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Despite being an integral part of the immune response in the tumor microenvironment (TME), few studies have mechanistically elucidated eosinophil functions in cancer outcomes. Eosinophils are a minor population of granulocytes that are mostly explored in asthma and allergic disorders. Their influence on primary and metastatic tumors, however, has recently come to light. Eosinophils' diverse armamentarium of mediators and receptors allows them to participate in innate and adaptive immunity, such as type 1 and type 2 immunity, and shape TME and tumor outcomes. Based on TME cells and cytokines, activated eosinophils drive other immune cells to ultimately promote or suppress tumor growth. Discovering exactly what conditions determine the pro-tumorigenic or anti-tumorigenic role of eosinophils allows us to take advantage of these signals and devise novel strategies to target cancer cells. Here, we first revisit eosinophil biology and differentiation as recognizing eosinophil mediators is crucial to their function in homeostatic and pathological conditions as well as tumor outcome. The bulk of our paper discusses eosinophil interactions with tumor cells, immune cells—including T cells, plasma cells, natural killer (NK) cells—and gut microbiota. Eosinophil mediators, such as IL-5, IL-33, granulocyte–macrophage colony-stimulating factor (GM-CSF), thymic stromal lymphopoietin (TSLP), and CCL11 also determine eosinophil behavior toward tumor cells. We then examine the implications of these findings for cancer immunotherapy approaches, including immune checkpoint blockade (ICB) therapy using immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cell therapy. Eosinophils synergize with CAR T cells and ICB therapy to augment immunotherapies. [ABSTRACT FROM AUTHOR]

Simple Summary: As a result of FDA approval of CAR-T cell treatments in the last few years, this immunotherapy has provided further direction to precision medicine through its combination with other therapeutic approaches. In the past year, several review articles have been published focusing on advances in this fast-developing field, especially with respect to efforts to overcome hurdles associated with applying CAR-T cells in solid tumors. This review paper focuses on combining CAR-T cell therapy with small molecule drugs, up-to-date progress in CAR-T cell therapy research, and advances in combined CAR-T immunotherapy with other treatments targeting solid tumors. Chimeric antigen receptors (CAR) T cells are T cells engineered to express membrane receptors with high specificity to recognize specific target antigens presented by cancer cells and are co-stimulated with intracellular signals to increase the T cell response. CAR-T cell therapy is emerging as a novel therapeutic approach to improve T cell specificity that will lead to advances in precision medicine. CAR-T cells have had impressive outcomes in hematological malignancies. However, there continue to be significant limitations of these therapeutic responses in targeting solid malignancies such as heterogeneous antigens in solid tumors, tumor immunosuppressive microenvironment, risk of on-target/off-tumor, infiltrating CAR-T cells, immunosuppressive checkpoint molecules, and cytokines. This review paper summarizes recent approaches and innovations through combination therapies of CAR-T cells and other immunotherapy or small molecule drugs to counter the above disadvantages to potentiate the activity of CAR-T cells. [ABSTRACT FROM AUTHOR]

The adoptive transfer of chimeric antigen receptor (CAR)-modified T cells is attracting growing interest for the treatment of malignant diseases. Early trials with anti-CD19 CAR T cells have achieved spectacular remissions in B-cell leukemia and lymphoma, so far refractory, very recently resulting in the Food and Drug Administration approval of CD19 CAR T cells for therapy. With further applications and increasing numbers of patients, the reproducible manufacture of high-quality clinical-grade CAR T cells is becoming an ever greater challenge. New processing techniques, quality-control mechanisms, and logistic developments are required to meet both medical needs and regulatory restrictions. This paper summarizes the state-of-the-art in manufacturing CAR T cells and the current challenges that need to be overcome to implement this type of cell therapy in the treatment of a variety of malignant diseases and in a greater number of patients. [ABSTRACT FROM AUTHOR]

Immunotherapy has recently emerged as a promising treatment for multiple myeloma (MM). There are now several monoclonal antibodies that target specific surface antigens on myeloma cells or the checkpoints of immune and myeloma cells. Elotuzumab (targeting SLAMF7), daratumumab (targeting CD38), and pembrolizumab (targeting PD-1) have shown clinical activity in clinical studies with relapsed/refractory MM. Dendritic cell vaccination is a safe strategy that has shown some efficacy in a subset of myeloma patients and may become a crucial part of MM treatment when combined with immunomodulatory drugs or immune check-point blockade. Genetically engineered T cells, such as chimeric antigen receptor T cells or T cell receptor-engineered T cells, have also shown encouraging results in recent clinical studies of patients with MM. In this paper, we discuss recent progress in immunotherapy for the treatment of MM. [ABSTRACT FROM AUTHOR]

Simple Summary: Exercise is associated with many aspects of a healthy lifestyle. Among these, exercise leads to the secretion of adrenaline and noradrenaline, which mobilize cells of the immune system, a process which is suggested to possess therapeutic value in cancer therapy, alone or in combination with immunotherapy. Strikingly, administration of β-blockers—which block the effect of adrenaline/noradrenaline—are also suggested to be useful in cancer therapy alone or in combination with immunotherapy. Herein we discuss the question of whether exercise and the administration of β-blockers could potentially be useful in cancer therapy. The incidence of cancer is increasing worldwide, which is to a large extent related to the population's increasing lifespan. However, lifestyle changes in the Western world are causative as well. Exercise is intrinsically associated with what one could call a "healthy life", and physical activity is associated with a lower risk of various types of cancer. Mouse models of exercise have shown therapeutic efficacy across numerous cancer models, at least in part due to the secretion of adrenaline, which mobilizes cells of the immune system, i.e., cytotoxic T and natural killer (NK) cells, through signaling of the β-2 adrenergic receptor (β2AR). Clinical trials aiming to investigate the clinical value of exercise are ongoing. Strikingly, however, the use of β-blockers—antagonists of the very same signaling pathway—also shows signs of clinical potential in cancer therapy. Cancer cells also express β-adrenergic receptors (βARs) and signaling of the receptor is oncogenic. Moreover, there are data to suggest that β2AR signaling in T cells renders the cell functionally suppressed. In this paper, we discuss these seemingly opposing mechanisms of cancer therapy—exercise, which leads to increased β2AR signaling, and β-blocker treatment, which antagonizes that same signaling—and suggest potential mechanisms and possibilities for their combination. [ABSTRACT FROM AUTHOR]