Promising Antigens for the New Frontier of Targeted Immunotherapy in Multiple Myeloma

The incorporation of novel agents in recent treatments in multiple myeloma (MM) has improved the clinical outcome of patients. Specifically, the approval of monoclonal antibody (MoAb) against CD38 (daratumumab) and SLAMF7 (elotuzumab) in relapsed and refractory MM (RRMM) represents an important milestone in the development of targeted immunotherapy in MM. These MoAb-based agents significantly induce cytotoxicity of MM cells via multiple effector-dependent mechanisms and can further induce immunomodulation to repair a dysfunctional tumor immune microenvironment. Recently, targeting B cell maturation antigen (BCMA), an even MM-specific antigen, has shown high therapeutic activities by chimeric antigen receptor T cells (CAR T), antibody-drug conjugate (ADC), bispecific T-cell engager (BiTE), as well as bispecific antibody (BiAb), with some already approved for heavily pretreated RRMM patients. New antigens, such as orphan G protein-coupled receptor class C group 5 member D (GPRC5D) and FcRH5, were identified and rapidly moved to ongoing clinical studies. We here summarized the pathobiological function of key MM antigens and the status of the corresponding immunotherapies. The potential challenges and emerging treatment strategies are also discussed.

Relapse of tagraxofusp treated blastic plasmacytoid dendritic cell neoplasm with loss of CD123 expression

Tagraxofusp, a CD123-based-targeted immunotherapy, was recently approved to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN) with excellent response. Also, a subset of BPDCN shows resistance to tagraxofusp. These resistant cases continue to express CD123, which forms the basis of the continued utility of tagraxofusp in newer combination chemotherapies to overcome resistance in BPDCN. Herein, we report a case of an elderly male with BPDCN that achieved complete remission on initial primary treatment with tagraxofusp. However, BPDCN relapsed after 1.5 years while on treatment, with loss of CD123 expression. At relapse, the neoplasm was comprehensively immunophenotyped by flow cytometry (performed on both peripheral blood and bone marrow specimen) and by immunohistochemical evaluation of the bone marrow clot section. The neoplasm at relapse was diagnostic of BPDCN with a lack of CD123 expression. This case highlights a potential limitation of current and upcoming tagraxofusp-based multidrug therapies, at least in a subset of refractory BPDCN. We believe our report will serve as a sentinel to incite future investigations involving alternate resistance mechanisms in BDPCN.

STING Signaling and Skin Cancers

Recent developments in immunotherapy against malignancies overcome the disadvantages of traditional systemic treatments; however, this immune checkpoint treatment is not perfect and cannot obtain a satisfactory clinical outcome in all cases. Therefore, an additional therapeutic option for malignancy is needed in oncology. Stimulator of interferon genes (STING) has recently been highlighted as a strong type I interferon driver and shows anti-tumor immunity against various malignancies. STING-targeted anti-tumor immunotherapy is expected to enhance the anti-tumor effects and clinical outcomes of immunotherapy against malignancies. In this review, we focus on recent advancements in the knowledge gained from research on STING signaling in skin cancers. In addition to the limitations of STING-targeted immunotherapy, we also discuss the clinical application of STING agonists in the treatment of skin cancer.

JQ1 Synergize with Anti-CD47 Antibody to Enhance the Function of Macrophages and Repress the Progression of Burkitt Lymphoma

Background: M2 macrophages, as the most prominent immune cells in Burkitt lymphoma (BL), are promising targets and anti-CD47 antibody could enhance the phagocytosis but be unable to eradicate tumor cells. JQ1, a C-MYC inhibitor, may enhance the function of macrophages and be a choice for combination therapy. Methods: The effect JQ1, on the expression of CD47 was measured. Then the synergy of JQ1 and anti-CD47 antibody was measured using phagocytosis assays. The effect of JQ1 on the polarization of macrophages was also detected. Finally, the efficiency and safety of JQ1 and anti-CD47 antibody combination therapy was explored in a groin orthotopically implanted Raji tumor model. Results: JQ1 could suppress the expression of CD47 on the surface of BL cells, thus synergize with anti-CD47 antibody to enhance the phagocytosis of macrophages. JQ1 could polarize macrophages from M2 to M1 while inhibiting the proliferation, inducing the apoptosis and blocking the cell cycle of BL cells. Finally, JQ1 and anti-CD47 antibody combination therapy could repress the progression of BL in NOD/SCID mice. Conclusions: Macrophages may be a promising target in BL and JQ1 combined with anti-CD47 antibody may be a potential therapeutic choice, providing theoretical basis for the use of this new targeted immunotherapy in clinical practice.

Purified Native and Recombinant Major Alternaria Alternata Allergen (Alt a 1) Induces Allergic Asthma in the Murine Model

Aeroallergens such us the spores of Alternaria alternata are described as the most important agents associated with respiratory allergies and severe asthma. Various experimental models of asthma have been developed using A. alternata extracts to study the pathogenesis of asthma, establishing the main parameters that trigger the asthmatic response. In this study, we describe a mouse model of asthma induced only by Alt a 1. To induce the allergic response, mice were challenged intranasally with the major allergen of A. alternata, Alt a 1. The presence of eosinophils in the lungs, elevated concentrations of Th2 family cytokines, lymphocyte proliferation and elevated IgE total serum levels indicated that the sensitisation and challenge with Alt a 1 induced the development of airway inflammation. Histological studies showed an eosinophilic cellular infiltrate in the lung tissue of mice instilled with Alt a 1. We demonstrate that Alt a 1 alone is capable of inducing a lung inflammatory response with an increase in IgE serum levels mimicking the allergic asthma immunoresponse when it is administered into BALB/c mice. This model will allow the evaluation of the immunoregulatory or immunotolerant capacity of several molecules that can be used in targeted immunotherapy for fungal allergic asthma.

Treatment of Chikungunya Virus (CHIKV) Using Targeted Immunotherapy

Chikungunya virus (CHIKV) is the most common mosquito-borne Alphavirus infecting humans worldwide. Up to date, there are no antiviral treatments or vaccines approved to treat or prevent CHIKV for which treatments remain symptomatic based on clinical manifestations. Hence, designing effective therapies to either prevent or treat CHIKV infection is of paramount importance. Interestingly, monoclonal antibodies (mAbs) are known to be significantly important in mediating protective immunity in CHIV infection. During the last decades, numerous animal studies have reported the protective and prophylactic efficacy of human and mouse anti-CHIKV mAbs isolated from convalescent patients. However, the therapeutic benefits of these anti-CHIKV mAbs can be limited by multiple factors. Thus, it becomes pertinent to better understand the CHIKV infection dynamics, mitigate the undesired mAbs-associated effects and improve therapies. In this review, we critically discuss CHIKV antiviral infectious mechanisms and address how the improved understanding of the latter may pave the way to better targeted immunotherapies.