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Breakthroughs in Cancer-Related Immunotherapy

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (1 October 2021) | Viewed by 51175

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Special Issue Editor

Dr. Peter Kern

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West-German Cancer Center, Women's Department, University Hospital of Essen, 45147 Essen, Germany
Interests: breast cancer; breast surgery; breast reconstruction; onco-plastic surgery; minimal invasive breast surgery; magnetic resonance imaging; mammography; tomosynthesis; breast ultrasound; three-dimensional imaging; targeted breast surgery; intraoperative ultrasound; hybrid imaging
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Immunotherapy (IT) has created breakthroughs in difficult-to-treat tumors such as solid tumors and hematologic entities. (ICIs) such as PD1- and PD-L1-directed therapies as well as Anti-CTLA-4 have evolved as the coming game-changers in metastatic melanoma, breast cancer, gynecological cancers, renal cancer, and colorectal cancer. Metastatic melanoma has received the greatest benefits from immunotherapy, with nivolumab (anti-PD1) and ipilimumab (anti-CTLA-4) expanding the prognosis in metastatic melanoma beyond what has been achievable by any other therapy. A new paradigm shift in other solid tumors was the first FDA approval based on a molecular diagnosis of microsatellite instability (MSI) in endometrial cancer or other tumors with this molecular feature. Combinations of ICIs with chemotherapy renders immunological ‘‘cold“ tumors succeptible to immunotherapy, i.e., ‘‘hot“ tumors.

Costly immunotherapies are only feasible with biomarkers to select the correct patient populations. This Cancers Special Issue ‘‘Breakthrough in Immuno-Oncology“ encourages scientists to publish their work in companion diagnostics and predictive biomarkers of immunotherapy, including the determination of tumor mutational burden (TMB) and T-cell inflamed expression profile (T-GEP) as well as the treatment of solid tumors in phase I–III trials.

Prof. Peter Kern
Guest Editor

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Keywords

cancer antigen
immune targets and harnessing of immune response
activation of T-cells
tumor-infiltrating lymphocytes (TILs)
CD 8+ cytotoxic T-cells
PD1-PD-L1-checkpoint inhibitors
AKTi
CTLA-4i
tumor mutational burden (TMB)

Published Papers (13 papers)

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10 pages, 577 KiB

Open AccessArticle

Phase I Trial of Oral Yeast-Derived β-Glucan to Enhance Anti-GD2 Immunotherapy of Resistant High-Risk Neuroblastoma

by Fiorella Iglesias Cardenas, Audrey Mauguen, Irene Y. Cheung, Kim Kramer, Brian H. Kushner, Govind Ragupathi, Nai-Kong V. Cheung and Shakeel Modak

Cancers 2021, 13(24), 6265; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246265 - 14 Dec 2021

Cited by 6 | Viewed by 2164

Abstract

Beta glucans, complex polysaccharides, prime leukocyte dectin-1 and CR3-receptors and enhance anti-tumor cytotoxicity of complement-activating monoclonal antibodies. We conducted a phase I study (clinicaltrials.gov NCT00492167) to determine the safety of the combination of yeast-derived beta glucan (BG) and anti-GD2 murine monoclonal antibody 3F8 in patients with relapsed or refractory high-risk neuroblastoma. Patients received intravenous 3F8 (fixed dose of 10 mg/m²/day × 10 days) and oral BG (dose-escalated from 10–200 mg/kg/day × 17 days in cohorts of 3–6 patients each). Forty-four patients completed 141 cycles. One patient developed DLT: transient self-limiting hepatic transaminase elevation 5 days after starting BG (120 mg/kg/day). Overall, 1, 3, 12 and 24 evaluable patients had complete response, partial response, stable and progressive disease, respectively, at the end of treatment. Positive human anti-mouse antibody response and dectin-1 rs3901533 polymorphism were associated with better overall survival. BG dose level and serum BG levels did not correlate with response. Progression-free and overall survival at 2 years were 28% and 61%, respectively. BG lacked major toxicity. Treatment with 3F8 plus BG was associated with anti-neuroblastoma responses in patients with resistant disease. Although the maximal tolerated dose for yeast BG was not reached, considering the large volume of oral BG, we recommended 40 mg/kg/day as the phase II dose. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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15 pages, 1580 KiB

