Discovery paves the way to ‘off-the-shelf’ cervical cancer therapy

CRISPR gene editing

Researchers from Japan have used CRISPR gene editing to enhance the effectiveness of rejuvenated cytotoxic T lymphocytes (rejTs) for targeted immunotherapy.

RejTs constitute a promising approach for treating cervical cancer, though rejection by the host’s immune system is a major hurdle.

In a recent study, researchers from Japan demonstrated how gene-edited rejTs can enable them to evade cytotoxic T cells and natural killer cells while also exhibiting enhanced anti-tumour activity.

HPV vaccines are an effective way to mitigate the risk of developing cervical cancer but don’t work against established cancers. RejTs can be engineered to target HPV-specific antigens that are expressed predominantly in cervical cancer cells, constituting a type of targeted immunotherapy.

Ideally, rejTs would be produced from induced pluripotent stem cells (iPSCs) gathered from the patient themselves. However, this process is not clinically feasible in terms of both time and cost.

CRISPR-Cas9 ‘scarless’ gene editing

A research team including Chief Professor Miki Ando from Juntendo University School of Medicine, Japan, has achieved a breakthrough by developing robust iPSC-derived rejTs for cervical cancer treatment.

Professor Ando said: “In immunocompetent cervical cancer patients, the dominant problem is the rejection of foreign T lymphocytes by the recipient’s CD8+ T lymphocytes or natural killer (NK) cells.”

To overcome this issue, the team used CRISPR-Cas9 two-step ‘scarless’ gene editing on iPSCs derived from an HPV-specific cytotoxic T lymphocyte clone.

They first deleted all HLA class I antigens from the cells and then introduced the limited expression of two specific HLA antigens, HLA-A24 and HLA-E. This enabled the engineered cells to evade attacks from NK cells, which specifically target cells lacking these surface antigens.

The generated rejTs did not trigger attacks from either CD8+ T cells or NK cells while simultaneously achieving strong cytotoxicity against tumour cells.

Compared to the control group, mice engrafted with cervical cancer cells and injected with the gene-edited rejTs survived longer and exhibited significantly reduced tumour sizes and proliferation index.

Single-cell RNA sequencing analyses revealed that the population of rejTs was highly enriched with tissue resident memory T cells, which establish residence in the mucosa of the cervix and provide stronger protection.

Professor Ando concluded: “The HLA-engineered HPV-rejTs obtained using our method provide a sustainable and promising approach toward successful ‘off-the-shelf’ T cell therapy, which could help in overcoming cervical cancer. We are planning on conducting an investigator-initiated clinical trial in 2024.”

Diana Spencer, Senior Digital Content Editor, DDW

Related Articles

Join FREE today and become a member
of Drug Discovery World

Membership includes:

  • Full access to the website including free and gated premium content in news, articles, business, regulatory, cancer research, intelligence and more.
  • Unlimited App access: current and archived digital issues of DDW magazine with search functionality, special in App only content and links to the latest industry news and information.
  • Weekly e-newsletter, a round-up of the most interesting and pertinent industry news and developments.
  • Whitepapers, eBooks and information from trusted third parties.
Join For Free