Table Of Content

Sujata P. Sawarkar Vandana S. Nikam Shariq Syed Editors Immunotherapy – A Novel Facet of Modern Therapeutics Immunotherapy – A Novel Facet of Modern Therapeutics Sujata P. Sawarkar (cid:129) Vandana S. Nikam (cid:129) Shariq Syed Editors Immunotherapy – A Novel Facet of Modern Therapeutics Editors SujataP.Sawarkar VandanaS.Nikam DepartmentofPharmaceutics DepartmentofPharmacology,STES’sSmt. SVKM’sDr.Bhanuben KashibaiNavaleCollegeofPharmacy NanavatiCollegeofPharmacy S.P.PuneUniversity Mumbai,Maharashtra,India Pune,Maharashtra,India ShariqSyed SchoolofPharmacy Anjuman-I-Islam’s,Kalsekar TechnicalCampus Mumbai,Maharashtra,India ISBN978-981-15-9037-5 ISBN978-981-15-9038-2 (eBook) https://doi.org/10.1007/978-981-15-9038-2 #SpringerNatureSingaporePteLtd.2021 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthe materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation, broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology nowknownorhereafterdeveloped. Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublication doesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevant protectivelawsandregulationsandthereforefreeforgeneraluse. The publisher, the authors, and the editorsare safeto assume that the adviceand informationin this bookarebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsor theeditorsgiveawarranty,expressedorimplied,withrespecttothematerialcontainedhereinorforany errorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregardtojurisdictional claimsinpublishedmapsandinstitutionalaffiliations. ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSingaporePteLtd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Contents 1 Immunotherapy:AConcept. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 VritikaKulwalandSujataSawarkar 2 ImmunotherapyinCancer:ImmuneCheckpointInhibitors; ChangingOncologyTreatmentParadigm. . . . . . . . . . . . . . . . . . . . 21 ShariqSyed 3 VaccinesasImmunotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 PratikOgale,VandanaS.Nikam,ManishGautam,SunilGairola, andS.S.Jadhav 4 ImmunotherapyforAutoimmuneDiseases. . . . . . . . . . . . . . . . . . . 63 AniketMali,ApurvaSawant,AnaghaMahadik,andSujitNair 5 ImmunotherapyinNeurodegenerativeDisorders. . . . . . . . . . . . . . 117 DipanjaliKamthe,NetraGosavi,andVandanaS.Nikam 6 CompanionDiagnosticsandClinicalBiomarkersfor Immunotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 VandanaS.Nikam 7 NovelDrugDeliverySystemsforImmunotherapeutics. . . . . . . . . . 153 KrishnaBaxi,MuniraMomin,andSujataSawarkar 8 Discovery,ScreeningMethods,DesignConsiderations, andScale-upAspectsofImmunotherapeuticDrugs. . . . . . . . . . . . 173 PratikshaPalaheandVinalPardhi 9 Pharmacokinetics,Pharmacodynamics,andToxicologyAspects ofImmunotherapeutics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 PreetiKulkarni,ParsshavaMehta,BharatiShriyan,KalpitaGawit, VikramGota,andMinalGhante vv vi Contents 10 RegulatoryAffairsandIntellectualPropertyRightsin Immunotherapeutics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 KedarSuvarnapathaki,SanjayD.Sawant,andInduNambiar 11 FutureImmunotherapyChallengesandPerspectives. . . . . . . . . . . 247 AmritaDate,VandanaS.Nikam,ShariqSyed,andSujataP.Sawarkar About the Editors SujataP.Sawarkar isProfessorandHeadofDepartment,Pharmaceutics,SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, India. Before joining academics Dr. Sujata Sawarkar was associated with major pharmaceutical companies inIndia at managerial position, in the field of Research and Development, formulation development of conventional and novel dosage forms for regulated and domestic market.Severaloralsoliddosageformsandsterileproductsdevelopedbyherteam havereceivedapprovalinUSandEUandhavebeencommercialized.Shehasabout total 22 years of research and teaching experience. Her research interests include Formulation Development of novel drug delivery and targeted systems based on nanotechnologyfororal,ophthalmic,colonicandvaginaldelivery,developmentof evaluation techniques for novel drug delivery systems, Translational research. Dr. Sujata Sawarkar has been Executive Member of Controlled Release Society (India Chapter) since 2014 and Secretary of Controlled Release Society (India Chapter) CRS IC for 2017-2019. She has been invited reviewer for Indian Drugs, AAPS PharmSciTech, International Journal of Nanomedicine Dove Press, Drug Design, Development and Therapy, Journal of Bioequivalence & Bioavailability, EuropeanJournalofPharmaceuticsandBiopharmaceuticsandJournalofCosmetic