Journal of Clinical Medicine

Editorial

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Open AccessEditorial

Cancer Immunotherapy: Harnessing the Immune System to Fight Cancer

by Alessandro Rizzo, Veronica Mollica, Matteo Santoni and Francesco Massari

J. Clin. Med. 2022, 11(21), 6356; https://doi.org/10.3390/jcm11216356 - 27 Oct 2022

Cited by 2 | Viewed by 987

Abstract

The advent of cancer immunotherapy has represented an unprecedented revolution in patients with hematological and solid tumors [...] Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Current and Future Perspectives of a Therapeutic Revolution)

3 pages, 544 KiB

Open AccessEditorial

Cancer Immunotherapy: Current and Future Perspectives on a Therapeutic Revolution

by Alessandro Rizzo, Veronica Mollica, Matteo Santoni and Francesco Massari

J. Clin. Med. 2021, 10(22), 5246; https://doi.org/10.3390/jcm10225246 - 11 Nov 2021

Cited by 2 | Viewed by 1548

Abstract

The advent of immunotherapy has revolutionized the treatment landscape of several hematological and solid tumors [...] Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Current and Future Perspectives of a Therapeutic Revolution)

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Research

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15 pages, 799 KiB

Open AccessArticle

Expert Clinical Management of Severe Immune-Related Adverse Events: Results from a Multicenter Survey on Hot Topics for Management

by Mar Riveiro-Barciela, Maria Jose Soler, Ana Barreira-Diaz, Sheila Bermejo, Sebastian Bruera and Maria E. Suarez-Almazor

J. Clin. Med. 2022, 11(20), 5977; https://doi.org/10.3390/jcm11205977 - 11 Oct 2022

Cited by 3 | Viewed by 1473

Abstract

There are differences in recommendations for the management of immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs). To assess the real-world management of irAEs, three surveys regarding ICI-induced hepatitis (IIH), renal irAEs, and myositis were developed and sent to experts in [...] Read more.

There are differences in recommendations for the management of immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs). To assess the real-world management of irAEs, three surveys regarding ICI-induced hepatitis (IIH), renal irAEs, and myositis were developed and sent to experts in each area. Fifty-six surveys were completed (17 IIH, 20 renal irAEs, and 19 myositis). All experts agreed on performing imaging in every suspected case of severe IIH. Sixty-five percent agreed on performing a liver biopsy in patients not responding to corticosteroids. The most common indication for corticosteroid use (59%) was for severe IIH not improving after discontinuation of ICIs. Additionally, 60% of the experts agreed on performing a biopsy for stage 2/3 acute kidney injury (AKI), and 70% recommended imaging for any stage of AKI. Thirty-five percent favored corticosteroids in AKI patients with creatinine levels 2–3-fold above baseline. For myositis, 58% would recommend a muscle biopsy in a patient with weakness and creatine kinase levels of 5000 U/L; 47% would also opt for an endomyocardial biopsy when the troponin levels are increased. Fifty-eight percent recommended oral corticosteroids for myositis, and 37% recommended additional therapy, mainly immunoglobulins. These results show substantial differences in expert practice patterns for the management of severe liver, kidney, and muscular irAEs. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Current and Future Perspectives of a Therapeutic Revolution)

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7 pages, 411 KiB

Open AccessArticle

Blood Based Biomarkers as Predictive Factors for Hyperprogressive Disease

by Hasan Cagri Yildirim, Deniz Can Guven, Oktay Halit Aktepe, Hakan Taban, Feride Yilmaz, Serkan Yasar, Sercan Aksoy, Mustafa Erman, Saadettin Kilickap and Suayib Yalcin

J. Clin. Med. 2022, 11(17), 5171; https://doi.org/10.3390/jcm11175171 - 01 Sep 2022

Cited by 1 | Viewed by 1439

Abstract

Purpose: With the widespread use of immunotherapy agents, we encounter treatment responses such as hyperprogression disease (HPD) that we have not seen with previous standard chemotherapy and targeted therapies. It is known that survival in patients with HPD is shorter than in patients [...] Read more.

Purpose: With the widespread use of immunotherapy agents, we encounter treatment responses such as hyperprogression disease (HPD) that we have not seen with previous standard chemotherapy and targeted therapies. It is known that survival in patients with HPD is shorter than in patients without HPD. Therefore, it is important to know the factors that will predict HPD. We aimed to identify HPD-related factors in patients treated with immunotherapy. Methods: A total of 121 adult metastatic cancer patients treated with immunotherapy for any cancer were included. Baseline demographics, the ECOG performance status, type of tumors and baseline blood count parameters were recorded. Possible predisposing factors were evaluated with univariate and multivariate analyses. Results: The median age was 62.28 (interquartile range (IQR) 54.02–67.63) years, and the median follow-up was 12.26 (IQR 5.6–24.36) months. Renal cell carcinoma (33%) and melanoma (33.8%) were the most common diagnoses. Twenty patients (16.5%) had HPD. A high LDH level (p: 0.001), hypoalbuminemia (p: 0.016) and an NLR > 5 (p: 0.007) were found to be associated with hyperprogression. Sex (female vs. male, p: 0.114), age (>65 vs. <65, p: 0.772), ECOG (0 vs. 1–4, p: 0.480) and the line of treatment (1–5, p: 0.112) were not found to be associated with hyperprogression. Conclusions: In this study, we observed HPD in 16.5% of immunotherapy-treated patients and increased HPD risk in patients with a high LDH level (p: 0.001), hypoalbuminemia (p: 0.016) and an NLR > 5 (p: 0.007). Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Current and Future Perspectives of a Therapeutic Revolution)

