What do we know about cancer immunotherapy? Long-term survival and immune-related adverse events

Immunotherapy delivered a new therapeutic option to the oncologist: Ipilimumab (anti-CTLA-4), Nivolumab and Pembrolizumab (anti-PD1), and Atezolizumab (anti-PD-L1) increase overall survival and show a better safety profile compared to chemotherapy in patients with metastatic melanoma, lung, renal cancer among others. But all that glitters is not gold and there is an increasing number of reports of adverse effects while using immune-checkpoint inhibitors. While chemotherapy could weaken the immune system, this novel immunotherapy could hyper-activate it, resulting in a unique and distinct spectrum of adverse events, called immune-related adverse events (IRAEs). IRAEs, ranging from mild to potentially life-threatening events, can involve many systems, and their management is radically different from that of cytotoxic drugs: immunosuppressive treatments, such as corticoids, infliximab or mycophenolate mofetil, usually result in complete reversibility, but failing to do so can lead to severe toxicity or even death. Patient selection is an indirect way to reduce adverse events minimizing the number of subjects exposed to this drugs: unfortunately PDL-1, the actual predictive biomarker, would not allow clinicians select or exclude patients for treatment with checkpoint inhibitors

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Tumor-associated macrophage-secreted 14-3-3ζ signals via AXL to promote pancreatic cancer chemoresistance.

Pancreatic ductal adenocarcinoma (PDAC) is an inherently chemoresistant tumor. Chemotherapy leads to apoptosis of cancer cells, and in previous studies we have shown that tumor-associated macrophage (TAM) infiltration increases following chemotherapy in PDAC. Since one of the main functions of macrophages is to eliminate apoptotic cells, we hypothesized that TAMs phagocytose chemotherapy-induced apoptotic cells and secrete factors, which favor PDAC chemoresistance. To test this hypothesis, primary human PDAC cultures were treated with conditioned media (CM) from monocyte-derived macrophage cultures incubated with apoptotic PDAC cells (MØApopCM). MØApopCM pretreatment rendered naïve PDAC cells resistant to Gemcitabine- or Abraxane-induced apoptosis. Proteomic analysis of MØApopCM identified YWHAZ/14-3-3 protein zeta/delta (14-3-3ζ), a major regulator of apoptotic cellular pathways, as a potential mediator of chemoresistance, which was subsequently validated in patient transcriptional datasets, serum samples from PDAC patients and using recombinant 14-3-3ζ and inhibitors thereof. Moreover, in mice bearing orthotopic PDAC tumors, the antitumor potential of Gemcitabine was significantly enhanced by elimination of TAMs using clodronate liposomes or by pharmacological inhibition of the Axl receptor tyrosine kinase, a 14-3-3ζ interacting partner. These data highlight a unique regulatory mechanism by which chemotherapy-induced apoptosis acts as a switch to initiate a protumor/antiapoptotic mechanism in PDAC via 14-3-3ζ/Axl signaling, leading to phosphorylation of Akt and activation of cellular prosurvival mechanisms. The data presented therefore challenge the idea that apoptosis of tumor cells is therapeutically beneficial, at least when immune sensor cells, such as macrophages, are present.

What do we know about cancer immunotherapy? Long-term survival and immune-related adverse events.

Immunotherapy delivered a new therapeutic option to the oncologist: Ipilimumab (anti-CTLA-4), Nivolumab and Pembrolizumab (anti-PD1), and Atezolizumab (anti-PD-L1) increase overall survival and show a better safety profile compared to chemotherapy in patients with metastatic melanoma, lung, renal cancer among others. But all that glitters is not gold and there is an increasing number of reports of adverse effects while using immune-checkpoint inhibitors. While chemotherapy could weaken the immune system, this novel immunotherapy could hyper-activate it, resulting in a unique and distinct spectrum of adverse events, called immune-related adverse events (IRAEs). IRAEs, ranging from mild to potentially life-threatening events, can involve many systems, and their management is radically different from that of cytotoxic drugs: immunosuppressive treatments, such as corticoids, infliximab or mycophenolate mofetil, usually result in complete reversibility, but failing to do so can lead to severe toxicity or even death. Patient selection is an indirect way to reduce adverse events minimizing the number of subjects exposed to this drugs: unfortunately PDL-1, the actual predictive biomarker, would not allow clinicians select or exclude patients for treatment with checkpoint inhibitors.

