Outcomes and Challenges of CRISPR-Based Cancer Therapies: A Review of 32 Clinical Trials
Background
Cancer is characterized by genetic heterogeneity and the ability to adapt to therapeutic pressures, leading to treatment resistance. Chemotherapy and radiation therapy can damage rapidly dividing normal cells, and targeted therapies may lose efficacy as tumors develop resistance mechanisms. Immunotherapies face challenges such as T-cell exhaustion, loss of tumor-associated antigens, and immunosuppressive tumor microenvironments.
CRISPR/Cas9 gene editing technology allows for the precise targeting and modification of specific DNA sequences. This approach differs from conventional therapies by directly targeting cancer-causing mutations and enabling the simultaneous modulation of multiple immune cell properties. However, off-target editing, chromosomal rearrangements, in vivo delivery efficiency, and complex cell manufacturing processes have hindered clinical translation.
A research team from Taylor's University Malaysia reviewed PubMed, Web of Science, and ClinicalTrials.gov to analyze the current status of CRISPR-based cancer therapies in clinical and translational research between 2013 and 2026. The analysis included 32 studies, encompassing completed and ongoing trials, as well as discontinued, withdrawn, and pre-recruitment studies. Therefore, the number of trials should not be interpreted as the number of cases with proven efficacy. The study was published in the international journal Frontiers in Oncology in July 2026. Original article
Key Findings
The clinical strategies can be broadly categorized into three approaches: ex vivo editing of patient- or donor-derived immune cells, direct correction or disruption of oncogenic mutations, and modulation of tumor-supporting signaling pathways and microenvironments. Ex vivo immune cell editing is the most advanced area, as it allows for the assessment of editing efficiency and off-target mutations before cell administration, and avoids systemic delivery of Cas9.
Early trials, such as NCT02793856 for non-small cell lung cancer and NCT03081715 for esophageal cancer, evaluated the safety and feasibility of removing the PDCD1 immune checkpoint gene from T cells. Subsequent development has focused on multiplex gene editing. CB-010, a candidate for relapsed/refractory B-cell non-Hodgkin lymphoma, combines CD19 chimeric antigen receptor T-cell (CAR-T) therapy with editing of TRAC and PDCD1. CB-011, a candidate for multiple myeloma, is designed to target B-cell maturation antigen (BCMA) while modulating TRAC and B2M. CTX112 targets CD19, TRAC, B2M, TGFBR2, and Regnase-1 to reduce immune rejection, graft-versus-host disease, and T-cell exhaustion. Clinical trial design and targets
The review reported that objective responses and in vivo persistence of edited cells were observed in CD19- and BCMA-targeted products. However, most studies are in early stages and lack comparative arms, making it difficult to isolate the contribution of CRISPR editing to efficacy. In solid tumors, dense extracellular matrix, heterogeneous target expression, and immunosuppressive environments hinder the delivery of cells and editing tools to the entire tumor.
Significance and Prospects
The current clinical value of CRISPR lies in its ability to precisely re-engineer living therapeutic agents, such as CAR-T cells and tumor-infiltrating lymphocytes (TILs), rather than directly correcting cancer cell DNA in vivo. TRAC editing inhibits endogenous T-cell receptor expression and promotes uniform CAR expression, while B2M modulation reduces immune rejection of donor cells. This approach also enables the production of allogeneic "off-the-shelf" cell therapies that can be administered to multiple patients.
Base editing and prime editing, which can create base substitutions or short insertions/deletions without double-strand DNA cleavage, are promising approaches for improving precision. Combining these technologies with lipid nanoparticles or tumor-targeted nanocarriers may alleviate delivery problems in solid tumors. However, most of these approaches are still in preclinical or early clinical stages.
The remaining challenges are clear. Off-target cleavage and chromosomal rearrangements need to be monitored long-term, and editing efficiency, cell persistence, and objective response rates should be reported using consistent criteria across trials. As the number of genes edited increases, manufacturing quality control and regulatory validation become more complex. This review is a descriptive review, not a meta-analysis of clinical trial results, and promising safety signals should not be extrapolated to definitive survival benefits.
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
The most realistic application scenario is the rapid delivery of pre-manufactured allogeneic CRISPR-CAR-T cells to patients with relapsed/refractory hematological malignancies. This would reduce the need for patient-specific T-cell collection and weeks-long custom manufacturing, while allowing manufacturers to produce multiple doses from the same cell source. Before treatment, off-target editing, chromosomal abnormalities, residual Cas9, and the homogeneity of edited cells should be assessed as release criteria.
In solid tumors, a strategy of tumor biopsy and single-cell analysis to identify antigens and immunosuppressive pathways, followed by administration of CISH or TGFBR2-edited tumor-infiltrating lymphocytes, may be a priority. However, if tumor infiltration and antigen heterogeneity are not addressed, even improved editing precision may have limited clinical efficacy. Industrial success will depend on how quickly long-term safety data, automated cell production, and standardized metrics for comparing therapies can be established.