Massari F.

Mollica V.

Rizzo A.

Santoni M.

English

Archivio istituzionale della ricerca - Alma Mater Studiorum Università di Bologna

Journal ofClinical MedicineEditorialCancer Immunotherapy: Current and Future Perspectives on aTherapeutic RevolutionAlessandro Rizzo 1,* , Veronica Mollica 1, Matteo Santoni 2 and Francesco Massari 1Citation: Rizzo, A.; Mollica, V.;Santoni, M.; Massari, F. CancerImmunotherapy: Current and FuturePerspectives on a TherapeuticRevolution. J. Clin. Med. 2021, 10,5246. https://doi.org/10.3390/jcm10225246Received: 31 October 2021Accepted: 10 November 2021Published: 11 November 2021Publisher’s Note: MDPI stays neutralwith regard to jurisdictional claims inpublished maps and institutional affil-iations.Copyright: © 2021 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).1 Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni-15,40121 Bologna, Italy; veronica.mollica7@gmail.com (V.M.); fmassari79@gmail.com (F.M.)2 Medical Oncology Unit, Macerata General Hospital, 62100 Macerata, Italy; mattymo@alice.it* Correspondence: Rizzo.alessandro179@gmail.comThe advent of immunotherapy has revolutionized the treatment landscape of severalhematological and solid tumors [1,2], and the number of patients eligible for immune-based cancer therapies continues to rise as these treatments are currently part of the first-or later-line standards for many malignancies [3–5]. Over the past decade, an impressivenumber of trials have been conducted on the role of immune checkpoint inhibitors, withthe results of these studies paving the way towards the Immunotherapy Era in cancercare [6,7]. The first immune checkpoint inhibitor approved by the United States Foodand Drug Administration (FDA) was ipilimumab, approved in 2011 for the treatment ofadvanced melanoma, following the results of the pivotal phase III trial conducted by Hodiand colleagues [8,9]. More than ten years after the publication of this study, there is aplethora of ongoing trials aiming to evaluate the efficacy and safety of immune checkpointinhibitors, as a monotherapy or in combination with other anticancer agents [10,11]; thus,the number of cancer patients receiving immunotherapy is expected to further increase inthe near future, especially considering that a wide range of combination therapies is beingexplored, with the aim of producing a synergistic effect [12,13].For example, the treatment scenario of metastatic renal cell carcinoma (mRCC) hasrecently undergone a revolution following the results of landmark phase III clinical trialson immune checkpoint inhibitor–tyrosine kinase inhibitor combinations [14,15], such aspembrolizumab plus axitinib, nivolumab plus cabozantinib, pembrolizumab plus lenva-tinib [16,17], as well as dual checkpoint bloackade with nivolumab plus ipilimumabin intermediate–poor-risk patients [18,19]. These treatments currently represent novelstandards of treatment, as is recommended by the most up-to-date international guide-lines [20,21].However, several important issues have yet to be addressed in cancer immunotherapy.Among these, the efficacy of immune checkpoint inhibitors is considerably limited in some“immunologically cold” tumors (pancreatic adenocarcinoma, prostate cancer, biliary tractcancer, etc.), in which immunotherapy is still trying to find its therapeutic niche [22–25].Moreover, and among the main challenges, the lack of predictive biomarkers that are ableto guide therapeutic choices in several malignancies represents another important unmetneed in this setting [26–28]. Several potentially useful predictors have been evaluated andare under assessment including, among others, PD-L1 expression, TMB, MSI, TILs and thegut microbiome [29–31].This Special Issue aims to highlight key open questions and future perspectives in mod-ern cancer immunotherapy, including novel immune checkpoint inhibitors