A current perspective on cancer immune therapy: step-by-step approach to constructing the magic bullet.

Immunotherapy is the new trend in cancer treatment due to the selectivity, long lasting effects, and demonstrated improved overall survival and tolerance, when compared to patients treated with conventional chemotherapy. Despite these positive results, immunotherapy is still far from becoming the perfect magic bullet to fight cancer, largely due to the facts that immunotherapy is not effective in all patients nor in all cancer types. How and when will immunotherapy overcome these hurdles? In this review we take a step back to walk side by side with the pioneers of immunotherapy in order to understand what steps need to be taken today to make immunotherapy effective across all cancers. While early scientists, such as Coley, elicited an unselective but effective response against cancer, the search for selectivity pushed immunotherapy to the side in favor of drugs focused on targeting cancer cells. Fortunately, the modern era would revive the importance of the immune system in battling cancer by releasing the brakes or checkpoints (anti-CTLA-4 and anti-PD-1/PD-L1) that have been holding the immune system at bay. However, there are still many hurdles to overcome before immunotherapy becomes a universal cancer therapy. For example, we discuss how the redundant and complex nature of the immune system can impede tumor elimination by teeter tottering between different polarization states: one eliciting anti-cancer effects while the other promoting cancer growth and invasion. In addition, we highlight the incapacity of the immune system to choose between a fight or repair action with respect to tumor growth. Finally we combine these concepts to present a new way to think about the immune system and immune tolerance, by introducing two new metaphors, the "push the accelerator" and "repair the car" metaphors, to explain the current limitations associated with cancer immunotherapy.

Current evidence for cancer stem cells in gastrointestinal tumors and future research perspectives.

Cancer stem cells (CSCs) are a very heterogeneous subpopulation of "stem-like" cancer cells that have been identified in many cancers, including leukemias and solid tumors. It is believed that CSCs drive tumor growth, malignant behavior and are responsible for the initiation of metastatic spread. In addition, CSCs have been implicated in chemotherapy and radiotherapy resistance. Current evidence supports the theory that CSCs share at least two main features of normal stem cells: self-renewal and differentiation, properties that contribute to tumor survival even in the presence of aggressive chemotherapy; however, the mechanism(s) governing the unique biology of CSCs remain unclear. In the field of gastrointestinal cancer, where we face very low survival rates across different tumor types, unraveling the role of CSCs in gastrointestinal tumors should improve our knowledge of cancer biology and chemoresistance, ultimately benefiting patient survival. Towards this end, much effort is being invested in the characterization of CSCs as a means of overcoming drug resistance and controlling metastatic spread. In this review we will cover the concept of CSCs, the current evidence for CSCs in gastrointestinal tumors and future research directions.

[Superior mesenteric venous thrombosis. Report of 2 cases and review of the literature]. / Trombosi venosa mesenterica superiore. Presentazione di due casi e revisione della letteratura.

Mesenteric venous thrombosis is an uncommon but often fatal form of intestinal ischaemia. The authors present two cases of severe small intestinal ischaemia due to superior mesenteric vein thrombosis, the first associated with oral contraceptive use and a congenital methylene-tetrahydrofolate reductase defect and the second associated with atypical intestinal mycobacterial disease and acquired immunodeficiency syndrome. The authors review the relevant literature using the Medline search facility and comment on the changing aspects of MVT syndrome with regard to aetiological factors, diagnostic approach and surgical or pharmacological therapy.