What 32 Clinical Trials Reveal About CRISPR Cancer Therapy and the Barriers in Solid Tumors
Background
Even within the same cancer diagnosis, tumors differ in their genetic mutations and cellular states, and they can adapt to treatment pressure and acquire resistance. Chemotherapy and radiation also damage normal cells that divide rapidly, while targeted drugs often lose effectiveness against tumors that bypass a single signaling pathway. Cell-based immunotherapies face barriers too, including T-cell exhaustion and an immunosuppressive tumor microenvironment.
CRISPR/Cas9 is a gene-editing tool in which guide RNA directs the Cas9 protein to a specific DNA sequence to remove or alter a gene. It differs from existing treatments in that it can target cancer-driving mutations directly and adjust multiple properties of immune cells at once. However, off-target editing, chromosomal rearrangements, inefficient delivery into the body, and complex cell-manufacturing processes have impeded clinical application.
A 2026 review in Frontiers in Oncology surveyed literature from 2013–2026 indexed in PubMed and Web of Science, along with registrations in ClinicalTrials.gov, to summarize the clinical and translational status of CRISPR-based cancer therapies. Early signals of clinical activity have emerged in ex vivo edited immune-cell therapies, but applications in solid tumors remain limited. The 32 trials counted by the review included studies that were completed or ongoing, as well as terminated, withdrawn, or not yet recruiting. The number of trials should therefore not be taken as the number of cases in which efficacy in patients has been established.
Key findings
The review covered three broad treatment strategies: editing a patient’s or donor’s immune cells ex vivo; directly correcting or disrupting cancer-driving mutations; and modulating signaling pathways and the microenvironment that support tumors. Ex vivo immune-cell editing was the most advanced area. Researchers can assess editing efficiency and abnormal variants before administering the cells, without having to deliver Cas9 systemically.
Early trials in non-small cell lung cancer (NCT02793856) and esophageal cancer (NCT03081715) evaluated safety and feasibility by knocking out the immune-checkpoint gene PDCD1 in T cells. Development has since moved toward editing multiple genes. CB-010, a candidate for relapsed or refractory B-cell non-Hodgkin lymphoma, combines TRAC and PDCD1 editing with chimeric antigen receptor T cells (CAR-T) that recognize CD19. The multiple myeloma candidate CB-011 targets B-cell maturation antigen (BCMA) and is designed to modulate TRAC and B2M. CTX112 is a CD19-targeting CAR-T candidate; the review lists TRAC, B2M, TGFBR2, and Regnase-1 as genes associated with its multiplex editing approach. These designs aim to reduce immune rejection, graft-versus-host disease, and T-cell exhaustion at the same time.
The review reported objective responses and persistence of edited cells in the body for CD19- and BCMA-targeted products. However, most studies are at an early stage, and efficacy measures such as objective response rate, progression-free survival, and overall survival have been reported only to a limited extent. It is therefore difficult to determine the contribution of CRISPR editing itself to treatment outcomes. Unlike blood cancers, solid tumors are difficult for cells and editing tools to reach throughout the tumor because of dense extracellular matrix, heterogeneous target expression, and an immunosuppressive environment.
Implications and outlook
CRISPR’s current clinical value is most evident in the precise redesign of living therapies such as CAR-T cells and tumor-infiltrating lymphocytes. Disrupting TRAC suppresses expression of the endogenous T-cell receptor. In designs that insert a CAR at the TRAC locus, more uniform CAR expression may also be possible. Modulating B2M is used to reduce immune elimination of donor cells. These approaches also open the possibility of producing allogeneic, “off-the-shelf” cell therapies for multiple patients.
Base editing substitutes specific bases without creating DNA double-strand breaks, while prime editing can also make short insertions or deletions in addition to base substitutions. Combining these approaches with lipid nanoparticles or tumor-targeted nanocarriers could help alleviate delivery problems in solid tumors. In cancer, these in vivo editing and delivery strategies remain mainly at the preclinical exploration stage.
Key challenges remain. Researchers need to track off-target cleavage and chromosomal rearrangements over the long term and report editing efficiency, cell persistence, and objective response rates using consistent criteria across trials. Manufacturing quality control and regulatory validation also become more complex as more genes are edited. This review is narrative, not a meta-analysis that statistically combines clinical trial results, so promising safety signals should not be presented as established survival benefits. The review’s scope and trial designs are available in the full review.
The advent of CRISPR/Cas9 genome editing has significantly transformed the landscape of cancer therapeutics by facilitating precise and programmable manipulation of disease-associated genetic modifications. This review comprehensively evaluates the current clinical and translational landscape of CRISPR/Cas9-based cancer therapies through an analysis of published literature and registered clinical trials. The current CRISPR/Cas9 applications in oncology are primarily centred on three mechanistic strategies: immune cell engineering for enhanced tumor recognition, direct targeting of oncogenic mutations, and modulation of tumor-supportive pathways. Analysis of 32 clinical trials indicates that CRISPR-based interventions have demonstrated encouraging safety profiles and early signs of clinical activity, particularly in
A realistic development scenario is to provide premanufactured allogeneic CRISPR-CAR-T cells to patients with relapsed or refractory blood cancers. This could reduce the burden of patient-specific cell manufacturing and allow production to be standardized, but the review does not establish shorter supply times or lower costs. Clinical expansion will require assessments of off-target editing and chromosomal abnormalities, manufacturing consistency, and long-term follow-up data.
Different cell-therapy approaches are being developed for solid tumors. The review describes a CISH-edited tumor-infiltrating lymphocyte trial for gastrointestinal cancers and a TGFBR2-knockout, IL13Rα2-targeting CAR-T trial for glioblastoma and grade 3–4 IDH-mutant astrocytoma. These are development examples; they do not establish treatment efficacy or which approach should be prioritized. Unless tumor penetration and antigen heterogeneity are addressed, greater editing precision alone may have limited clinical impact.