and immune-based combinations, mechanisms of action (Figure 1), potential biomarkers predictive ofresponse, experimental treatments, and other timely and emergent topics. Internationalexperts in this field will examine key approaches that are under active investigation inclinical and preclinical research, presenting critical analyses and integrating their ownperspectives on promising drugs in clinical trials and the latest therapeutic strategies.J. Clin. Med. 2021, 10, 5246. https://doi.org/10.3390/jcm10225246 https://www.mdpi.com/journal/jcmJ. Clin. Med. 2021, 10, 5246 2 of 3J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 3   in clinical and preclinical research, presenting critical analyses and integrating their own perspectives on promising drugs in clinical trials and the latest therapeutic strategies.  Figure 1. Schematic figure representing the mechanism of action of immune checkpoint inhibitors: (A) Immune checkpoint inhibits T-cell activation; (B) PD-1 inhibitors lead to T-cell activation. Author Contributions: Conceptualization, all authors; methodology, all authors; software, all au-thors; validation, all authors; formal analysis, all authors; investigation, all authors; resources, all authors; data curation, all authors; writing—original draft preparation, all authors; writing—review and editing, all authors; visualization, all authors; supervision, all authors; project administration, all authors; funding acquisition, all authors. All authors have read and agreed to the published ver-sion of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not Applicable. Informed Consent Statement: Not Applicable. Data Availability Statement: Not Applicable. Conflicts of Interest: The authors declare no conflicts of interest. References 1. Reck, M.; Rodríguez–Abreu, D.; Robinson, A.G.; Hui, R.; Csőszi, T.; Fülöp, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J. Clin. Oncol. 2019, 37, 537–546. https://doi.org/10.1200/jco.18.00149. 2. Powles, T.; Walker, J.; Williams, J.A.; Bellmunt, J. The evolving role of PD-L1 testing in patients with metastatic urothelial car-cinoma. Cancer Treat. Rev. 2020, 82, 101925. https://doi.org/10.1016/j.ctrv.2019.101925. 3. Massari, F.; Rizzo, A.; Mollica, V.; Rosellini, M.; Marchetti, A.; Ardizzoni, A.; Santoni, M. Immune-based combinations for the treatment of metastatic renal cell carcinoma: A meta-analysis of randomised clinical trials. Eur. J. Cancer 2021, 154, 120–127. https://doi.org/10.1016/j.ejca.2021.06.015. 4. Motzer, R.J.; Tannir, N.M.; McDermott, D.F.; Frontera, O.A.; Melichar, B.; Choueiri, T.K.; Plimack, E.R.; Barthélémy, P.; Porta, C.; George, S.; et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2018, 378, 1277–1290. https://doi.org/10.1056/nejmoa1712126. 5. Lemery, S.; Keegan, P.; Pazdur, R. First FDA Approval Agnostic of Cancer Site—When a Biomarker Defines the Indication. N. Engl. J. Med. 2017, 377, 1409–1412. https://doi.org/10.1056/nejmp1709968. 6. de Miguel, M.; Calvo, E. Clinical Challenges of Immune Checkpoint Inhibitors. Cancer Cell 2020, 38, 326–333. 7. Yang, Y. Cancer immunotherapy: Harnessing the immune system to battle cancer. J. Clin. Investig. 2015, 125, 3335–3337. https://doi.org/10.1172/jci83871. 8. Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N. Engl. J. Med. 2010, 363, 711–723. https://doi.org/10.1056/nejmoa1003466. 