Dermatology.Dr.SujataSawarkarhasreceivedresearchprojectgrantsworthabout 85 lakhs rupees (8.5 million INR i.e. about 1.19 million USD) from Industry and Governmentfundingagency.Shehaspresentedabout50researchpapersinnational and international conferences like CRS Inc. and AAPS. She has several papers publishedinpeerreviewedjournalslikeAAPSPharmSciTech,InternationalJournal of Pharmaceutics, Critical Reviews in Therapeutic Drug Carrier systems, Drug DevelopmentandTranslationalResearch,FrontiersinPharmacology,ExpertOpin- iononDrugDelivery.Shehascoauthored5bookchaptersandtwobooks.Dr.Sujata Sawarkar has been awarded IDMA award for reviewer, Research and Industry Outcome by SVKM’s Dr. Bhanuben Nanavati College of Pharmacy in 2018 and 2020,ReceivedTravelGrantfromControlledReleaseSocietyandAllIndiaCouncil ofTechnicalEducationforattendingandpresentingpaperat42ndand46thAnnual Meeting&ExpositionoftheControlledReleaseSocietyinJuly2015andJuly2019 respectively.Shehasseveralpaperspublishedinpeer-reviewedjournalslikeAAPS PharmSciTech,InternationalJournalofPharmaceutics.Shehasco-authored2book chaptersandonebook. vviiii viii AbouttheEditors Vandana S. Nikam is presently Associate Professor and Head of Department, Pharmacology, at STES’s Smt. Kashibai Navale College of Pharmacy, S. P. Pune University,India.Beforeherpresentassociation,shewasaPost-DoctoralFellowat Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. Dr. Nikam has pursued her Master’s degree in Molecular Bioengineering from the Technical University of Graz, Austria and a Doctoral degree from School of Medicine,UniversityofGiessen,Giessen,Germany.Dr.Nikam’sresearchinterests and expertise include stem cells, tissue remodeling and regeneration, toxicology, understanding molecular and cellular biology of underlying diseases. She has receivedanhonorariumfromUnitedTherapeutic,NC,USA,Fellowshipawardfor MasterofScienceinMolecularBioeng.(M.Sc.)fromTechnicalUniversityofGraz, Austria and received the scholarship from Afro- Asiatische Institute, Graz, Austria. She has several papers published in peer-reviewed journals like British JournalofPharmacology,EurRespirJ,AAPSPharmSciTech,JProteomeRes,AmJ Respir Cell Mol Biol and Pneumologie. She attended and presented her research work at several international conferences like American Thoracic Society Meeting (ATS)2006,2009,SymposiumoftheAustrianPharmacologicalSociety(APHAR) 2004, European Respiratory Society (ERS) 2006, Austrian Academy of Sciences Proceedings 2008, American Association for Cancer Research (AACR) Annual Meeting,2013. Shariq Syed ispresently Interim Dean and AssociateProfessorat AIKTC School ofPharmacyandAdvisortoBoard,MedleyPharmaceuticals.Earlier,hehasserved as Senior Research Investigator, Bristol Myers-Squibb, USA (2007-2012). At Bristol Myer Squibb, he was part of Ipilimumab drug development team, and has collaboratedwithDr.JamesAllison,immunologistandNobelLaureateoftheyear 2018. At Bristol Myer Squibb, he was responsible for all key aspects of Clinical Pharmacology in Oncology therapeutic area for large and small molecule drugs/ compounds, Co-lead Clinical Pharmacology development of Brivanib®, a novel Kinase inhibitor for Liver cancer and contributed to NDA submission package of Yervoy®, a breakthrough therapy in immune-oncology approved for skin cancer. Dr.Shariq’sresearchinterestandexpertiseincludeClinicalPharmacology,Pharma- cokinetics, understanding drug exposure-response relationship (PK-PD) in early Proof of concept (POC) trials. He has received Pharma Ratan Young Achiever Award for his contribution tothe field of Immuno-oncology and award from Rho-ChiHonorsociety(HonorSocietyinPharmaceuticalSciences).Heisaninvited reviewer of the European Journal of Drug Metabolism and Pharmacokinetics, Current ClinicalPharmacology.He isamember ofAmericanAssociation ofPhar- maceuticalScientists,electedmemberofAmericanCollegeofClinicalPharmacol- ogy, elected Member of American Society of Clinical Pharmacology and Therapeutics,amemberoftheIndianSocietyofClinicalResearch.Hehaspublished severalresearcharticlesinpeer-reviewedinternationaljournals. 