Engaging Pattern Recognition Receptors in Solid Tumors to Generate Systemic Antitumor Immunity.

Malignant tumors frequently exploit innate immunity to evade immune surveillance. The priming, function, and polarization of antitumor immunity fundamentally depends upon context provided by the innate immune system, particularly antigen presenting cells. Such context is determined in large part by sensing of pathogen specific and damage associated features by pathogen recognition receptors (PRRs). PRR activation induces the delivery of T cell priming cues (e.g. chemokines, co-stimulatory ligands, and cytokines) from antigen presenting cells, playing a decisive role in the cancer immunity cycle. Indeed, endogenous PRR activation within the tumor microenvironment (TME) has been shown to generate spontaneous antitumor T cell immunity, e.g., cGAS-STING mediated activation of antigen presenting cells after release of DNA from dying tumor cells. Thus, instigating intratumor PRR activation, particularly with the goal of generating Th1-promoting inflammation that stokes endogenous priming of antitumor CD8+ T cells, is a growing area of clinical investigation. This approach is analogous to in situ vaccination, ultimately providing a personalized antitumor response against relevant tumor associated antigens. Here I discuss clinical stage intratumor modalities that function via activation of PRRs. These approaches are being tested in various solid tumor contexts including melanoma, colorectal cancer, glioblastoma, head and neck squamous cell carcinoma, bladder cancer, and pancreatic cancer. Their mechanism (s) of action relative to other immunotherapy approaches (e.g., antigen-defined cancer vaccines, CAR T cells, dendritic cell vaccines, and immune checkpoint blockade), as well as their potential to complement these approaches are also discussed. Examples to be reviewed include TLR agonists, STING agonists, RIG-I agonists, and attenuated or engineered viruses and bacterium. I also review common key requirements for effective in situ immune activation, discuss differences between various strategies inclusive of mechanisms that may ultimately limit or preclude antitumor efficacy, and provide a summary of relevant clinical data.

The role of innate immunity in the immunopathology and treatment of HBV infection.

In this review we give a brief update on sensors recently determined to be capable of detecting HBV, and examine how the virus represses the induction of pro-inflammatory cytokines like type I interferons. We overview cellular components of innate immunity that are present at high frequencies in the liver, and discuss their roles in HBV control and/or pathogenesis. We argue that many innate effectors have adaptive-like features or can exert specific effects on HBV through immunoregulation of T cells. Finally we consider current and possible future strategies to manipulate innate immunity as novel approaches towards a functional cure for HBV.

Targeting CD47 as a therapeutic strategy: A common bridge in the therapy of COVID-19-related cancers.

Macrophages are essential mediators of innate immunity. Non-self-cells resist phagocytosis through the expression of the checkpoint molecule CD47. CD47, as the integrin-associated protein, is overexpressed on tumor and SARS-CoV-2-infected cells as a potential surface biomarker for immune surveillance evasion. CD47-signal-regulating protein alpha (SIRPα) interaction is a promising innate immunotarget. Previous findings based on monoclonal antibodies (mAbs) or fusion proteins that block CD47 or SIRPα have been developed in cancer research. While CD47 efficacy in infectious diseases, especially severe COVID-19 studies, is lacking, focus on macrophage-mediated immunotherapy that increases "eat me" signals in combination therapy with mAbs is optimistic. This integrin-related protein can be as a potential target to therapy for COVID-19. Here, we concentrate on the role of the CD47 signaling pathway as a novel therapeutic strategy for COVID-19-associated cancer treatment.

CD47-SIRPα-targeted therapeutics: status and prospects.

