Cancer Vaccines

Learning from history:
Cancer vaccines and the immunogenicity problem

Immunotherapeutic cancer vaccines have generated a lot of interest from oncologists since it was discovered that immune activation can lead to a specific antitumor response.1 However, despite initial progress, most cancer vaccines have failed to drive sufficient tumor immunogenicity, leading to poor clinical responses.1 The reason for this may be that previous vaccine models used inadequate vaccine designs and/or target antigens.1

Defining vaccines:

Immunotherapeutic cancer vaccine: Creates a specific antitumor response against existing disease manifestations.1

Classic vaccination: Inoculates a patient against future disease manifestations, generally for external pathogens.2

Driving antitumor immune stimulation

The goal of sustained, tumor immunotherapeutic responses is common to all cancer vaccine designs.1 Peptide-based vaccines aim to accomplish this by presenting tumor-specific proteins (also referred to as antigens) to the host immune system.1 When successful, this enables the body to recognize tumor cells as harmful and attack them.1

However, most studies in peptide vaccines have not demonstrated a clinical benefit.1 This inability to drive durable antitumor immunity may be due to three factors: the need for adjuvant immune stimulation, failure to segment patients based on human leukocyte antigen (HLA) haplotype, and poor antigen selection.1

Optimizing immunostimulation

A hallmark of cancer’s immune system evasion is the ability to depress dendritic cell (DC) function.1 At the same time, effective cancer vaccines often rely on antigen presentation by DCs.1 Thus, inhibition of antigen presentation by DCs makes cancer vaccine efficacy, and peptide cancer vaccine efficacy in particular, difficult to achieve.1 Therefore, therapeutic strategies for improved cancer vaccine efficacy may benefit from initial DC stimulation to drive tumor-directed immune responses.1

HLA haplotype patient segmenting

HLA haplotypes are genetically determined combinations of HLA complexes that ensure immune systems recognize oncogenic peptides as foreign.3,4 Peptide-based vaccines are considered HLA restricted, which means they can only be administered to those patients with HLA haplotypes that help the immune system recognize and respond to the presented antigen.1,4 Therefore, understanding the relationship between cancer vaccine design and HLA haplotype may help ensure appropriate antitumor immune activity.1,5,6

Antigen selection and why WT1 is a viable candidate

Another key factor that may boost peptide-based vaccine immune responses is selecting appropriate antigens, like Wilms’ Tumor 1 (WT1).1,7,8

The WT1 protein has been observed in various types of hematologic malignancies and solid tumors, including glioblastoma multiforme, while being functionally absent in most normal tissues.9-14 WT1 also demonstrates oncogenic potential by enabling tumor invasion, metastases, and treatment resistance.12,15,16

While this reveals WT1 as an attractive pathway for therapy, what makes WT1 of special interest to immunotherapy is its capacity to affect diverse immune responses. WT1 has multiple immunogenic epitopes capable of eliciting both cytotoxic and helper T lymphocyte tumor-directed responses.17,18

Achieving cancer vaccine immunotherapy

Combining immunostimulation with HLA haplotype patient segmenting and the selection of WT1 as a tumor antigen may be a rational strategy to increase tumor-specific immunotherapeutic responses for peptide-based cancer vaccines.1,7,8

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