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11 pages, 2341 KiB

Open AccessArticle

Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepaRG Tumor Cells

by Hani Oweira, Imad Lahdou, Stefan Mehrle, Elias Khajeh, Rajan Nikbakhsh, Omid Ghamarnejad, Peter Terness, Christoph Reißfelder, Mahmoud Sadeghi and Ali Ramouz

J. Clin. Med. 2022, 11(16), 4794; https://doi.org/10.3390/jcm11164794 - 16 Aug 2022

Cited by 5 | Viewed by 1733 | Correction

Abstract

There are two main enzymes that convert tryptophan (Trp) to kynurenine (Kyn): tryptophan-2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Kyn accumulation can promote immunosuppression in certain cancers. In this study, we investigated Trp degradation to Kyn by IDO and TDO in primary human hepatocytes [...] Read more.

There are two main enzymes that convert tryptophan (Trp) to kynurenine (Kyn): tryptophan-2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Kyn accumulation can promote immunosuppression in certain cancers. In this study, we investigated Trp degradation to Kyn by IDO and TDO in primary human hepatocytes (PHH) and tumoral HepaRG cells. To quantify Trp-degradation and Kyn-accumulation, using reversed-phase high-pressure liquid chromatography, the levels of Trp and Kyn were determined in the culture media of PHH and HepaRG cells. The role of IDO in Trp metabolism was investigated by activating IDO with IFN-γ and inhibiting IDO with 1-methyl-tryptophan (1-DL-MT). The role of TDO was investigated using one of two TDO inhibitors: 680C91 or LM10. Real-time PCR was used to measure TDO and IDO expression. Trp was degraded in both PHH and HepaRG cells, but degradation was higher in PHH cells. However, Kyn accumulation was higher in the supernatants of HepaRG cells. Stimulating IDO with IFN-γ did not significantly affect Trp degradation and Kyn accumulation, even though it strongly upregulated IDO expression. Inhibiting IDO with 1-DL-MT also had no effect on Trp degradation. In contrast, inhibiting TDO with 680C91 or LM10 significantly reduced Trp degradation. The expression of TDO but not of IDO correlated positively with Kyn accumulation in the HepaRG cell culture media. Furthermore, TDO degraded L-Trp but not D-Trp in HepaRG cells. Kyn is the main metabolite of Trp degradation by TDO in HepaRG cells. The accumulation of Kyn in HepaRG cells could be a key mechanism for tumor immune resistance. Two TDO inhibitors, 680C91 and LM10, could be useful in immunotherapy for liver cancers. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Current and Future Perspectives of a Therapeutic Revolution)

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13 pages, 1708 KiB

Open AccessArticle

The Association between Early Changes in Neutrophil-Lymphocyte Ratio and Survival in Patients Treated with Immunotherapy

by Deniz Can Guven, Taha Koray Sahin, Enes Erul, Ibrahim Yahya Cakir, Enes Ucgul, Hasan Cagri Yildirim, Oktay Halit Aktepe, Mustafa Erman, Saadettin Kilickap, Sercan Aksoy and Suayib Yalcin

J. Clin. Med. 2022, 11(15), 4523; https://doi.org/10.3390/jcm11154523 - 03 Aug 2022

Cited by 8 | Viewed by 1731

Abstract

Dynamic changes in the blood-based biomarkers could be used as a prognostic biomarker in patients treated with immune checkpoint inhibitors (ICIs), although the data are limited. We evaluated the association between the neutrophil–lymphocyte ratio (NLR) and early NLR changes with survival in ICI-treated [...] Read more.

