Vaccine Therapies for Cancer: Then and Now

Abstract

There are strong biologic and preclinical rationales for the development of therapeutic cancer vaccines; however, the clinical translation of this treatment strategy has been challenging. It is now understood that many previous clinical trials of cancer vaccines used target antigens or vaccine designs that inherently lacked sufficient immunogenicity to induce clinical responses. Despite the historical track record, breakthrough advances in cancer immunobiology and vaccine technologies have supported continued interest in therapeutic cancer vaccinations, with the hope that next-generation vaccine strategies will enable patients with cancer to develop long-lasting anti-tumor immunity. There has been substantial progress identifying antigens and vaccine vectors that lead to strong and broad T cell responses, tailoring vaccine designs to achieve optimal antigen presentation, and finding combination partners employing complementary mechanisms of action (e.g., checkpoint inhibitors) to overcome the diverse methods cancer cells use to evade and suppress the immune system. Results from randomized, phase 3 studies testing therapeutic cancer vaccines based on these advances are eagerly awaited. Here, we summarize the successes and failures in the clinical development of cancer vaccines, address how this historical experience and advances in science and technology have shaped efforts to improve vaccines, and offer a clinical perspective on the future role of vaccine therapies for cancer.

Fig. 1

Diverse therapeutic cancer vaccine platforms have a common mechanism of action [12]. [Figure reproduced from Maeng H et al. F1000Res. 2019 https://doi.org/10.12688/f1000research.18693.1. Licensed under CC BY 4.0.] CD cluster of differentiation, IFN interferon, IL interleukin, IL2Rα IL-2 receptor alpha, MHC major histocompatibility complex, TCR T cell receptor

Fig. 2

Optimal antigen processing and presentation by DCs is important for effective immune-mediated tumor cell destruction [6]. Antigens enter DCs through multiple mechanisms, including endocytosis, phagocytosis, pinocytosis, and receptor-mediated uptake. These antigens are processed by DCs into peptide fragments (epitopes) before being loaded onto MHC class I molecules through cross priming or MHC class II molecules through the classical exogenous presentation pathway. T cell recognition of these epitopes occurs via binding between the TCR and the peptide-MHC complex on the DC. Following epitope recognition, CD40L expressed by CD4+ T cells activates DC-expressed CD40 to promote DC maturation and IL-12 secretion. This subsequently stimulates CD28 signaling and activation of CD8+ T cells. When the TCR of an effector CD8+ T cell binds to a tumor cell, an immunological synapse forms and lytic granules are secreted by the effector CD8+ T cell, resulting in tumor cell destruction. Note: Cytosolic and vacuolar pathways for cross-presentation have been described. The figure presents the cytosolic pathway as it has been suggested this is the predominant pathway for cross-presentation [78]. [Figure adapted with permission of the Journal of Clinical Investigation, from “Therapeutic Cancer Vaccines,” Cornelis J.M. Melief et al, Volume 125, Issue 9, 2015; permission conveyed through Copyright Clearance Center, Inc.] CD cluster of differentiation, CLIP class II-associated invariant chain peptide, DC dendritic cell, ER endoplasmic reticulum, FasL Fas ligand, IL interleukin, MHC major histocompatibility complex, SLP synthetic long peptide, TAP transporter of antigen processing, TCR T cell receptor, TNF tumor necrosis factor, TRAIL TNF-related apoptosis-inducing ligand