Personalized Cancer Vaccines: Clinical Landscape, Challenges, and Opportunities

Abstract

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.

Keywords: adjuvant; cancer immunotherapy; clinical pharmacology; clinical trials; drug development; personalized therapeutic cancer vaccine; tumor neoantigen.

Graphical abstract

Figure 1

Immune Mechanisms That Underlie Tumor Immunity to Successfully Induce Anti-tumor T Cell Responses in the Human Body Therapeutic cancer vaccines (TCVs) aim to generate potent immune responses by presentation of antigens to dendritic cells that traffic through the lymphatics and present cancer antigens to naive T cells. Activated cytotoxic T lymphocytes proliferate, multiply, and traffic throughout the body, and they can provide long-lasting immunologic memory. (A) TCV action and combination immunotherapy impacts on specific components of the cancer immunity cycle. (B) T cell activation, effector function, and immunological memory specific to TCV therapy. Adapted with permission from presentation by Chen and Mellman and Song et al.

Figure 2

Clinical Trial Landscape for Personalized TCVs (A–K) Twenty-three personalized TCVs currently in phase 1 or 2 from 13 major sponsors: (A) trials per sponsor; (B) type of vaccine; (C) phase of trial; (D) number of antigens; (E) indication; (F) combination partner; (G) route of administration; (H) delivery system; (I) vaccine administration frequency; (J) vaccine doses per year; and (K) number of vaccine dose levels tested.

Figure 3

Complexity of Dosing Strategy and Dose-Response for a Personalized Neoantigen-Based TCV Favorable absorption and distribution of antigen-encoder/antigen to lymphoid organs are precursors to enable successful immune activation, anti-tumor CTL activity, and effective tumor killing. After neoantigen encoding mRNA is packaged into nanocarriers and infused (steps 1 and 2), mRNA and carrier component concentrations are measured in systemic circulation, which may relate to uptake by lymphoid organs for processing of neoantigens (steps 3 and 4). After processing of neoantigens, immune monitoring of antigen-specific T cell responses is evaluated (step 5); however, due to heterogeneity in dose-response relationships across multiple antigens or epitopes in a personalized TCV (steps 6 and 7), it can be difficult to determine specific associations between various personalized TCV components and any resulting clinical response (step 8). Illustrated findings are hypothetical and do not represent actual clinical trial data. CR, complete response; D, dose level; ELISPOT, enzyme-linked immunospot assay; LNK, linker; MHC, major histocompatibility complex; Neo, neoantigen; PD, pharmacodynamics; PK, pharmacokinetics; PR, partial response; SD, stable disease; UTR, untranslated region.

Figure 4

Immune Cells in PBMCs Acquired from Patients Detect and Inform on Antigen-Specific T Lymphocyte Response ELISPOT identifies CD8⁺ T cell responses to a given antigen after PBMCs are treated with an antigen of interest and stimulated ex vivo, leading to CD8⁺ T cell activation in response to a tumor-specific antigen and secretion of IFN-γ captured on an immobilized surface as insoluble spots that are enumerated. Tetramer analysis using MHC multimers loaded with antigen peptides detects T cells specific to a particular peptide-MHC complex in response to a TCV. Immune-monitoring relationships in response to TCVs may be used to help inform clinical decisions. Adapted from presentation by Caushi and Smith.