Coronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the most threatening pandemic in modern history. The aim of this systematic review and meta-analysis was to investigate the associations between serum albumin concentrations and COVID-19 disease severity and adverse outcomes. A systematic literature search was conducted in PubMed, from inception to October 30, 2020. Sixty-seven studies in 19,760 COVID-19 patients (6141 with severe disease or poor outcome) were selected for analysis. Pooled results showed that serum albumin concentrations were significantly lower in patients with severe disease or poor outcome (standard mean difference, SMD: − 0.99 g/L; 95% CI, − 1.11 to − 0.88, p < 0.001). In multivariate meta-regression analysis, age (t =  − 2.13, p = 0.043), publication geographic area (t = 2.16, p = 0.040), white blood cell count (t =  − 2.77, p = 0.008) and C-reactive protein (t =  − 2.43, p = 0.019) were significant contributors of between-study variance. Therefore, lower serum albumin concentrations are significantly associated with disease severity and adverse outcomes in COVID-19 patients. The assessment of serum albumin concentrations might assist with early risk stratification and selection of appropriate care pathways in this group.

Purpose: This study was aimed at evaluating the feasibility, safety, immunologic and clinical responses in patients with follicular lymphoma treated with monocyte-derived dendritic cells generated in the presence of IFNa and GM-CSF (IFN-DC) in combination with low doses of rituximab.Patients and Methods: Firstly, we analyzed in vitro and in vivo the immunologic properties of IFN-DC against follicular lymphoma. Thus, we performed a phase I trial in 8 patients with refractory and relapsed follicular lymphoma based on sequential intranodal injections of low-dose of rituximab and unloaded IFN-DC and report the safety, clinical, and immunologic results of the enrolled patients.Results: Preclinical studies indicated that IFN-DC can synergize with rituximab leading to increased cytotoxicity and T-cell tumor infiltration. The clinical evaluation showed that the combined treatment was totally safe. The overall response rate was 50%, PET-negative complete response rate 37%, and remission is still ongoing in 2/4 of responding patients (median follow-up 26 months, range 11-47). Notably, following the combined therapy all patients showed induction/enhancement of T-cell responses by CD107 degranulation or IFNg ELISPOT assay against patient-specific tumor IGHV sequences.Conclusions: These results represent the proof-of-principle on the effectiveness of unloaded IFN-DC in inducing durable clinical responses and promoting induction of tumor-specific peripheral T cells, thus suggesting the occurrence of an effective endogenous antitumor vaccination. The overall findings indicate that some unique properties of IFN-DC can be successfully exploited to induce/enhance antitumor responses, thus representing a valuable antitumor strategy for novel and more effective combination therapies in patients with cancer.

CD4+ T cells have been and are still largely regarded as the orchestrators of immune responses, being able to differentiate into distinct T helper cell populations based on differentiation signals, transcription factor expression, cytokine secretion, and specific functions. Nonetheless, a growing body of evidence indicates that CD4+ T cells can also exert a direct effector activity, which depends on intrinsic cytotoxic properties acquired and carried out along with the evolution of several pathogenic infections. The relevant role of CD4+ T cell lytic features in the control of such infectious conditions also leads to their exploitation as a new immunotherapeutic approach. This review aims at summarizing currently available data about functional and therapeutic relevance of cytotoxic CD4+ T cells in the context of viral infections and virus-driven tumors.

This work reports the effective antitumor activity of patient-derived cytokine-induced killer (CIK) cells against autologous chemo-resistant melanoma Cancer Stem Cells (CSCs).CSCs are clinical relevant targets, associated with disease relapse. We demonstrate that chemotherapy kills indeed proliferating melanoma cells but spares tumorigenic CSCs, in vitro and in vivo. The MHCindependent immunotherapy with CIK cells was proved successful in this challenging framework.Consistent findings were obtained in selected cases of BRAF mutated melanoma treated with small molecule BRAFi. Our data, generated within an autologous system, support the exploration of CIK cells in clinical trials. Cost effectiveness, safety profile and ability to overcome tumor MHC-downregulation are favorable issues to be considered in clinical perspective. CIK cells may be integrated at different levels in the composite therapeutic scenario of metastatic melanoma, offering an additional weapon to control tumor spread and promote its eradication. ABSTRACT PurposeThe MHC-unrestricted activity of cytokine-induced killer (CIK) cells against chemo-surviving melanoma cancer stem cells (mCSCs) was explored, as CSCs are considered responsible for chemo-resistance and relapses. Experimental designPutative mCSCs were visualized by engineering patient-derived melanoma cells (MCs) with a lentiviralvector encoding eGFP under expression control by stemness gene promoter oct4. Their stemness potential was confirmed in vivo by limiting dilution assays.We explored the sensitivity of eGFP CIK cell activity against chemoresistant mCSCs was confirmed vivo in two distinct immunodeficient murine models. ResultsWe visualized eGFP + mCSCs (14±2.1%) in 11 MCs. The tumorigenic precursor rate in vivo was higher within eGFP-positive MCs (1/42) compared with the eGFP-negative counterpart (1/4870).In vitro mCSCs were relatively resistant to CHT and BRAFi, but killed by CIK cells ( ConclusionsThese findings are the first demonstration that immunotherapy with CIK cells is active against autologous mCSCs surviving chemotherapy or BRAFi. An experimental platform for mCSC study and rationale for CIK cells in melanoma clinical study is provided.

Cytokine-induced killer (CIK) cells are ex vivo expanded T lymphocytes endowed with potent MHC-independent antitumor activity. CIK cells are emerging as promising therapeutic approach in the field of cancer adoptive immunotherapy, with biologic features favoring their transferability into clinical applications. Aim of this review is to present the biologic characteristic of CIK cells, discussing the main preclinical findings and initial clinical applications in the field of solid tumors.

De novo malignancies constitute an emerging cause of morbidity after solid organ transplant (SOT), significantly affecting the long-term survival of transplant recipients. Pharmacologic immunosuppression may functionally impair the immunosurveillance in these patients, thereby increasing the risk of cancer development. Nevertheless, the multiplicity and heterogeneity of the immune effects induced by immunosuppressive drugs limit the current possibilities to reliably predict the risk of de novo malignancy in SOT patients. Therefore, there is the pressing need to better characterize the immune dysfunctions induced by the different immunosuppressive regimens administered to prevent allograft rejection to tailor more precisely the therapeutic schedule and decrease the risk of de novo malignancies. We herein highlight the impact exerted by different classes of immunosuppressants on the most relevant immune cells, with a particular focus on the effects on dendritic cells (DCs), the main regulators of the balance between immunosurveillance and tolerance.

Preclinical findings and initial clinical reports showed the potentialities and drawbacks of different adoptive immunotherapy strategies. The expansion of tumor infiltrating lymphocytes is difficult to be reproduced outside melanoma. Genetically redirected T cells appear to be a promising option and initial reports are encouraging against patients with sarcomas. Adoptive immunotherapy with MHC-unrestricted effectors such as NK, CIK or γδ T cells has recently shown great preclinical potential in sarcoma setting and biologic features that may favor clinical transferability. Combination of different immunotherapy approaches and integration with conventional treatments appear to be key issues for successful designing of next clinical trials.

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