Open AccessArticle

Opportunities and Limitations of Pelvic Exenteration Surgery

by Björn Lampe, Verónica Luengas-Würzinger, Jürgen Weitz, Stephan Roth, Friederike Rawert, Esther Schuler, Sabrina Classen-von Spee, Nando Fix, Saher Baransi, Anca Dizdar, Peter Mallmann, Klaus-Dieter Schaser and Andreas Bogner

Cancers 2021, 13(24), 6162; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246162 - 07 Dec 2021

Cited by 13 | Viewed by 4783

Abstract

Purpose: The practice of exenterative surgery is sometimes controversial and has garnered a certain scepticism. Surgical studies are difficult to conduct due to insufficient data. The aim of this review is to present the current standing of pelvic exenteration from a surgical, gynaecological and urological point of view. Methods: This review is based upon a literature review (MEDLINE (PubMed), CENTRAL (Cochrane) and EMBASE (Elsevier)) of retrospective studies on exenterative surgery from 1993–2020. Using MeSH (Medical Subject Headings) search terms, 1572 publications were found. These were evaluated and screened with respect to their eligibility using algorithms and well-defined inclusion and exclusion criteria. Therefore, the guidelines for systematic reviews (PRISMA) were used. Results: A complete tumour resection (R0) often represents the only curative option for advanced pelvic carcinomas and their recurrences. A recent systematic review showed significant symptom relief in 80% of palliative patients after pelvic exenteration. Surgical limitations (distant metastases, involvement of the pelvic wall, etc.) are diminished by adequate surgical expertise and close interdisciplinary cooperation. While the mortality rate is low (2–5%), the still relatively high morbidity rate (32–84%) can be minimized by optimizing the perioperative setting. Following exenterations, roughly 79–82% of patients report satisfying results according to PROs (patient-reported outcomes). Conclusion: Due to multimodality treatment strategies combined with extended surgical expertise and patients’ preferences, pelvic exenteration can be offered nowadays with low mortality and acceptable postoperative quality of life. The possibilities of surgical treatment are often underestimated. A multi-centre database (PelvEx Collaborative) was established to collect data and experiences to optimize the research in this field. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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14 pages, 6466 KiB

Open AccessArticle

CD8+ T Lymphocytes Immune Depletion and LAG-3 Overexpression in Hodgkin Lymphoma Tumor Microenvironment Exposed to Anti-PD-1 Immunotherapy

by Jean-Marie Michot, Severine Mouraud, Julien Adam, Julien Lazarovici, Camille Bigenwald, Charlotte Rigaud, Lambros Tselikas, Peggy Dartigues, Alina Danu, Amélie Bigorgne, Veronique Minard, David Ghez, Aurélien Marabelle, Laurence Zitvogel and Vincent Ribrag

Cancers 2021, 13(21), 5487; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215487 - 31 Oct 2021

Cited by 9 | Viewed by 2383

Abstract

Background: Resistance to anti-PD-1 remains a considerable clinical challenge for the treatment of patients with classical Hodgkin lymphoma (cHL), and mechanisms of anti-PD-1 resistance remain unknown. This pilot study aims to investigate the tumor microenvironment in patients with cHL relapsing after anti-PD-1. Methods: This study investigated tumor samples of eight patients with cHL, including four patients exposed to anti-PD-1 with a paired longitudinal histological analysis before and after anti-PD-1, and four patients not exposed to anti-PD-1 who served as control for the cellular biological investigations. Fresh cells tumor microenvironment analysis included phenotypic characterization of their T cell surfaces immune checkpoint markers PD-1, PD-L1, ICOS, TIM-3, LAG-3, 41-BB and BTLA. Tumor tissues immunohistochemistry staining included CD30, CD4, CD8, CD68, CD163, PD-L1, PD-1, LAG-3 and TIM-3. Findings: Paired longitudinal tumor tissues analysis in the tumor microenvironment found a CD8+ lymphocytes tumor depletion and an increase of LAG-3 staining after anti-PD-1 exposure. The fresh cells analysis of the tumor microenvironment in patients exposed to anti-PD-1 found CD8+ lymphocyte depletion, with an elevated CD4+/CD8+ lymphocytes ratio (median ratio 9.77 in exposed anti-PD-1 versus 2.39 in not-exposed anti-PD-1 patients; p = 0.0943). On the cell surfaces of CD4+ lymphocytes, the median positive expression of LAG-3 was significantly higher in the samples exposed to anti-PD-1 compared to the controls (15.05 [IQR:17.91–10.65] versus 3.84 [IQR 1.87–6.57]; p = 0.0376). Interpretation: This pilot study proposes hypotheses for understanding the resistance to immunotherapies in patients with Hodgkin lymphoma. Hodgkin lymphoma exposed to anti-PD-1 correlated in tumor microenvironment with an immune depletion of CD8+ T lymphocytes and overexpression of LAG-3 on CD4+ helper T lymphocytes. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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13 pages, 1173 KiB

