus on lung cancer. By mining existing sequencing data, we further demonstrate that the expression levels of TNF and TACE are significantly decreased in lung adenocarcinoma patients, while the TNFR1/TNFR2 balance are increased. We conclude that the biomarker potential of TNFα alone will most likely not provide conclusive findings, but that TACE could have a key role along with the delicate balance of sTNFα/tmTNFα as well as TNFR1/TNFR2, hence stressing the importance of more research into the potential of rationalized treatments that combine TNFα pathway modulators with immunotherapy for lung cancer patients.

Immune stimulation and antibody response of chicks to different doses/units of the Nigerian live infectious bursa disease vaccine

Vaccination failure is one of the major constraints to disease control in poultry. To investigate Infectious bursa disease (IBD)-vaccination failures (frequently/globally reported), batches of the Nigerian live-vaccine were tested for viral units before vaccinating following chick-groups: 16 doses (65,536 units), 8 doses (32,768 units), 4 doses (6,384 units), 2 doses (8,192 units), 1 dose (4,096 units), 1:2 dose (2,048 units), 1:4 dose (1,024 units), 1:8 dose (512 units), 1:16 dose (256 units) and control. Each batch gave 4,096 viral units. Mean bursa weight/body weight ratios (immune stimulation) and mean antibody titres of the chick-groups were 47.40 ±5.45 and 51.20 ±7.83; 44.25 ±7.28 & 48.00 ±9.24; 45.25 ± 4.28 and 64.00 ± 0.00; 43.00 ±7.58 and 101.60 ± 35.05; 44.60 ± 5.51 and 128.00 ± 0.00; 42.60 ± 6.23 and 268.80 ± 16.00; 40.50 ± 1.76 and 80.00 ±16.00; 31.40 ± 3.80 and 80.00 ± 27.71; 37.18 ± 4.07 and 89.60 ± 15.68 and 26.20 ± 3.31 and 19.20 ± 5.99, respectively. Half (2,048 units) of the recommended 1-dose gave optimal antibody-titre. The higher doses gave lower antibody-titres like the lower doses but immune stimulation continued to increase as doses/units increased. Both over-stimulating the immune system (too high vaccine-doses/viral-units/viral-virulence) and under-stimulation cause vaccination failure.