Personalized Cancer Vaccines: Clinical Landscape, Challenges, and Opportunities
Authors: Colby S. Shemesh, Joy C. Hsu, Iraj Hosseini, Ben-Quan Shen, Anand Rotte, Patrick Twomey, Sandhya Girish, Benjamin Wu
Journal: Molecular Therapy (2020)

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. 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. 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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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