CD47 is a "don't eat me" signal to phagocytes that is overexpressed on many tumor cells as a potential mechanism for immune surveillance evasion. CD47 and its interaction with signal-regulating protein alpha (SIRPα) on phagocytes is therefore a promising cancer target. Therapeutic antibodies and fusion proteins that block CD47 or SIRPα have been developed and have shown activity in preclinical models of hematologic and solid tumors. Anemia is a common adverse event associated with anti-CD47 treatment, but mitigation strategies-including use of a low 'priming' dose-have substantially reduced this risk in clinical studies. While efficacy in single-agent clinical studies is lacking, findings from studies of CD47-SIRPα blockade in combination with agents that increase 'eat me' signals or with antitumor antibodies are promising. Magrolimab, an anti-CD47 antibody, is the furthest along in clinical development among agents in this class. Magrolimab combination therapy in phase Ib/II studies has been well tolerated with encouraging response rates in hematologic and solid malignancies. Similar combination therapy studies with other anti-CD47-SIRPα agents are beginning to report. Based on these early clinical successes, many trials have been initiated in hematologic and solid tumors testing combinations of CD47-SIRPα blockade with standard therapies. The results of these studies will help determine the role of this novel approach in clinical practice and are eagerly awaited.

Embracing nanomaterials' interactions with the innate immune system.

Immunotherapy has firmly established itself as a compelling avenue for treating disease. Although many clinically approved immunotherapeutics engage the adaptive immune system, therapeutically targeting the innate immune system remains much less explored. Nanomedicine offers a compelling opportunity for innate immune system engagement, as many nanomaterials inherently interact with myeloid cells (e.g., monocytes, macrophages, neutrophils, and dendritic cells) or can be functionalized to target their cell-surface receptors. Here, we provide a perspective on exploiting nanomaterials for innate immune system regulation. We focus on specific nanomaterial design parameters, including size, form, rigidity, charge, and surface decoration. Furthermore, we examine the potential of high-throughput screening and machine learning, while also providing recommendations for advancing the field. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

A HER2 Tri-Specific NK Cell Engager Mediates Efficient Targeting of Human Ovarian Cancer.

Clinical studies validated antibodies directed against HER2, trastuzumab, and pertuzumab, as useful methodology to target breast cancer cases where HER2 is expressed. The hope was that HER2 targeting using these antibodies in ovarian cancer patients would prove useful as well, but clinical studies have shown lackluster results in this setting, indicating a need for a more comprehensive approach. Immunotherapy approaches stimulating the innate immune system show great promise, although enhancing natural killer (NK) function is not an established mainstream immunotherapy. This study focused on a new nanobody platform technology in which the bispecific antibody was altered to incorporate a cytokine. Herein we describe bioengineered CAM1615HER2 consisting of a camelid VHH antibody fragment recognizing CD16 and a single chain variable fragment (scFv) recognizing HER2 cross-linked by the human interleukin-15 (IL-15) cytokine. This tri-specific killer engager (TriKETM) showed in vitro prowess in its ability to kill ovarian cancer human cell lines. In addition, we demonstrated its efficacy in inducing potent anti-cancer effects in an in vivo xenograft model of human ovarian cancer engrafting both cancer cells and human NK cells. While previous approaches with trastuzumab and pertuzumab faltered in ovarian cancer, the hope is incorporating targeting and cytokine priming within the same molecule will enhance efficacy in this setting.

NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo.

We improved the bispecific antibody platform that primarily engages natural killer (NK) cells to kill cancer cells through antibody-dependent cellular cytotoxicity (ADCC) by adding IL-15 as a crosslinker that expands and self-sustains the effector NK cell population. The overall goal was to target B7-H3, an established marker predominantly expressed on cancer cells and minimally expressed on normal cells, and prove that it could target cancer cells in vitro and inhibit tumor growth in vivo. The tri-specific killer engager (TriKETM) was assembled by DNA shuffling and ligation using DNA encoding a camelid anti-CD16 antibody fragment, a wild-type IL-15 moiety, and an anti-B7-H3 scFv (clone 376.96). The expressed and purified cam1615B7H3 protein was tested for in vitro NK cell activity against a variety of tumors and in vivo against a tagged human MA-148 ovarian cancer cell line grafted in NSG mice. cam1615B7H3 showed specific NK cell expansion, high killing activity across a range of B7-H3+ carcinomas, and the ability to mediate growth inhibition of aggressive ovarian cancer in vivo. cam1615B7H3 TriKE improves NK cell function, expansion, targeted cytotoxicity against various types of B7-H3-positive human cancer cell lines, and delivers an anti-cancer effect in vivo in a solid tumor setting.