1 Immunotherapy: A Concept Vritika Kulwal and Sujata Sawarkar Abstract Immunotherapy has emerged as a promising therapeutic strategy to combat cancer,autoimmunediseasesandinfectiousdiseasesinthelastfewtwodecades. Immunotherapyisatypeoftreatmentwhichinvolvesinduction,enhancement,or suppression of the immune system. This modern approach has changed the paradigm and revolutionized the concept of modern therapeutics. The approach lies on understanding the molecular basis of the disease and making medicine personalized, accurate, and precise. The therapy relies on the host’s immune system and can be broadly categorized as activation or suppression immunotherapies. Health authorities worldwide have accepted and acknowl- edgedthesignificanceofimmunotherapy.Asaresultofthisnumeroustherapeu- ticmoietiesbasedonimmunotherapyhavereceivedregulatoryapprovalandare being used in clinical practice. This chapter discusses a broad overview of the concept and principle of immunotherapy and its utility in a wide plethora of diseases. Keywords Immunotherapy·Adaptive·Activation·Cytokine·Lymphocytes Immunotherapy is a type of treatment which involves induction, enhancement, or suppression of the immune system. Immunotherapy is a therapeutic strategy that targets or manoeuvres subjects/patient’s immune systems (Naran et al. 2018). Immunotherapy aims to utilize the host’s immune system to eradicate diseased cells. In recent times immunotherapy has been envisaged for many diseases that V.Kulwal·S.Sawarkar(*) SVKM’sDr.BhanubenNanavatiCollegeofPharmacy,UniversityofMumbai,Mumbai,India e-mail:[email protected] #SpringerNatureSingaporePteLtd.2021 1 S.P.Sawarkaretal.(eds.),Immunotherapy–ANovelFacetofModernTherapeutics, https://doi.org/10.1007/978-981-15-9038-2_1 2 V.KulwalandS.Sawarkar may or may not be of genetic or of infectious origin. The therapy is broadly categorized into two classes. Immunotherapies that evoke immune response are termedasactivationimmunotherapieswhilethosewhichsuppressimmuneresponse areknownassuppressiveimmunotherapies(Wraith2017).Activationtherapiesare commonly used for diseases like cancer while suppressive immunotherapy is used for autoimmune diseases. Additionally, immunotherapy is also classified based on passive (adaptive, antibody-based) and active (vaccine, specific allergen based) approaches. Passive immunotherapy includes supplementing immune components like antibodies or immune cells to patients. In this approach, the host’s immune response is not invoked whereas in Active immunotherapy, involves triggering immuneresponsewhereinantibodiesareproducedandT-cellsareactivated.Immu- notherapy is now being seen as a promising approach for certain ailments wherein othertherapiesarefailing,howevertheoriginofimmune-basedtherapyiswayback inthenineteenthcentury. 1.1 History and Origin of Immunotherapy Manipulation of the immune system to treat diseases first started when there was developmentofvaccinationstrategyfortheprotectionofhumansagainstsmallpox infection. The idea was to bring subjects in contact with the cowpox virus so that immunity is boosted, as it was observed by the British Lady Montague in Turkey. Dr. Charles Maitland conducted the first trial in immunotherapy in the eighteenth century.ThisconceptwasfurtherundertakenbyEdwardJenner,whodevelopedthe true cowpox vaccine which became the first-ever clinically effective vaccination. Bavaria was the first country in the world where smallpox vaccination was made mandatory by law in the year 1807. Studies in the field of immunology and infectious disease were conducted and observed a growth in the subsequent years but exploring the field of immunotherapy in cancer began in the late nineteenth century. It was more than 135 years ago that two German physicians Buschand Fehleisen independently observed that after infection with erysipelas, there was tumour regression in cancer patients. In 1868, Busch observed tumour shrinkage after intentionally infecting a cancer patient with erysipelas. Further Fehleisen, in 1882,repeatedthisexerciseofinfectingwitherysipelasandalsoidentifiedStrepto- coccuspyogenesastheagentcausingerysipelas.Intheyear1891,WilliamColeyan American surgeon at Memorial Hospital in New York observed Regression of unresectable sarcoma due to erysipelas infection. More than 1000 patients were observedwithregression and cure. Therefore this method gained wide acceptance. Butlateron,theuseoftoxinswasdiscontinuedbecauseofthefailuretofollowgood scientific protocols and inconsistency in results. Also the development of radiation therapy and chemotherapy for cancer, further ledto loss of interest inthis therapy. Laterin1976Moralesetal.provedtheefficacyofthebacteriumBacillusCalmette- Guérin(BCG)intreatingsuperficialbladdercancer.Theclinicaltrialwasconducted on the basis of study conducted by Old et al. in 1959 in which anti-tumour effects wereexhibitedbyBCGinamousemodel.ApartfromtheworkonBCG,Oldalso