HLA Mice: A Versatile Tool to Evaluate Cancer Vaccine Efficacy

by: Peter Chew, PhD, Ivan Gladwyn-Ng, PhD | Published: June 20, 2024

 

Key TakeawaysKey Takeaways

  • Transgenic HLA mice from Taconic Biosciences are a valuable tool for evaluating cancer vaccines, enabling researchers to study how human immune systems respond to vaccines.
  • The SCIB1 cancer vaccine showed promising efficacy in HLA-DR4 mice. The vaccine inhibited tumor growth and increased survival in mice, especially when combined with an anti-PD-1 antibody.
  • Several factors can influence how well HLA mice function, so researchers need to consider these differences when choosing a mouse model.

 

Cancer vaccines are a promising avenue for immunotherapy development. Like other vaccines, they often utilize rational design by in silico modeling for epitope identification and selection, but in vivo confirmatory testing is frequently required to confirm immunogenicity by the human immune system.

Transgenic mice that express chimeric human HLA molecules are powerful tools to evaluate cancer immunotherapy, such as cancer vaccines, in several ways. Examples are the evaluation of HLA-restricted CTL epitope responses in vivo, determining the immunogenicity of novel cancer vaccines, and testing expansion of T cells and therapeutic efficacy.

Cancer vaccine demonstrates anti-tumor efficacy in tumor model using HLA-DR4 mice from Taconic Biosciences

In 2016, Scancell researchers successfully evaluated the efficacy of their therapeutic SCIB1 vaccine in Taconic’s HLA-DR4 mice tumor model1. This DNA-based cancer vaccine contains multiple tumor-specific epitopes restricted by various HLAs, one of which is the HLA-DR4-restricted gp10044-59 epitope. SCIB1 was previously shown to induce high frequency and avidity CD8 and CD4 T cell responses in HLA-DR4 mice and melanoma patients2,3.

The scientists first sequenced the chimeric HLA-DR4 transgene from Taconic’s HLA-DR4 mice. Next, they expressed this transgene in a C57BL/6 melanoma cell line, B16F1, to create the B16F1-DR4 cell line. HLA-DR4 mice were challenged with 2.5x104 or 1.5x105 B16F1-DR4 cells subcutaneously on the right flank on day 0 and then immunized with SCIB1 bullets via gene gun intradermally on days 3, 7, and 10. 

It has been reported that the expansion and function of infiltrating high avidity T cells induced by vaccination could be compromised within the tumor by upregulation of PD-1 and engagement with PD-L1 in the melanoma tumor microenvironment4-6. Thus, anti-PD-1 antibody was also assessed in combination with SCIB1 for anti-tumor efficacy. 

This study revealed that either SCIB1 or PD-1 blockage alone resulted in significant inhibition of tumor growth and increased survival of B16-DR4 tumor-bearing HLA-DR4 mice from around 20% to 40% at 60 days post-tumor implant (Figure 1A and 1B). However, combination of SCIB1 and PD-1 blockage led to even greater tumor growth inhibition and further increased survival of these mice up to 80% at 60 days post tumor engraftment (Figures 1A and 1B).

Days post tumor chart

 

Figure 1. SCIB1 DNA cancer vaccine confers anti-tumor response and combination with anti PD-1 further enhances therapeutic efficiency in HLA-DR4 mice transplanted with chimeric HLA-DR4-expressing B16 melanoma tumor. Survival percentage (A) and tumor volume (B) for HLA-DR4 mice.
Figure adapted from Xue W, et al. SCIB1, a huIgG1 antibody DNA vaccination, combined with PD-1 blockade induced efficient therapy of poorly immunogenic tumors. Oncotarget. 2016;7(50):83088-83100. doi:10.18632/oncotarget.13070.  Licensed under CC BY 4.0 (www.creativecommons.org/licenses/by/4.0/).

Number of CD45+ per million tumor cells

 

Figure 2. Combination of SCIB1 DNA Cancer Vaccine and PD-1 blockade increases T cell infiltrate into tumors. Number of CD45+ T cell infiltrate per million tumor cells (A). Number of CD8+ T cell infiltrate per million tumor cells (B).
Figure adapted from Xue W, et al. SCIB1, a huIgG1 antibody DNA vaccination, combined with PD-1 blockade induced efficient therapy of poorly immunogenic tumors. Oncotarget. 2016;7(50):83088-83100. doi:10.18632/oncotarget.13070.  Licensed under CC BY 4.0 (www.creativecommons.org/licenses/by/4.0/).

 

Critically, combination of SCIB1 and anti-PD-1 resulted in significant increase of total T cells (Figure 2A) and cytotoxic CD8+ T cells (Figure 2B) into B16-DR4 tumor.

As of March 2024, the SCIB1 cancer vaccine has successfully undergone phase I/II clinical trials in melanoma patients7.

Taconic’s chimeric HLA mice ensure efficient activation of murine T Cells  

To increase the efficiency of HLA recognition by murine T cells, Taconic Biosciences provides chimeric HLA mice with a humanized antigen-binding domain coupled with murine MHC domains that activate downstream mouse T cells. This ensures that the specificity of HLA-restricted epitope presentation is not compromised in chimeric HLA-expressing cells while still allowing for efficient downstream activation of CD4 or CD8 T cells.

Not all HLA mice perform the same

It is important to note that not all HLA-related mouse models perform similarly with respect to HLA restriction, which can differ based on:

  • Genetic design of the HLA gene: either chimeric or fully humanized
  • HLA gene copy number
  • HLA transgene insertion sites
  • Mouse MHC expressed or knocked out
  • Background strain differences

Featured Model

Abb Knockout/Transgenic HLA-DR4

Transgenic mice with the HLA-DR4 allele are used to study the development of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.
View Model

These different factors can significantly impact antigen presentation and immunodominance, affecting the outcome of studies. Thus, it is important to take into consideration the differences between different HLA mouse strains when selecting one of these models.

HLA mice from Taconic have been used to study human class I- or class II-restricted T cells in autoimmune diseases, infectious diseases, and vaccine development. As valuable tools in evaluating human HLA restricted T cell-mediated vaccine efficacy in oncology, they also offer researchers greater translatability in studying immune responses.

References:

  1. Xue W, Brentville VA, Symonds P, et al. SCIB1, a huIgG1 antibody DNA vaccination, combined with PD-1 blockade induced efficient therapy of poorly immunogenic tumors. Oncotarget. 2016;7(50):83088-83100. doi:10.18632/oncotarget.13070
  2. Metheringham RL, Pudney VA, Gunn B, Towey M, Spendlove I, Durrant LG. Antibodies designed as effective cancer vaccines. MAbs. 2009;1(1):71-85. doi:10.4161/mabs.1.1.7492
  3. Poulam MP, Lorigan P, Plummer R et al. An adjuvant clinical trial of SCIB1, a DNA vaccine that targets dendritic cells in vivo, in fully resected melanoma patients. American Society of Clinical Oncology 2015 Annual Meeting; May 29-June 2; Chicago, IL
  4. Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013;5(200):200ra116. doi:10.1126/scitranslmed.3006504
  5. Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007;104(9):3360-3365. doi:10.1073/pnas.0611533104
  6. Duraiswamy J, Freeman GJ, Coukos G. Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res. 2013;73(23):6900-6912. doi:10.1158/0008-5472.CAN-13-1550
  7. SCIB1 & iSCIB1+. Scancell. Accessed March 2024. https://www.scancell.co.uk/scib1-iscib1.