Clinical Update: Promising Results From First-of-Its-Kind CRISPR Trial To Treat Solid Tumours

PACT Pharma is a privately-held biopharmaceutical company developing personalised neo-antigen-specific and off-the-shelf T cell receptor (TCR)-T cell therapies to treat a range of solid tumours.

Last week, the company shared results from a Phase 1 clinical trial evaluating an experimental CRISPR-edited cancer-specific TCR-T cell therapy, which involved 16 adult participants with breast, colon or lung cancer. The trial was conducted in collaboration with nine academic centres using PACT Pharma's proprietary tumour-specific TCR-T cell engineering platforms. The findings were published in Nature.

A tumour-specific TCR-T cell therapy that attacks cancer

Our immune systems contain T cells that can recognise and kill cancer cells through recognition of neo-antigens by the T cell receptor (TCR). Neo-antigens are a class of tumour-specific antigens that arise through somatic mutations in the genomes of cancer cells.

In most cases, the number of naturally-occurring cancer-targeting T cells will be much too low to mount an immune response capable of eradicating a patient's tumour(s). The therapeutic strategy behind PACT's experimental candidate is devised to boost a patient's own immune sytem by redirecting their T cells to fight cancer.

For the new experimental therapy, which is referred to as NeoTCR-P1, the team sequenced DNA from blood samples and tumour biopsies for every patient in the trial to identify neo-antigens that would trigger a cancer-specific T cell response. They then applied a series of in silico and laboratory analyses to identify TCRs that would be capable of recognising these neo-antigen-specific TCRs.

Patients' T cells were then isolated and CRISPR-edited via electroporation with Cas9 protein, guide RNAs to knock-out the endogenous TCR genes (TCRα (TRAC) and TCRβ (TRBC)), and a HR template plasmid encoding the transgenic neoTCR.

These edited T cells were then scaled up to large numbers and up to three neoTCR-transgenic cell products, each expressing a distinct patient-specific neoTCR, were administered intravenously to each patient following a course of conditioning chemotherapy (to dampen the immune response and make way for the edited cells).

Promising results so far in first-of-its-kind trial

In the published manuscript, the authors report that the CRISPR-edited T cells preferentially trafficked to the tumour and could be recovered from post-infusion biopsies in all patients where biopsies were available. They also note that the CRISPR-edited T cells frequently represented the top 2-20% of immune cells in the tumour, and a reduction in tumour size was observed in some lesions of a single patient with lung cancer.

Expected side effects associated with conditioning chemotherapy were observed across the cohort, and two patients exhibited potential side effects from the gene-edited cells, including transient fevers and chills, and confusion. Overall, the findings show that the NeoTCR-P1 cells were well tolerated with promising early indications of clinical activity.

The NeoTCR-P1 trial is the first to evaluate a gene-edited therapeutic candidate that has undergone knock-out of endogenous genes (i.e. naturally-occuring TCR-encoding genes) by substitution with genes isolated from the same patient, in this case the identified neoTCR-encoding genes.

We will continue to provide further updates on this trial as they emerge. For a complete overview of current gene editing clinical trials, check out CRISPR Medicine News' Clinical Trials Database.