9. Hwu, P. Treating cancer by targeting the immune system. N. Engl. J. Med. 2010, 363, 779–781. https://doi.org/10.1056/NEJMe1006416. Figure 1. Sche atic figure representing the mechanism of action of i mune checkpoint inhibitors: (A) Immune checkpointinhibits T-cell activation; (B) PD-1 inhibitors lead to T-cell activation.Author Contributions: Conceptualization, al authors; et l , al authors; soft are, al au-thors; validation, al authors; for al analysis, al authors; investigation, al authors; resources, allauthors; data curation, al authors; riting original draft preparation, al authors; riting reviewand editing, all authors; visualization, all authors; upervision, all uthors; project administration, allauthors; fundi g acquisition, all authors. All authors have read an greed to the published v rsionof the manuscript.Funding: This research received no external funding.Institutional Review Board Statement: Not ap licable.Infor ed Consent Statement: ot applicable.Data Availability Statement: Not applicable.Conflicts of Interest: The authors declare no conflict of interest.References1. Reck, M.; Rodríguez–Abreu, D.; Robinson, A.G.; Hui, R.; Cső zi, T.; Fülöp, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; et al.Updated Analysis of KEYNOTE-024: Pembrolizumab Versu Platinum-Based Chemotherapy for Advanced Non–Small-CellLung Cancer With PD-L1 Tumor Prop tion Sc re f 50% Greater. J. Clin. Oncol. 2019, 37, 537–546. [CrossRef]2. Powles, T.; Walker, J.; Williams, J.A.; Bellmunt, J. The evolving role of PD-L1 testing in patients with metastatic urothelialcarcinoma. Cancer Treat. Rev. 2020, 82, 101925. [CrossRef] [PubMed]3. Massari, F.; Rizzo, A.; Mollica, V.; Rosellini, M.; Marchetti, A.; Ardizzoni, A.; Santoni, M. Immune-based combinations for thetre tment of metastatic renal cell carcinoma: A meta-analysis of rand mised cli ical trials. Eur. J. Cancer 2021, 154, 120–127.[CrossRef]4. Motzer, R.J ; Tannir, N.M.; McDermott, D.F.; Frontera, O.A.; Melichar, B.; Choueiri, T.K.; Plimack, E.R.; Barthélémy, P.; Porta, C.;Ge rg , S.; et al. N volumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2018, 378,1277–1290. [CrossRef]5. Lemery, S.; Keegan, P.; Pazdur, R First FDA Approval Agnostic of Cancer Site—When a Biomarker Defines the Indication.N. Engl. J. Med. 2017, 377, 1409–1412. [CrossRef]6. De Miguel, M.; Calvo, E. Clinical C allenges of Immune Ch ck oint Inhibitors. Cancer Cell 2020, 38, 326–333. [CrossRef]7. Yang, Y. Cancer immunotherapy: Harnessing the i system t battle cancer. J. Clin. Investig. 2015, 1 5, 5–3337. [CrossRef]8. Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.;Hassel, J.C.; et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N. Engl. J. Med. 2010, 363, 711–723.[CrossRef] [PubMed]9. Hwu, P. Treating cancer by targeting the mmune system. N. Engl. J. Med. 2010, 363, 779–781. [CrossRef] [PubMed]10. Hunter, K.A.; Socinski, M.A.; Villaruz, L.C. PD-L1 Testing in Guiding Patient Selection for PD-1/PD-L1 Inhibitor Therapy inLung Cancer. Mol. Diagn. Ther. 2018, 22, 1–10. [CrossR f]11. Yarchoan, M.; Hopkins, A.; Jaffee, E.M. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N. Engl. J. Med. 2017,377, 2500–2501. [CrossRef] [PubMed]12. Bergerot, P.; Lamb, P.; Wang, E.; Pal, S.K. Cabozantinib in Combination with Immunotherapy for Advanced Renal Cell Carcinomaand Urothelial Carcinoma: Rationale and Clinical Evidence. Mol. Cancer Ther. 2019, 18, 2185–2193. [CrossRef] [PubMed]J. Clin. Med. 2021, 10, 5246 3 of 313. Cheng, A.-L.; Hsu, C.; Chan, S.L.; Choo, S.-P.; Kudo, M. Challenges of combination therapy with immune checkpoint inhibitorsfor hepatocellular carcinoma. J. Hepatol. 2020, 72, 307–319. [CrossRef] [PubMed]14. Motzer, R.J.; Rini, B.I.; McDermott, D.F.; Frontera, O.A.; Hammers, H.J.; Carducci, M.A.; Salman, P.; Escudier, B.; Beuselinck, B.;Amin, A.; et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: Extendedfollow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019, 20, 1370–1385. [CrossRef]15. Rini, B.I.; Plimack, E.R.; Stus, V.; Gafanov, R.; Hawkins, R.; Nosov, D.; Pouliot, F.; Alekseev, B.; Soulières, D.; Melichar, B.; et al.Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 2019, 380, 1116–1127.[CrossRef]16. Massari, F.; Mollica, V.; Rizzo, A.; Cosmai, L.; Rizzo, M.; Porta, C. Safety evaluation of immune-based combinations in patientswith advanced renal cell carcinoma: A systematic review and meta-analysis. Expert Opin. Drug Saf. 2020, 19, 1329–1338.