Open AccessArticle

Prognostic Impact of Immunoglobulin Kappa C (IGKC) in Early Breast Cancer

by Marcus Schmidt, Karolina Edlund, Jan G. Hengstler, Anne-Sophie Heimes, Katrin Almstedt, Antje Lebrecht, Slavomir Krajnak, Marco J. Battista, Walburgis Brenner, Annette Hasenburg, Jörg Rahnenführer, Mathias Gehrmann, Pirkko-Liisa Kellokumpu-Lehtinen, Ralph M. Wirtz and Heikki Joensuu

Cancers 2021, 13(14), 3626; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143626 - 20 Jul 2021

Cited by 9 | Viewed by 2953

Abstract

We studied the prognostic impact of tumor immunoglobulin kappa C (IGKC) mRNA expression as a marker of the humoral immune system in the FinHer trial patient population, where 1010 patients with early breast cancer were randomly allocated to either docetaxel-containing or vinorelbine-containing adjuvant chemotherapy. HER2-positive patients were additionally allocated to either trastuzumab or no trastuzumab. Hormone receptor-positive patients received tamoxifen. IGKC was evaluated in 909 tumors using quantitative real-time polymerase chain reaction, and the influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan–Meier estimates. Interactions were analyzed using Cox regression. IGKC expression, included as continuous variable, was independently associated with DDFS in a multivariable analysis also including age, molecular subtype, grade, and pT and pN stage (HR 0.930, 95% CI 0.870–0.995, p = 0.034). An independent association with DDFS was also found in a subset analysis of triple-negative breast cancers (TNBC) (HR 0.843, 95% CI 0.724–0.983, p = 0.029), but not in luminal (HR 0.957, 95% CI 0.867–1.056, p = 0.383) or HER2-positive (HR 0.933, 95% CI 0.826–1.055, p = 0.271) cancers. No significant interaction between IGKC and chemotherapy or trastuzumab administration was detected (P_interaction = 0.855 and 0.684, respectively). These results show that humoral immunity beneficially influences the DDFS of patients with early TNBC. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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11 pages, 2387 KiB

Open AccessArticle

The Soluble Factor from Oral Cancer Cell Lines Inhibits Interferon-γ Production by OK-432 via the CD40/CD40 Ligand Pathway

by Go Ohe, Yasusei Kudo, Kumiko Kamada, Yasuhiro Mouri, Natsumi Takamaru, Keiko Kudoh, Naito Kurio and Youji Miyamoto

Cancers 2021, 13(13), 3301; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133301 - 30 Jun 2021

