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      Immunotherapy and Its Development for Gynecological (Ovarian, Endometrial and Cervical) Tumors: From Immune Checkpoint Inhibitors to Chimeric Antigen Receptor (CAR)-T Cell Therapy

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          Gynecological cancers represent a group of malignancies with high incidence and mortality, despite their relative sensitivity to platinum-based chemotherapy. This review aims to illustrate the state of research in the field of immunotherapy, and in particular, deals with the development of CAR-T cell therapy, which represents a very promising treatment in the hematological field, but is still taking its first tentative steps in solid tumors.

          Abstract

          Gynecological tumors are malignancies with both high morbidity and mortality. To date, only a few chemotherapeutic agents have shown efficacy against these cancer types (only ovarian cancer responds to several agents, especially platinum-based combinations). Within this context, the discovery of immune checkpoint inhibitors has led to numerous clinical studies being carried out that have also demonstrated their activity in these cancer types. More recently, following the development of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, this strategy was also tested in solid tumors, including gynecological cancers. In this article, we focus on the molecular basis of gynecological tumors that makes them potential candidates for immunotherapy. We also provide an overview of the main immunotherapy studies divided by tumor type and report on CAR technology and the studies currently underway in the area of gynecological malignancies.

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          Most cited references110

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          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

          This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.
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            Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.

            Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti-PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti-PD-1 therapy. Copyright © 2015, American Association for the Advancement of Science.
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              Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

              The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                17 February 2021
                February 2021
                : 13
                : 4
                : 840
                Affiliations
                [1 ]Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Via P. Maroncelli 40, 47014 Meldola, Italy; chiara.casadei@ 123456irst.emr.it (C.C.); marialaura.iaia@ 123456irst.emr.it (M.L.I.); alberto.farolfi@ 123456irst.emr.it (A.F.); vincenza.conteduca@ 123456irst.emr.it (V.C.); cristian.lolli@ 123456irst.emr.it (C.L.); nicole.brighi@ 123456irst.emr.it (N.B.); amelia.altavilla@ 123456irst.emr.it (A.A.); giovanni.martinelli@ 123456irst.emr.it (G.M.); ugo.degiorgi@ 123456irst.emr.it (U.D.G.)
                [2 ]Clinical Oncology, Arcispedale Sant’Anna University Hospital, 44124 Ferrara, Italy; itoma.mf@ 123456ausl.fe.it
                [3 ]Istituto Dermopatico dell’Immacolata, IDI IRCCS, 00167 Rome, Italy; g.poti@ 123456idi.it
                [4 ]Medical Oncology Unit 1, University of Genoa, Ospedale Policlinico San Martino IRCCS, 16132 Genoa, Italy
                [5 ]Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Via P. Maroncelli 40, 47014 Meldola, Italy; giorgia.ravaglia@ 123456irst.emr.it
                Author notes
                Author information
                https://orcid.org/0000-0002-9973-4869
                https://orcid.org/0000-0002-3289-8041
                https://orcid.org/0000-0002-6921-714X
                https://orcid.org/0000-0002-1025-4210
                https://orcid.org/0000-0001-7520-2908
                Article
                cancers-13-00840
                10.3390/cancers13040840
                7922040
                33671294
                83abbd38-1919-4926-a23a-e8d89bbc1e48
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 January 2021
                : 14 February 2021
                Categories
                Review

                chimeric antigen receptor (car)-t cell therapy,lymphocytes,immunotherapy,ovarian cancer,endometrial cancer,cervical cancer

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