Dynamic changes in the blood-based biomarkers could be used as a prognostic biomarker in patients treated with immune checkpoint inhibitors (ICIs), although the data are limited. We evaluated the association between the neutrophil–lymphocyte ratio (NLR) and early NLR changes with survival in ICI-treated patients. We retrospectively evaluated the data of 231 patients with advanced-stage cancer. We recorded baseline clinical characteristics, baseline NLR and fourth-week NLR changes, and survival data. A compound prognostic score, the NLR2-CEL score, was developed with the following parameters: baseline NLR (<5 vs. ≥5), ECOG status (0 vs. ≥1), Charlson Comorbidity Index (CCI, <9 vs. ≥9), LDH (N vs. ≥ULN), and fourth-week NLR change (10% or over NLR increase). In the multivariable analyses, higher NLR (HR: 1.743, p = 0.002), 10% or over NLR increase in the fourth week of treatment (HR: 1.807, p = 0.001), higher ECOG performance score (HR: 1.552, p = 0.006), higher LDH levels (HR: 1.454, p = 0.017), and higher CCI (HR: 1.400, p = 0.041) were associated with decreased OS. Compared to patients with the lowest scores, patients in the highest score group had significantly lower OS (HR: 7.967, 95% CI: 3.531–17.979, p < 0.001) and PFS. The composite score had moderate success for survival prediction, with an AUC of 0.702 (95% CI: 0.626–0.779, p < 0.001). We observed significantly lower survival in patients with higher baseline NLR values and increased NLR values under treatment. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Current and Future Perspectives of a Therapeutic Revolution)

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Review

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15 pages, 2129 KiB

Open AccessReview

Myocarditis Induced by Immunotherapy in Metastatic Melanoma—Review of Literature and Current Guidelines

by Anna M. Czarnecka, Marcin Kleibert, Iga Płachta, Paweł Rogala, Michał Wągrodzki, Przemysław Leszek and Piotr Rutkowski

J. Clin. Med. 2022, 11(17), 5182; https://doi.org/10.3390/jcm11175182 - 01 Sep 2022

Cited by 2 | Viewed by 2117

Abstract

Immunotherapy is a widely used treatment modality in oncology. Immune checkpoint inhibitors, as a part of immunotherapy, caused a revolution in oncology, especially in melanoma therapy, due to the significant prolongation of patients’ overall survival. These drugs act by activation of inhibited immune [...] Read more.

Immunotherapy is a widely used treatment modality in oncology. Immune checkpoint inhibitors, as a part of immunotherapy, caused a revolution in oncology, especially in melanoma therapy, due to the significant prolongation of patients’ overall survival. These drugs act by activation of inhibited immune responses of T lymphocytes against cancer cells. The mechanism responsible for the therapy’s high efficacy is also involved in immune tolerance of the patient’s own tissues. The administration of ICI therapy to a patient can cause severe immune reactions against non-neoplastic cells. Among them, cardiotoxicity seems most important due to the high mortality rate. In this article, we present the history of a 79 year-old patient diagnosed with melanoma who died due to myocarditis induced by ICI therapy, despite the fast administration of recommended immunosuppressive therapy, as an illustration of possible adverse events of ICI. Additionally, we summarize the mechanism, risk factors, biomarkers, and clinical data from currently published guidelines and studies about ICI-related myocarditis. The fast recognition of this fatal adverse effect of therapy may accelerate the rapid introduction of treatment and improve patients’ outcomes. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Current and Future Perspectives of a Therapeutic Revolution)

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8 pages, 897 KiB

Open AccessReview

Pathologic Complete Response in Urothelial Carcinoma Patients Receiving Neoadjuvant Immune Checkpoint Inhibitors: A Meta-Analysis

by Alessandro Rizzo, Veronica Mollica, Matteo Santoni, Gennaro Palmiotti and Francesco Massari

J. Clin. Med. 2022, 11(4), 1038; https://doi.org/10.3390/jcm11041038 - 17 Feb 2022

Cited by 3 | Viewed by 1426

Abstract

Background. Immune checkpoint inhibitors (ICIs) have been evaluated as neoadjuvant treatment in urothelial carcinoma (UC) patients, with these agents reporting encouraging pathologic complete response (pCR) rates. Herein, we performed a systematic review and meta-analysis aimed at evaluating the incidence of pCR in UC [...] Read more.

Background. Immune checkpoint inhibitors (ICIs) have been evaluated as neoadjuvant treatment in urothelial carcinoma (UC) patients, with these agents reporting encouraging pathologic complete response (pCR) rates. Herein, we performed a systematic review and meta-analysis aimed at evaluating the incidence of pCR in UC patients treated with neoadjuvant ICI. Moreover, we investigated the impact of PD-L1 expression in this patient population, exploring the possible role of PD-L1 status as predictive biomarker. Materials and Methods. We retrieved all the relevant trials through PubMed/Medline, Cochrane Library and EMBASE; moreover, proceedings of the main international oncological meetings were also searched for relevant abstracts. Eligible trials assessed pre-operative ICI in UC patients. Results. Our meta-analysis has highlighted a pooled pCR rate of 36.6% in the overall population; interestingly, pCR was higher in PD-L1 positive compared with PD-L1 negative UCs (49.5% versus 35.1%, respectively). Conclusions. Positive signals emanating from neoadjuvant immunotherapy should encourage the scientific community to persist in the long road toward finding more effective treatments for UC patients. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Current and Future Perspectives of a Therapeutic Revolution)

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