[CrossRef]17. Sheng, I.Y.; Rini, B.I. Immunotherapy for renal cell carcinoma. Expert Opin. Biol. Ther. 2019, 19, 897–905. [CrossRef] [PubMed]18. Dizman, N.; Arslan, Z.E.; Feng, M.; Pal, S.K. Sequencing Therapies for Metastatic Renal Cell Carcinoma. Urol. Clin. N. Am. 2020,47, 305–318. [CrossRef]19. Gao, X.; McDermott, D.F. Ipilimumab in combination with nivolumab for the treatment of renal cell carcinoma. Expert Opin. Biol.Ther. 2018, 18, 947–957. [CrossRef]20. Powles, T.; ESMO Guidelines Committee. Electronic address: Clinicalguidelines@esmo.org. Recent eUpdate to the ESMOClinical Practice Guidelines on renal cell carcinoma on cabozantinib and nivolumab for first-line clear cell renal cancer: Renal cellcarcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2021, 32, 422–423.21. Thana, M.; Wood, L.A. What Do International Guidelines Say About First-line Therapy for Clear-cell Metastatic Renal CellCarcinoma? Eur. Urol. Focus 2020, 6, 48–52. [CrossRef] [PubMed]22. Piha-Paul, S.A.; Oh, D.; Ueno, M.; Malka, D.; Chung, H.C.; Nagrial, A.; Kelley, R.K.; Ros, W.; Italiano, A.; Nakagawa, K.; et al.Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE -158 andKEYNOTE-028 studies. Int. J. Cancer 2020, 147, 2190–2198. [CrossRef] [PubMed]23. Rizzo, A.; Mollica, V.; Cimadamore, A.; Santoni, M.; Scarpelli, M.; Giunchi, F.; Cheng, L.; Lopez-Beltran, A.; Fiorentino, M.;Montironi, R.; et al. Is There a Role for Immunotherapy in Prostate Cancer? Cells 2020, 9, 2051. [CrossRef]24. Sunami, Y.; Kleeff, J. Immunotherapy of pancreatic cancer. Prog. Mol. Biol. Transl. Sci. 2019, 164, 189–216. [PubMed]25. Santoni, M.; Conti, A.; Piva, F.; Massari, F.; Ciccarese, C.; Burattini, L.; Cheng, L.; Lopez-Beltran, A.; Scarpelli, M.; Santini, D.; et al.Role of STAT3 pathway in genitourinary tumors. Futur. Sci. OA 2015, 1, FSO15. [CrossRef]26. McNamara, M.G.; Jacobs, T.; Lamarca, A.; Hubner, R.A.; Valle, J.W.; Amir, E. Impact of high tumor mutational burden in solidtumors and challenges for biomarker application. Cancer Treat. Rev. 2020, 89. [CrossRef]27. Goodman, A.M.; Kato, S.; Bazhenova, L.; Patel, S.P.; Frampton, G.M.; Miller, V.; Stephens, P.J.; Daniels, G.A.; Kurzrock, R. TumorMutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. Mol. Cancer 2017, 16,2598–2608. [CrossRef] [PubMed]28. Wang, Z.; Duan, J.; Cai, S.; Han, M.; Dong, H.; Zhao, J.; Zhu, B.; Wang, S.; Zhuo, M.; Sun, J.; et al. Assessment of Blood TumorMutational Burden as a Potential Biomarker for Immunotherapy in Patients With Non–Small Cell Lung Cancer With Use of aNext-Generation Sequencing Cancer Gene Panel. JAMA Oncol. 2019, 5, 696–702. [CrossRef]29. Rizzo, A.; Mollica, V.; Massari, F. Expression of Programmed Cell Death Ligand 1 as a Predictive Biomarker in MetastaticUrothelial Carcinoma Patients Treated with First-line Immune Checkpoint Inhibitors Versus Chemotherapy: A Systematic Reviewand Meta-analysis. Eur. Urol. Focus 2021. [CrossRef]30. Chalmers, Z.R.; Connelly, C.F.; Fabrizio, D.; Gay, L.; Ali, S.M.; Ennis, R.; Schrock, A.; Campbell, B.; Shlien, A.; Chmielecki, J.; et al.Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017, 9, 1–14.[CrossRef]31. Santoni, M.; Bracarda, S.; Nabissi, M.; Massari, F.; Conti, A.; Bria, E.; Tortora, G.; Santoni, G.; Cascinu, S. CXC and CC chem-okinesas angiogenic modulators in nonhaematological tumors. Biomed. Res. Int. 2014, 2014, 768758. [CrossRef] [PubMed]

Cancer immunotherapy: Current and future perspectives on a therapeutic revolution

https://cris.unibo.it/bitstream/11585/908781/1/J%20Clin%20Med%202021%20%5bEdit%20Ale%5d%20.pdf

Cancer immunotherapy: Current and future perspectives on a therapeutic revolution

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Archivio istituzionale della ricerca - Alma Mater Studiorum Università di Bologna