Cited by 2 | Viewed by 1640

Abstract

(1) Background: OK-432 is a penicillin-killed, lyophilized formulation of a low-toxicity strain (Su) of Streptococcus pyogenes (Group A). It is a potent immunotherapy agent for several types of cancer, including oral cancer. We previously showed that (i) OK-432 treatment induces a high amount of IFN-γ production from peripheral blood mononuclear cells (PBMCs), and (ii) conditioned medium (CM) from oral cancer cells suppresses both the IFN-γ production and cytotoxic activity of PBMCs driven by OK-432. The aim of this study was to determine the inhibitory mechanism of OK-432-induced IFN-γ production from PBMCs by CM. (2) Methods: We performed cDNA microarray analysis, quantitative RT-PCR, and ELISA to reveal the inhibitory mechanism of CM. (3) Results: We found that CD40 plays a key role in IFN-γ production via IL-12 production. Although OK-432 treatment upregulated the expression levels of the IL-12p40, p35, and CD40 genes, CM from oral cancer cells downregulate these genes. The amount of IFN-γ production by OK-432 treatment was decreased by an anti-CD40 neutralizing antibody. (4) Conclusions: Our study suggests that uncertain soluble factor(s) produced from oral cancer cells may inhibit IFN-γ production from PBMCs via suppressing the CD40/CD40L–IL-12 axis. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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17 pages, 1909 KiB

Open AccessArticle

CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade

by Julie Vackova, Ingrid Polakova, Shweta Dilip Johari and Michal Smahel

Cancers 2021, 13(8), 1935; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081935 - 16 Apr 2021

Cited by 13 | Viewed by 4390

Abstract

Cluster of differentiation (CD) 80 is mainly expressed in immune cells but can also be found in several types of cancer cells. This molecule may either activate or inhibit immune reactions. Here, we determined the immunosuppressive role of CD80 in the tumor microenvironment by CRISPR/Cas9-mediated deactivation of the corresponding gene in the mouse oncogenic TC-1 cell line. The tumor cells with deactivated CD80 (TC-1/dCD80-1) were more immunogenic than parental cells and induced tumors that gained sensitivity to cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade, as compared with the TC-1 cells. In vivo depletion experiments showed that the deactivation of CD80 switched the pro-tumorigenic effect of macrophages observed in TC-1-induced tumors into an anti-tumorigenic effect in TC-1/dCD80-1 tumors and induced the pro-tumorigenic activity of CD4⁺ cells. Moreover, the frequency of lymphoid and myeloid cells and the CTLA-4 expression by T helper (Th)17 cells were increased in TC-1/dCD80-1- compared with that in the TC-1-induced tumors. CTLA-4 blockade downregulated the frequencies of most immune cell types and upregulated the frequency of M2 macrophages in the TC-1 tumors, while it increased the frequency of lymphoid cells in TC-1/dCD80-1-induced tumors. Furthermore, the anti-CTLA-4 therapy enhanced the frequency of CD8⁺ T cells as well as CD4⁺ T cells, especially for a Th1 subset. Regulatory T cells (Treg) formed the most abundant CD4⁺ T cell subset in untreated tumors. The anti-CTLA-4 treatment downregulated the frequency of Treg cells with limited immunosuppressive potential in the TC-1 tumors, whereas it enriched this type of Treg cells and decreased the Treg cells with high immunosuppressive potential in TC-1/dCD80-1-induced tumors. The immunosuppressive role of tumor-cell-expressed CD80 should be considered in research into biomarkers for the prediction of cancer patients’ sensitivity to immune checkpoint inhibitors and for the development of a tumor-cell-specific CD80 blockade. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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19 pages, 2270 KiB

Open AccessArticle

The Antidiabetic Agent Acarbose Improves Anti-PD-1 and Rapamycin Efficacy in Preclinical Renal Cancer

by Rachael M. Orlandella, William J. Turbitt, Justin T. Gibson, Shannon K. Boi, Peng Li, Daniel L. Smith, Jr. and Lyse A. Norian

Cancers 2020, 12(10), 2872; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102872 - 06 Oct 2020

Cited by 14 | Viewed by 5912

Abstract

Although immune checkpoint inhibitors and targeted therapeutics have changed the landscape of treatment for renal cell carcinoma (RCC), most patients do not experience significant clinical benefits. Emerging preclinical studies report that nutrition-based interventions and glucose-regulating agents can improve therapeutic efficacy. However, the impact of such agents on therapeutic efficacy in metastatic kidney cancer remains unclear. Here, we examined acarbose, an alpha-glucosidase inhibitor and antidiabetic agent, in a preclinical model of metastatic kidney cancer. We found that acarbose blunted postprandial blood glucose elevations in lean, nondiabetic mice and impeded the growth of orthotopic renal tumors, an outcome that was reversed by exogenous glucose administration. Delayed renal tumor outgrowth in mice on acarbose occurred in a CD8 T cell-dependent manner. Tumors from these mice exhibited increased frequencies of CD8 T cells that retained production of IFNγ, TNFα, perforin, and granzyme B. Combining acarbose with either anti-PD-1 or the mammalian target of rapamycin inhibitor, rapamycin, significantly reduced lung metastases relative to control mice on the same therapies. Our findings in mice suggest that combining acarbose with current RCC therapeutics may improve outcomes, warranting further study to determine whether acarbose can achieve similar responses in advanced RCC patients in a safe and likely cost-effective manner. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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Review

