June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

Article  PubMed  PubMed Central  Google Scholar 

Marin, D. et al. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial. Nat. Med. 30, 772–784 (2024).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Leidner, R. et al. Neoantigen T-cell receptor gene therapy in pancreatic cancer. N. Engl. J. Med. 386, 2112–2119 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ghorashian, S. et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat. Med. 25, 1408–1414 (2019).

Article  CAS  PubMed  Google Scholar 

Narayan, V. et al. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat. Med. 28, 724–734 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Albelda, S. M. CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn. Nat. Rev. Clin. Oncol. 21, 47–66 (2024).

Article  PubMed  Google Scholar 

Parente-Pereira, A. C. et al. Synergistic chemoimmunotherapy of epithelial ovarian cancer using ErbB-retargeted T cells combined with carboplatin. J. Immunol. 191, 2437–2445 (2013).

Article  CAS  PubMed  Google Scholar 

Lee, Y. G. et al. Modulation of BCL-2 in both T cells and tumor cells to enhance chimeric antigen receptor T-cell immunotherapy against cancer. Cancer Discov. 12, 2372–2391 (2022). This study demonstrated that drug resistance mutations can enable CAR T cell combination therapy with venetoclax.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Valton, J. et al. A multidrug-resistant engineered CAR T cell for allogeneic combination immunotherapy. Mol. Ther. 23, 1507–1518 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wu, X. et al. Combined antitumor effects of sorafenib and GPC3-CAR T cells in mouse models of hepatocellular carcinoma. Mol. Ther. 27, 1483–1494 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wang, A. X., Ong, X. J., D’Souza, C., Neeson, P. J. & Zhu, J. J. Combining chemotherapy with CAR-T cell therapy in treating solid tumors. Front. Immunol. 14, 1140541 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gill, S. et al. Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia. Blood Adv. 6, 5774–5785 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Grosser, R., Cherkassky, L., Chintala, N. & Adusumilli, P. S. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell 36, 471–482 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rezaei, R. et al. Combination therapy with CAR T cells and oncolytic viruses: a new era in cancer immunotherapy. Cancer Gene Ther. 29, 647–660 (2022).

Article  CAS  PubMed  Google Scholar 

Tebas, P. et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N. Engl. J. Med. 370, 901–910 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Anzalone, A. V., Koblan, L. W. & Liu, D. R. Genome editing with CRISPR–Cas nucleases, base editors, transposases and prime editors. Nat. Biotechnol. 38, 824–844 (2020).

Article  CAS  PubMed  Google Scholar 

Doudna, J. A. The promise and challenge of therapeutic genome editing. Nature 578, 229–236 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wang, J. Y. & Doudna, J. A. CRISPR technology: a decade of genome editing is only the beginning. Science 379, eadd8643 (2023).

Article  CAS  PubMed  Google Scholar 

Gao, C. Genome engineering for crop improvement and future agriculture. Cell 184, 1621–1635 (2021).

Article  CAS  PubMed  Google Scholar 

Cai, P., Gao, J. & Zhou, Y. CRISPR-mediated genome editing in non-conventional yeasts for biotechnological applications. Microb. Cell Fact. 18, 63 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Wellhausen, N., Agarwal, S., Rommel, P. C., Gill, S. I. & June, C. H. Better living through chemistry: CRISPR/Cas engineered T cells for cancer immunotherapy. Curr. Opin. Immunol. 74, 76–84 (2022).

Article  CAS  PubMed  Google Scholar 

Katti, A., Diaz, B. J., Caragine, C. M., Sanjana, N. E. & Dow, L. E. CRISPR in cancer biology and therapy. Nat. Rev. Cancer 22, 259–279 (2022).

Article  CAS  PubMed  Google Scholar 

Zhang, L. et al. The construction of drug-resistant cancer cell lines by CRISPR/Cas9 system for drug screening. Sci. Bull. 63, 1411–1419 (2018).

Article  CAS  Google Scholar 

Ma, L. et al. CRISPR-Cas9–mediated saturated mutagenesis screen predicts clinical drug resistance with improved accuracy. Proc. Natl Acad. Sci. USA 114, 11751–11756 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wellhausen, N. et al. Epitope base editing CD45 in hematopoietic cells enables universal blood cancer immune therapy. Sci. Transl. Med. 15, eadi1145 (2023). This work demonstrated, for the first time, that CD45 can be druggable without haematopoietic toxicity by engineering the targeted epitope on CD45 in HSCs, thus enabling anti-CD45-directed therapies as universal blood cancer therapies.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Qasim, W. Genome-edited allogeneic donor “universal” chimeric antigen receptor T cells. Blood 141, 835–845 (2023).

Article  CAS  PubMed  Google Scholar 

Casirati, G. et al. Epitope editing enables targeted immunotherapy of acute myeloid leukaemia. Nature 621, 404–414 (2023). This work demonstrated, for the first time, that engineering epitopes of functionally relevant cell surface receptors can prevent on-target, off-tumour toxicities of CAR T cells.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Marone, R. et al. Epitope-engineered