The “most complicated therapy ever attempted in the clinic” demonstrates the safety and feasibility of personalised cancer treatment

Results from a recent clinical trial of a bespoke gene-edited T-cell cancer treatment have provided a compelling proof-of-concept for personalised advanced therapies [Foy SP, et al. Nature. 2022. https://doi.org/10.1038/s41586-022-05531-1]. The first-in-human Phase 1 study from PACT Pharma (San Francisco, CA) and collaborators employed CRISPR/Cas9 gene-editing technology to introduce patient-specific tumour-recognising T-cell receptors (TCRs) into the patient’s T cells, targeting them against the patient’s own cancer.

16 patients with refractory solid cancers (colon, breast, lung, ovarian or melanoma) underwent DNA and RNA sequencing to identify mutations specific to the patient’s tumour. Computational methods were then used to predict which peptides from these mutated genes (neoantigens) would be optimal targets for T-cell therapy. From these data, a library of neoantigen peptide—human leukocyte antigen complexes were generated for each patient (1841 in total) and used as reagents to capture neoantigen-binding T cells from the patient’s blood. Neoantigen-targeting TCR sequences (neoTCRs) were identified from the captured T cells, and a non-viral CRISPR/Cas9 platform was used on the patient’s T cells ex vivo to replace endogenous TCRs with the neoTCRs in a single step. The end result was an autologous cell therapy, engineered to specifically recognise the patient’s own cancer. Up to three neoTCR-engineered T-cell lines per patient were selected for clinical manufacturing, with each patient receiving an infusion of their personalised therapy following lymphodepletion.

Only two patients experienced adverse events that were likely attributable to the cell therapy: one patient experienced mild cytokine release syndrome, and another had severe encephalitis, but both quickly resolved. Post-treatment biopsies revealed that neoTCR-engineered T cells were present in the patients’ tumours in greater numbers than the endogenous cells pre-infusion, indicating that the engineered cells trafficked to and persisted near their targets. This finding is of particular note since the success of cellular immunotherapies in treating haematological cancers has, thus far, not been replicated in solid tumours due to a lack of tumour-specific target antigens and a hostile microenvironment that impedes access to the tumour.

While this feasibility study was not intended to confirm the efficacy of the therapy, tumour growth had nonetheless stalled in five of the 16 patients at 28 days post-treatment. The limited clinical benefit was attributed to low in vivo expansion of the neoTCR-engineered T cells, a constraint to be addressed through optimisation of the lymphodepletion conditioning regime, cell dose and the efficacy of the CRISPR editing.

The manufacture and administration of advanced therapies is often a complex and costly process, and this study in particular represents an unprecedented combination of technical achievements spanning genomics, CRISPR gene editing and adoptive cell therapy (ACT). Indeed, Antoni Ribas, a co-author of the study from UCLA, describes the work as “probably the most complicated therapy ever attempted in the clinic” [Ledford H. Nature. 2022;611:433–434]. Accordingly, the therapy is labour intensive, time consuming and expensive, but hints at the future of personalised therapies and provides hope for successful application of ACTs to solid tumours.

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