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Directing the Future Breakthroughs in Immunotherapy: The Importance of a Holistic Approach to the Tumour Microenvironment

by Hannah V. Newnes, Jesse D. Armitage, Katherine M. Audsley, Anthony Bosco and Jason Waithman

Cancers 2021, 13(23), 5911; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13235911 - 24 Nov 2021

Cited by 1 | Viewed by 1941

Abstract

Immunotherapy has revolutionised the treatment of cancers by exploiting the immune system to eliminate tumour cells. Despite the impressive response in a proportion of patients, clinical benefit has been limited thus far. A significant focus to date has been the identification of specific markers associated with response to immunotherapy. Unfortunately, the heterogeneity between patients and cancer types means identifying markers of response to therapy is inherently complex. There is a growing appreciation for the role of the tumour microenvironment (TME) in directing response to immunotherapy. The TME is highly heterogeneous and contains immune, stromal, vascular and tumour cells that all communicate and interact with one another to form solid tumours. This review analyses major cell populations present within the TME with a focus on their diverse and often contradictory roles in cancer and how this informs our understanding of immunotherapy. Furthermore, we discuss the role of integrated omics in providing a comprehensive view of the TME and demonstrate the potential of leveraging multi-omics to decipher the underlying mechanisms of anti-tumour immunity for the development of novel immunotherapeutic strategies. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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14 pages, 692 KiB

Open AccessReview

The Role of B Cells in Head and Neck Cancer

by Niki Gavrielatou, Ioannis Vathiotis, Panagiota Economopoulou and Amanda Psyrri

Cancers 2021, 13(21), 5383; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215383 - 27 Oct 2021

Cited by 9 | Viewed by 2984

Abstract

Head and neck cancer comprises a heterogenous, highly immune infiltrated malignancy, defined by a predominantly immunosuppressive tumor microenvironment (TME). In recent years, PD-1/PD-L1 immune checkpoint inhibitors have become the standard of care treatment, either as monotherapy or in combination with chemotherapy agents, thus revolutionizing the therapeutic landscape of recurrent/metastatic disease. As a result, preclinical research is increasingly focusing on TME composition and pathophysiology, aiming to comprehensively characterize the specific elements and interactions affecting anti-tumor immunity, as well as to unveil novel predictive biomarkers of immunotherapy outcomes. While T lymphocytic populations have been vastly explored regarding their effect on cancer development, B-cells constitute a far less investigated, yet possibly equally important, aspect of cancer immunity. B-cell presence, either as single cells or as part of tertiary lymphoid structures within the TME, has been associated with several anti-tumor defense mechanisms, such as antigen presentation, antibody production and participation in antibody-dependent cellular cytotoxicity, and has demonstrated prognostic significance for multiple types of malignancies. However, immunoregulatory B-cell phenotypes have also been identified both peripherally and within malignant tissue, bearing inhibitory effects on numerous immune response processes. Consequently, B-cells and their subsets demonstrate the potential to become valuable cancer biomarkers and acquire a leading role in future therapeutic strategies. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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10 pages, 689 KiB

Open AccessReview

Neoadjuvant and Adjuvant Immunotherapy in Non-Small Cell Lung Cancer—Clinical Trials Experience

by Izabela Chmielewska, Katarzyna Stencel, Ewa Kalinka, Rodryg Ramlau and Paweł Krawczyk

Cancers 2021, 13(20), 5048; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205048 - 09 Oct 2021

