Clinical Update: Gene-Editing Trials for Solid Cancers
There are currently more than 100 ongoing clinical trials for novel gene-edited candidate therapies developed using CRISPR-Cas, base editing, Cas-CLOVER, TALEN, meganuclease. These trials span broad disease areas including rare diseases of the eye, blood, immune system and others, familial hypercholesterolemia, infectious diseases, and cancer.
In this clinical update, we look at four ongoing gene-editing trials for solid cancers.
NeoTCR-P1, a CRISPR-edited TCR-T cell therapy for breast, colon and lung cancer (Phase 1)
PACT Pharma is sponsoring a Phase 1 clinical trial for NeoTCR-P1, an experimental CRISPR-edited cancer-specific T cell receptor (TCR)-T cell therapy, in adults with breast, colon or lung cancer. The trial is being conducted in collaboration with nine academic centres using PACT Pharma's proprietary tumour-specific TCR-T cell engineering platforms.
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. The therapeutic strategy behind NeoTCR-P1 is to boost a patient's own immune sytem by redirecting their T cells to fight cancer. This is achieved by CRISPR-editing patient T cells to express neo-antigen-specific TCRs.
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 genes identified as neoTCR-encoding genes.
Late last year, the company shared results from a trial in an article published in Nature. The data demonstrated 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.
P-MUC1C-ALLO1 - a donor-derived pan-specific CAR-T cell candidate for solid cancer (Phase 1)
Poseida Therapeutics is developing the first pan-specific CAR-T cell candidate for solid cancer. P-MUC1C-ALLO1 is an allogeneic CAR-T cell therapy designed to target cancer cells expressing the Mucin1 cell surface associated C-Terminal (MUC1-C) antigen.
P-MUC1C-ALLO1 is edited using Cas-CLOVER technology, and encompassses genetic edits that eliminate or minimise both host-vs-graft and graft-vs-host alloreactivity. The candidate is being evaluated in a Phase 1, open label, dose escalation and expanded cohort study in adults with a range of advanced or metastatic epithelial-derived solid tumours. A number of patients have been dosed so far and recruitment is still ongoing.
The company shared clinical data from the P-MUC1C-ALLO1 trial in December 2022, which revealed that as of November 14th 2022, seven patients with epithelial-derived cancers, including oesophageal, colorectal, breast, pancreatic and prostate carcinomas had been dosed with P-MUC1C-ALLO1, of which four patients were evaluable for response. This included a single pre-treated breast cancer patient who achieved a partial response and two patients with heavily pre-treated gastrointestinal tumours who achieved stable disease. The experimental therapy was safe and well-tolerated.
According to a company press release published in December 2022, Poseida believes that P-MUC1C-ALLO1 has the potential to treat a wide range of solid tumours derived from epithelial cells, including breast, ovarian, colorectal, lung, pancreatic and renal carcinomas, as well as other tumours that express a cancer-specific form of MUC1-C. Poseida previously demonstrated the elimination of tumour cells to undetectable levels in pre-eclinical models of both breast and ovarian cancer. Read more about Poseida's unique approaches to gene editing, delivery and optimisation of allogeneic cell therapies in our interview with then CEO Eric Ostertag here.
FT536 - a gene-edited CAR natural killer cell therapy candidate (Phase 1)
Fate Therapeutics announced in January 2022 that the FDA had approved its IND application for FT536 to enter a Phase 1 clinical trial for advanced solid tumours. According to a company press release, the company was planning to initiate a trial for FT536 as mono- and combination therapy along with tumour-targeting monoclonal antibody therapy for the treatment of multiple solid tumour indications, including advanced non-small cell lung cancer, colorectal cancer, head and neck cancer, gastric cancer, breast cancer, ovarian cancer, and pancreatic cancer.
FT536 is designed as a first-in-class, off-the-shelf, chimeric antigen receptor (CAR) natural killer (NK) cell product candidate. It is derived from a clonal master induced pluripotent stem cell line that undergoes multiple gene-editing steps with an undisclosed gene-editing modality, including the incorporation of a unique CAR that targets MICA and MICB, immune-activating stress proteins that are abundantly expressed by many solid and haematopoeitic tumour types, and which can be bound by NK cells and CD8+ T cells to activate a potent cytotoxic response.
FT536 also harbours a so-called ‘Universal Secondary Engager’, which is a modified CD16 receptor that is engineered to prevent its down-regulation and to enhance its binding to tumour-targeting antibodies. Additional edits include the addition of an IL-15 receptor fusion that augments NK cell activity as well as knockout of the CD38 gene, which promotes cell persistence and function in the hostile tumour microenvironment.
Recruitment of an estimated 322 participants is ongoing, with an estimated primary completion date (the date on which the last participant is expected to receive treatment) in June 2024. The off-the-shelf treatment regimen is designed to be administered in the outpatient setting. You can read more about the therapeutic strategy and research supporting FT536 here.
IOV-4001 - TALEN-edited cell therapy for advanced non small cell lung cancer (Phase 1/2)
In March 2022, Iovance Biotherapeutics received FDA clearance to initiate a Phase 1 clinical trial for IOV-4001, an autologous TALEN-edited cell therapy for unresectable or metastatic melanoma and stage III or IV non small cell lung cancer.
IOV-4001 is developed using Cellectis' TALEN® gene-editing technology under licence. Specifically, it is generated from tumour-infiltrating lymphocytes (TILs) that are isolated from patient tumours. TILs are a mixed population of lymphocytes (including B cells, T cells, and other immune cell types) that naturally invade and are implicated in killing tumour cells. Following isolation, the TILs are subjected to TALEN gene editing to inactivate the PD-1 protein.
PD-1 is an immune checkpoint protein found on the surfaces of healthy T cells as well as certain cancer cell types. Under normal physiological conditions, the interaction between PD-1 and its ligand PD-L1 mediates T cell immune suppression, but cancer cells can hijack this pathway to escape the immune response. The PD-1/PD-L1 interaction is a well-established target for cancer immunotherapy and to date various small molecule and antibody-based inhibitors of both interaction partners have been pursued as cancer treatments.
IOV-4001 is designed as an adoptive cell therapy that combines the natural anti-tumour activity of TILs with PD-1 knockout to prevent immune escape by cancer cells, and according to a company press release, IOV-4001 has the potential to become an optimised, next-generation TIL therapy for several solid tumour cancers. The company shared pre-clinical data supporting the potential of IOV-4001 at last year's American Association for Cancer Research Annual Meeting. Recruitment of 53 adult participiants is ongoing with an estimated primary completion date in June 2025.
For a complete overview of current gene editing clinical trials, check out CRISPR Medicine News' Clinical Trials Database.
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PACT Pharma, Inc.
Vertex Pharmaceuticals Incorporated