Personalized Cancer Vaccines: Clinical Landscape, Challenges, and Opportunities
2020; Elsevier BV; Volume: 29; Issue: 2 Linguagem: Inglês
10.1016/j.ymthe.2020.09.038
ISSN1525-0024
AutoresColby S. Shemesh, Joy Hsu, Iraj Hosseini, Ben‐Quan Shen, Anand Rotte, Patrick Twomey, Sandhya Girish, Benjamin Wu,
Tópico(s)Cancer Immunotherapy and Biomarkers
ResumoTremendous innovation is underway among a rapidly expanding repertoire of promising personalized immune-based treatments. Therapeutic cancer vaccines (TCVs) are attractive systemic immunotherapies that activate and expand antigen-specific CD8+ and CD4+ T cells to enhance anti-tumor immunity. Our review highlights key issues impacting TCVs in clinical practice and reports on progress in development. We review the mechanism of action, immune-monitoring, dosing strategies, combinations, obstacles, and regulation of cancer vaccines. Most trials of personalized TCVs are ongoing and represent diverse platforms with predominantly early investigations of mRNA, DNA, or peptide-based targeting strategies against neoantigens in solid tumors, with many in combination immunotherapies. Multiple delivery systems, routes of administration, and dosing strategies are used. Intravenous or intramuscular administration is common, including delivery by lipid nanoparticles. Absorption and biodistribution impact antigen uptake, expression, and presentation, affecting the strength, speed, and duration of immune response. The emerging trials illustrate the complexity of developing this class of innovative immunotherapies. Methodical testing of the multiple potential factors influencing immune responses, as well as refined quantitative methodologies to facilitate optimal dosing strategies, could help resolve uncertainty of therapeutic approaches. To increase the likelihood of success in bringing these medicines to patients, several unique development challenges must be overcome. Tremendous innovation is underway among a rapidly expanding repertoire of promising personalized immune-based treatments. Therapeutic cancer vaccines (TCVs) are attractive systemic immunotherapies that activate and expand antigen-specific CD8+ and CD4+ T cells to enhance anti-tumor immunity. Our review highlights key issues impacting TCVs in clinical practice and reports on progress in development. We review the mechanism of action, immune-monitoring, dosing strategies, combinations, obstacles, and regulation of cancer vaccines. Most trials of personalized TCVs are ongoing and represent diverse platforms with predominantly early investigations of mRNA, DNA, or peptide-based targeting strategies against neoantigens in solid tumors, with many in combination immunotherapies. Multiple delivery systems, routes of administration, and dosing strategies are used. Intravenous or intramuscular administration is common, including delivery by lipid nanoparticles. Absorption and biodistribution impact antigen uptake, expression, and presentation, affecting the strength, speed, and duration of immune response. The emerging trials illustrate the complexity of developing this class of innovative immunotherapies. Methodical testing of the multiple potential factors influencing immune responses, as well as refined quantitative methodologies to facilitate optimal dosing strategies, could help resolve uncertainty of therapeutic approaches. To increase the likelihood of success in bringing these medicines to patients, several unique development challenges must be overcome. Therapeutic cancer vaccines (TCVs) have been heavily investigated in clinical trials for the past 50 years as investigational immunotherapies that aim to elicit new, or strengthen existing, CD8+ cytotoxic T cell lymphocyte (CTL) tumor antigen-specific responses.1Finn O.J. The dawn of vaccines for cancer prevention.Nat. Rev. Immunol. 2018; 18: 183-194Crossref PubMed Scopus (95) Google Scholar,2Falzone L. Salomone S. Libra M. Evolution of cancer pharmacological treatments at the turn of the third millennium.Front. Pharmacol. 2018; 9: 1300Crossref PubMed Scopus (243) Google Scholar As TCVs target antigens predominantly associated with tumor cells, this approach can be safer than other therapies by avoiding off-target effects. TCVs have evolved as a promising class of drugs in the immuno-oncology space, and they comprise a diverse set of antigens, adjuvants, delivery vectors, and administration methods.3Lopes A. Vandermeulen G. Préat V. Cancer DNA vaccines: current preclinical and clinical developments and future perspectives.J. Exp. Clin. Cancer Res. 2019; 38: 146Crossref PubMed Scopus (108) Google Scholar Historically, hundreds of TCV clinical trials including dozens of pivotal investigations were largely unsuccessful in demonstrating a clear clinical benefit.4Rahma O.E. Gammoh E. Simon R.M. Khleif S.N. Is the "3+3" dose-escalation phase I clinical trial design suitable for therapeutic cancer vaccine development? A recommendation for alternative design.Clin. 