Lung cancer immunotherapy: progress, pitfalls, and promises.

Lung cancer is the primary cause of mortality in the United States and around the globe. Therapeutic options for lung cancer treatment include surgery, radiation therapy, chemotherapy, and targeted drug therapy. Medical management is often associated with the development of treatment resistance leading to relapse. Immunotherapy is profoundly altering the approach to cancer treatment owing to its tolerable safety profile, sustained therapeutic response due to immunological memory generation, and effectiveness across a broad patient population. Different tumor-specific vaccination strategies are gaining ground in the treatment of lung cancer. Recent advances in adoptive cell therapy (CAR T, TCR, TIL), the associated clinical trials on lung cancer, and associated hurdles are discussed in this review. Recent trials on lung cancer patients (without a targetable oncogenic driver alteration) reveal significant and sustained responses when treated with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint blockade immunotherapies. Accumulating evidence indicates that a loss of effective anti-tumor immunity is associated with lung tumor evolution. Therapeutic cancer vaccines combined with immune checkpoint inhibitors (ICI) can achieve better therapeutic effects. To this end, the present article encompasses a detailed overview of the recent developments in the immunotherapeutic landscape in targeting small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Additionally, the review also explores the implication of nanomedicine in lung cancer immunotherapy as well as the combinatorial application of traditional therapy along with immunotherapy regimens. Finally, ongoing clinical trials, significant obstacles, and the future outlook of this treatment strategy are also highlighted to boost further research in the field.

Pre-treatment with chicken IL-17A secreted by bioengineered LAB vector protects chicken embryo fibroblasts against Influenza Type A Virus (IAV) infection.

The recent advances in our understanding of the host factors in orchestrating qualitatively different immune responses against influenza Type A virus (IAV) have changed the perception of conventional approaches for controlling avian influenza virus (AIV) infection in chickens. Given that infection-induced pathogenicity and replication of influenza virus largely rely on regulating host immune responses, immunoregulatory cytokine profiles often determine the disease outcomes. However, in contrast to the function of other inflammatory cytokines, interleukin-17A (IL-17A) has been described as a 'double-edged sword', indicating that in addition to antiviral host responses, IL-17A has a distinct role in promoting viral infection. Therefore, in the present study, we investigated the chicken IL-17A mediated antiviral immune effects on IAVs infection in primary chicken embryo fibroblasts cells (CEFs). To this end, we first bioengineered a food-grade Lactic Acid Producing Bacteria (LAB), Lactococcus lactis (L. lactis), secreting bioactive recombinant chicken IL-17A (sChIL-17A). Next, the functionality of sChIL-17A was confirmed by transcriptional upregulation of several genes associated with antiviral host responses, including granulocyte-monocyte colony-stimulating factor (GM-CSF) (CSF3 in the chickens), interleukin-6 (IL-6), interferon-α (IFN-α), -ß and -γ genes in primary CEFs cells. Consistent with our hypothesis that such a pro-inflammatory state may translate to immunoprotection against IAVs infection, we observed that sChIL-17A pre-treatment could significantly limit the viral replication and protect the primary CEFs cells against two heterotypic IAVs such as A/turkey/Wisconsin/1/1966(H9N2) and A/PR/8/1934(H1N1). Together, the data presented in this work suggest that exogenous application of sChIL-17A secreted by modified LAB vector may represent an alternative strategy for improving antiviral immunity against avian influenza virus infection in chickens.

Translation of Mycobacterium Survival Strategy to Develop a Lipo-peptide based Fusion Inhibitor*.

The entry of enveloped virus requires the fusion of viral and host cell membranes. An effective fusion inhibitor aiming at impeding such membrane fusion may emerge as a broad-spectrum antiviral agent against a wide range of viral infections. Mycobacterium survives inside the phagosome by inhibiting phagosome-lysosome fusion with the help of a coat protein coronin 1. Structural analysis of coronin 1 and other WD40-repeat protein suggest that the trp-asp (WD) sequence is placed at distorted ß-meander motif (more exposed) in coronin 1. The unique structural feature of coronin 1 was explored to identify a simple lipo-peptide sequence (myr-WD), which effectively inhibits membrane fusion by modulating the interfacial order, water penetration, and surface potential. The mycobacterium inspired lipo-dipeptide was successfully tested to combat type 1 influenza virus (H1N1) and murine coronavirus infections as a potential broad-spectrum antiviral agent.

Mucosal delivery of live Lactococcus lactis expressing functionally active JlpA antigen induces potent local immune response and prevent enteric colonization of Campylobacter jejuni in chickens.

Successful colonization of the mucosal epithelial cells is the key early step for Campylobacter jejuni (C. jejuni) pathogenesis in humans. A set of Surface Exposed Colonization Proteins (SECPs) are known to take leading role in bacterial adhesion and subsequent host pathogenesis. Among the major SECPs, the constitutively expressed C. jejuni surface lipoprotein Jejuni lipoprotein A (JlpA), interacts with intestinal heat shock protein 90α (Hsp90α) and contributes in disease progression by triggering pro-inflammatory responses via activation of NF-κB and p38 MAP kinase pathways. In addition to its ability to express on the surface, high sequence conservation of JlpA protein among different Campylobacter spp make it a suitable vaccine target against C. jejuni. Given that chickens are the primary source for C. jejuni infection in humans and persistent cecal colonization significantly contribute in pathogen transmission, we explicitly used chickens as a model to test the immune-protective efficacy of JlpA protein. Taking into account that gastro-intestinal tract is the major site for C. jejuni colonization, we chose to use mucosal (intragastric) route as mode for JlpA antigen delivery. To deliver JlpA via mucosal route, we engineered a food grade Lactic acid producing bacteria, Lactococcus lactis (L. lactis) to express functionally active JlpA protein in the surface. Further, we demonstrated its ability to substantially improve the antigen specific local immune responses in the intestine along with significant immune-protection against enteric colonization of C. jejuni in chickens.

Intragastric delivery of recombinant Lactococcus lactis displaying ectodomain of influenza matrix protein 2 (M2e) and neuraminidase (NA) induced focused mucosal and systemic immune responses in chickens.

Compounding with the problem of frequent antigenic shift and occasional drift of the segmented genome of Avian Influenza Virus (AIV), vaccines based on major surface glycoproteins such as haemagglutinin (HA) to counter heterosubtypic AIV infection in chickens remain unsuccessful. In contrast, neuraminidase (NA), the second most abundant surface glycoprotein present in viral capsid is less mutable and, in some instances, successful in eliciting inter-species cross-reactive antibody responses. However, without selective activation of B-cells and T-cells, the ability of NA to induce strong cell mediated immune responses is limited, thus NA based vaccines cannot singularly address the risk of virus escape from host defence. To this end, the highly conserved ectodomain of influenza matrix protein-2 (M2e) has emerged as an attractive cross-protective vaccine target. The present study describes the potential of recombinant Lactococcus lactis (rL. lactis) in expressing functional influenza NA or M2e proteins and conferring effective mucosal and systemic immune responses in the intestine as well as in the upper respiratory airways (trachea) of chickens. In addition, lavages collected from trachea and intestine of birds administered with rL. lactis expressing influenza NA or M2e protein were found to protect MDCK cells against avian influenza type A/PR/8/34 (H1N1) virus challenge. Although minor, the differences in the expression of pro-inflammatory cytokines gene transcripts targeted in this study among the birds administered with either empty or rL. lactis could be attributed to the activation of innate response by L. lactis.