Although trials for solid tumors (e.g., CYAD-101, CTX130) show modest responses, challenges such as tumor heterogeneity and T cell exhaustion remain. Future research should focus on optimizing gene editing precision, integrating combination therapies, and advancing scalable manufacturing platforms. With expanded targets and cell types, UCAR therapies show promise for both hematologic and solid tumors, reshaping cancer treatment and patient outcomes.

CYAD-02 presented an higher engraftment and an improved clinical activity (17% objective response rate) compared to CYAD-01 (no objective response). Altogether, our data provide proof of principle that knock-down of MICA/B can enhance CAR T-cell persistence and efficacy while maintaining a good safety profile.

P1/2, N=17, Recruiting, Leucid Bio | Trial completion date: Jun 2027 --> May 2029 | Trial primary completion date: Jul 2025 --> May 2029

P1, N=12, Recruiting, CytoMed Therapeutics Pte Ltd | Not yet recruiting --> Recruiting | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Mar 2023 --> Nov 2025

P1/2, N=17, Recruiting, Leucid Bio

P1, N=36, Recruiting, Zhejiang University

P=N/A, N=9, Recruiting, Zhejiang University

P=N/A, N=9, Terminated, Hangzhou Cheetah Cell Therapeutics Co., Ltd | Phase classification: P1 --> P=N/A | Recruiting --> Terminated; end

P1, N=9, Not yet recruiting, CytoMed Therapeutics Pte Ltd

P1, N=34, Recruiting, Celyad Oncology SA | Not yet recruiting --> Recruiting | Phase classification: P1b --> P1

P1, N=9, Recruiting, Hangzhou Cheetah Cell Therapeutics Co., Ltd

In clinical trials, CYAD-01 showed a good tolerability profile but with a disappointing level of clinical activity when combined with cyclophosphamide / fludarabine preconditioning (DEPLETHINK trial, NCT03466320)...The knockdown of MICA/MICB appears to have a positive contribution to the initial clinical activity of CYAD-02 as compared to that achieved with the first generation CYAD-01 CAR T, together with good safety and tolerability...One approach to further drive the potency of NKG2D-based CAR T cells would likely be armoring the CAR T through using the T cell as a vehicle to secrete cytokines alongside the CAR. Overall, shRNA knockdown technology provides a means to modify CAR T function and here shows that single shRNA can target two independent genes to enhance the phenotype of the CAR Ts.