The Promise of Gene Editing in Cancer Approaches Fruition

A couple of decades ago, I was interviewing for hematology/oncology fellowships around the country. During an interview, a program director asked me a question that I had never thought about before and did not see coming. The question went something like this: “If you were the director of the National Cancer Institute and you had $3 billion to invest on 1 and only 1 area of oncology research, where would you spend it?”

The answer that popped out of my mouth was “gene therapy.” Immediately after I said it, I felt like I had given the wrong answer. Gene therapy was struggling. Around that time, an 18-year-old man with ornithine transcarbamy- lase deficiency had died from multiple organ failure triggered by an immune reaction to an investigational gene therapy treatment. Gene therapy trials were shut down and the future was unclear.

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More than 2 decades later, gene therapy now appears to be rising from the ashes, albeit in a different form and in combination with other novel therapies. Recent research published in The New England Journal of Medicine describes the results of clinical trials testing exagamglogene autotemcel (exa-cel; Casgevy) in patients with sickle cell disease and transfusion-dependent β-thalassemia.^1,2 Exa-cel was approved by the FDA on December 8, 2023, and represents the first approved therapy that is created with gene editing.

How will gene editing affect the field of oncology? That remains to be seen, but a report was published in The New England Journal of Medicine of base-edited chimeric antigen receptor (CAR) T cells used in 3 patients with relapsed T-cell acute lymphoblastic leukemia.³ The product used was an allogeneic CAR T-cell product created from healthy volunteer donors in which gene editing was used to ablate expression of TRBC, CD7, and CD52. The therapy showed potent activity in the 3 patients. The potential of gene editing for cancer remains to be seen. One has the sense that we are just beginning what could be a paradigm-changing course for the treatment of cancer. I’m beginning to wonder whether my answer more than 20 years ago may have been a wise one.

REFERENCES:

1. Frangoul H, Locatelli F, Sharma A, et al; CLIMB SCD-121 Study Group. Exagamglogene autotemcel for severe sickle cell disease. N Engl J Med. 2024;390(18):1649-1662. doi:10.1056/NEJMoa2309676

2. Locatelli F, Lang P, Wall D, et al; CLIMB THAL-111 Study Group. Exagamglogene autotemcel for transfusion dependent-thalassemia. N Engl J Med. 2024;390(18):1663-1676. doi:10.1056/NEJMoa2309673

3. Chiesa R, Georgiadis C, Syed F, et al. Base-edited CAR7 T cells for relapsed T-cell acute lymphoblastic leukemia. N Engl J Med. 2023;389(10):899-910. x.