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Immunopathol. 2019; 41: 69-85Crossref PubMed Scopus (28) Google Scholar Renewed investment and innovation are now underway, among a rapidly expanding repertoire of advanced TCV platforms. Among recent advances are personalized neoantigen-based TCVs with selective individualized antigens and new combination approaches to enhance immune activities compared to conventional TCVs against shared antigens.8Wirth T.C. Kühnel F. Neoantigen Targeting—dawn of a new era in cancer immunotherapy?.Front. Immunol. 2017; 8: 1848Crossref PubMed Scopus (50) Google Scholar, 9Zhang X. Sharma P.K. Peter Goedegebuure S. Gillanders W.E. Personalized cancer vaccines: targeting the cancer mutanome.Vaccine. 2017; 35: 1094-1100Crossref PubMed Scopus (43) Google Scholar, 10Sahin U. Türeci Ö. Personalized vaccines for cancer immunotherapy.Science. 2018; 359: 1355-1360Crossref PubMed Scopus (343) Google Scholar Given that neoantigen load has been correlated with response to existing immunotherapies,11Desrichard A. 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Our review aims to provide a detailed account of the key components and common mechanisms of action of TCVs, while focusing on personalized TCVs, including (1) assessing the current clinical trial landscapes, (2) summarizing vaccination strategies, combination immunotherapies, common obstacles in development, and the regulatory framework of personalized TCVs, and, lastly, (3) by providing insight into additional development aspects important for the clinical development of personalized TCVs. Many of the mechanisms of action and biology relevant for TCVs also apply to personalized TCVs. To successfully induce anti-tumor T cell responses in the human body, TCVs act on and exploit multiple aspects of cancer immunity, including cancer antigen presentation, T cell priming and activation, recognition of cancer cells by T cells, and several effector mechanisms to eliminate tumor cells.14Chen D.S. Mellman I. 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Academic Press, 2018Google Scholar To induce adaptive CTL-mediated anti-tumor responses, TCVs must assist in (1) presentation and recognition of immunogenic tumor antigens by antigen-presenting cells (APCs); (2) recruitment, antigen processing, and maturation of APCs; (3) induced expression of T cell costimulatory signals and cytokines by APCs; (4) interaction of APCs with the adaptive immune system to prime and activate CD8+ T cells; and, lastly, (5) localization of these elements to the tumor.16Song Q. Zhang C.D. Wu X.H. Therapeutic cancer vaccines: from initial findings to prospects.Immunol. Lett. 2018; 196: 11-21Crossref PubMed Scopus (36) Google Scholar, 17Coventry B.J. Therapeutic vaccination immunomodulation: forming the basis of all cancer immunotherapy.Ther. Adv. Vaccines Immunother. 2019; 7 (2515135519862234)PubMed Google Scholar, 18Zhang J. Shi Z. Xu X. Yu Z. Mi J. The influence of microenvironment on tumor immunotherapy.FEBS J. 2019; 286: 4160-4175Crossref PubMed Scopus (35) Google Scholar A schematic of common TCV immune mechanisms to induce human anti-tumor T cell responses is provided in Figure 1. Through these processes TCVs can generate long-lasting immunological memory capable of controlling tumor growth and inhibiting relapse and metastasis. In preclinical studies, it has been shown that long-lived memory T cell responses regenerate effector T cells to eliminate tumor cells.19Romero P. Banchereau J. Bhardwaj N. Cockett M. Disis M.L. Dranoff G. Gilboa E. Hammond S.A. Hershberg R. Korman A.J. et al.The human vaccines project: a roadmap for cancer vaccine development.Sci. Transl. 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Additionally, optimization and expansion of manufacturing capacity is underway with the goal of supporting more widespread use of personalized TCVs.54Hundal J. Miller C.A. Griffith M. Griffith O.L. Walker J. Kiwala S. Graubert A. McMichael J. Coffman A. Mardis E.R. Cancer immunogenomics: computational neoantigen identification and vaccine design.Cold Spring Harb. Symp. Quant. Biol. 2016; 81: 105-111Crossref PubMed Scopus (13) Google Scholar,55Bräunlein E. Krackhardt A.M. Identification and characterization of neoantigens as well as respective immune responses in cancer patients.Front. Immunol. 2017; 8: 1702Crossref PubMed Scopus (29) Google Scholar Many personalized TCVs have entered this space with accelerated development plans, despite considerable investment risk and uncertainty regarding the best platform given the many unproven methodologies among diverse algorithms for neoantigen prediction. Additional questions remain around optimal delivery, dosing, and identifying the best therapeutic setting.56Guo Y. Lei K. Tang L. Neoantigen vaccine delivery for personalized anticance
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