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
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
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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- Morse MA, Gwin WR, Mitchell DA. Vaccine therapies for cancer: then and now. Target Oncol. 2021;16(2):121-152.
- Ginglen JG, Doyle MQ. Immunization. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing: 2021.
- Comber JD, Philip R. MHC class I antigen presentation and implications for developing a new generation of therapeutic vaccines. Ther Adv Vaccines. 2014;2(3):77-89.
- Choo SY. The HLA system: genetics, immunology, clinical testing, and clinical implications. Yonsei Med J. 2007;48(1):11-23.
- Izumoto S, Tsuboi A, Oka Y, et al. Phase II clinical trial of Wilms tumor 1 peptide vaccination for patients with recurrent glioblastoma multiforme. J Neurosurg. 2008;108(5):963-971.
- Buteau C, Markovic SN, Celis E. Challenges in the development of effective peptide vaccines for cancer. Mayo Clin Proc. 2002;77(4):339-349.
- Maeng H, Terabe M, Berzofsky JA. Cancer vaccines: translation from mice to human clinical trials. Curr Opin Immunol. 2018;51:111-122.
- Cheever MA, Allison JP, Ferris AS, et al. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res. 2009;15(17):5323-5337.
- Oji Y, Suzuki T, Nakano Y, et al. Overexpression of the Wilms’ tumor gene WT1 in primary astrocytic tumors. Cancer Sci. 2004;95(10):822-827.
- Dennis SL, Manji SS, Carrington DP, et al. Expression and mutation analysis of the Wilms’ tumor 1 gene in human neural tumors. Int J Cancer. 2002;97(5):713-715.
- Nakatsuka S, Oji Y, Horiuchi T, et al. Immunohistochemical detection of WT1 protein in a variety of cancer cells. Mod Pathol. 2006;19(6):804-814.
- Chen MY, Clark AJ, Chan DC, et al. Wilms’ tumor 1 silencing decreases the viability and chemoresistance of glioblastoma cells in vitro: a potential role for IGF-1R de-repression. J Neurooncol. 2011;103(1):87-102.
- Mahzouni P, Meghdadi Z. WT1 protein expression in astrocytic tumors and its relationship with cellular proliferation index. Adv Biomed Res. 2013;2:33.
- Coosemans A. Wilms’ tumour gene 1 (WT1) as an immunotherapeutic target. Facts Views Vis Obgyn. 2011;3(2):89-99.
- Nakahara Y, Okamoto H, Mineta T, Tabuchi K. Expression of the Wilms’ tumor gene product WT1 in glioblastomas and medulloblastomas. Brain Tumor Pathol. 2004;21(3):113-116.
- Chidambaram A, Filmore HL, Van Meter TE, Dumur CI, Broaddus WC. Novel report of expression and function of CD97 in malignant gliomas: correlation with Wilms tumor 1 expression and glioma cell invasiveness. J Neurosurg. 2012;116(4):843-853.
- Goto M, Nakamura M, Suginobe N, et al. DSP-7888, a novel cocktail design of WT1 peptide vaccine, and its combinational immunotherapy with immune checkpoint-blocking antibody against PD-1. Blood. 2016;128(22):4715.
- Spira A, Hansen AR, Harb WA, et al. Multicenter, open-label, phase I study of DSP-7888 dosing emulsion in patients with advanced malignancies. Target Oncol. Published online ahead of print, May 3, 2021. doi:10.1007/s11523-021-00813-6.