Cited by 11 | Viewed by 3767

Abstract

Across all tumor types, we observe that the role of immunotherapy has increased rapidly. Due to a number of potential advantages, it is considered in neoadjuvant treatment of localized tumors. In neoadjuvant settings, immunotherapy addresses micrometastatic diseases at the moment of their formation. However, some issues concerning neoadjuvant and adjuvant immunotherapy still has to be covered. The choice of drug and use of monotherapy or combination regimens remains unclear. The timing of surgery and preoperative evaluation of neoadjuvant immunotherapy efficacy is challenging. Although there is currently limited confirmed clinical data to support the use of immune checkpoint blockade in the neoadjuvant and adjuvant settings, there are many studies exploring this strategy in NSCLC patients. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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16 pages, 799 KiB

Open AccessReview

CD137⁺ T-Cells: Protagonists of the Immunotherapy Revolution

by Alessio Ugolini and Marianna Nuti

Cancers 2021, 13(3), 456; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13030456 - 26 Jan 2021

Cited by 16 | Viewed by 5197

Abstract

The CD137 receptor (4-1BB, TNF RSF9) is an activation induced molecule expressed by antigen-specific T-cells. The engagement with its ligand, CD137L, is capable of increasing T-cell survival, proliferation, and cytokine production. This allowed to identify the CD137⁺ T-cells as the real tumor-specific activated T-cell population. In fact, these cells express various TCRs that are specific for a wide range of tumor-derived peptides, both shared and neoantigenic ones. Moreover, their prevalence in sites close to the tumor and their unicity in killing cancer cells both in vitro and in vivo, raised particular interest in studying their potential role in different strategies of immunotherapy. They indeed showed to be a reliable marker able to predict patient’s outcome to immune-based therapies as well as monitor their response. In addition, the possibility of isolating and expanding this population, turned promising in order to generate effector antitumor T-cells in the context of adoptive T-cell therapies. CD137-targeting monoclonal antibodies have already shown their antitumor efficacy in cancer patients and a number of clinical trials are thus ongoing to test their possible introduction in different combination approaches of immunotherapy. Finally, the intracellular domain of the CD137 receptor was introduced in the anti-CD19 CAR-T cells that were approved by FDA for the treatment of pediatric B-cell leukemia and refractory B-cell lymphoma. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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16 pages, 855 KiB

Open AccessReview

Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer

by Antonio Lopez-Beltran, Alessia Cimadamore, Ana Blanca, Francesco Massari, Nuno Vau, Marina Scarpelli, Liang Cheng and Rodolfo Montironi

Cancers 2021, 13(1), 131; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13010131 - 03 Jan 2021

Cited by 144 | Viewed by 8961

Abstract

A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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14 pages, 311 KiB

Open AccessReview

Immunotherapy in Solid Tumors and Gut Microbiota: The Correlation—A Special Reference to Colorectal Cancer

by Asimina Koulouridi, Ippokratis Messaritakis, Nikolaos Gouvas, John Tsiaoussis and John Souglakos

Cancers 2021, 13(1), 43; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13010043 - 25 Dec 2020

Cited by 16 | Viewed by 3088

Abstract

Over the last few years, immunotherapy has been considered as a key player in the treatment of solid tumors. Immune checkpoint inhibitors (ICIs) have become the breakthrough treatment, with prolonged responses and improved survival results. ICIs use the immune system to defeat cancer by breaking the axes that allow tumors to escape immune surveillance. Innate and adaptive immunity are involved in mechanisms against tumor growth. The gut microbiome and its role in such mechanisms is a relatively new study field. The presence of a high microbial variation in the gut seems to be remarkably important for the efficacy of immunotherapy, interfering with innate immunity. Metabolic and immunity pathways are related with specific gut microbiota composition. Various studies have explored the composition of gut microbiota in correlation with the effectiveness of immunotherapy. Colorectal cancer (CRC) patients have gained little benefit from immunotherapy until now. Only mismatch repair-deficient/microsatellite-unstable tumors seem to respond positively to immunotherapy. However, gut microbiota could be the key to expanding the use of immunotherapy to a greater range of CRC patients. Full article

(This article belongs to the Special Issue Breakthroughs in Cancer-Related Immunotherapy)

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