First-in-human Phase 1 CRISPR Gene Editing Cancer Trials: Are We Ready?

Abstract

A prospective first-in-human Phase 1 CRISPR gene editing trial in the United States for pa-tients with melanoma, synovial sarcoma, and multiple myeloma offers hope that gene editing tools may usefully treat human disease. An overarching ethical challenge with first-in-human Phase 1 clinical trials, however, is knowing when it is ethically acceptable to initiate such trials on the basis of safety and effi-cacy data obtained from pre-clinical studies. If the pre-clinical studies that inform trial design are them-selves poorly designed – as a result of which the quality of pre-clinical evidence is deficient – then the ethical requirement of scientific validity for clinical research may not be satisfied. In turn, this could mean that the Phase 1 clinical trial will be unsafe and that trial participants will be exposed to risk for no potential benefit. To assist sponsors, researchers, clinical investigators and reviewers in deciding when it is ethically acceptable to initiate first-in-human Phase 1 CRISPR gene editing clinical trials, structured processes have been developed to assess and minimize translational distance between pre-clinical and clinical research. These processes draw attention to various features of internal validity, construct validi-ty, and external validity. As well, the credibility of supporting evidence is to be critically assessed with particular attention to optimism bias, financial conflicts of interest and publication bias. We critically ex-amine the pre-clinical evidence used to justify the first-in-human Phase 1 CRISPR gene editing cancer trial in the United States using these tools.We conclude that the proposed trial cannot satisfy the ethical requirement of scientific validity because the supporting pre-clinical evidence used to inform trial design is deficient.

Clinical applications of CRISPR‐based genome editing and diagnostics

“…The initial clinical trials involving ex vivo CRISPR‐based immunotherapies are being watched with much anticipation. Given that the research community is still optimizing the technology for editing human cells, some believe it is too early to enter clinical trials . While every effort is being taken to ensure effectiveness and safety, much can only be determined by performing human trials.…”

“…Given that the research community is still optimizing the technology for editing human cells, some believe it is too early to enter clinical trials. 121 While every effort is being taken to ensure effectiveness and safety, much can only be determined by performing human trials. In addition to unpredictable outcomes, another major hurdle is in the cost of manufacturing CRISPR therapeutics at a scale that is economically feasible.…”

The potential of CRISPR/Cas9 genome editing for the study and treatment of intervertebral disc pathologies

“…Another CRISPR/Cas9 application in humans is the ex vivo‐programmed cell death protein 1 ( PD1 ) gene deactivation in T‐lymphocytes of a lung cancer patient and subsequent introduction of the edited cells into the patient, which was based on previous encouraging in vitro results . PD‐1 gene modification is a promising approach that should be clinically trialed for other malignancies, but caution in trial designs with CRISPR/Cas9 needs to be taken when it comes to ethical requirements of scientific validity …”

“…A new planned trial investigating the safety of the ex vivo CCR5 modification in CD34+ hematopoietic stem cells by CRISPR/Cas9 is ongoing in HIV-positive patients to prevent AIDS development (clinicaltrial.gov: NCT 03164135).Another CRISPR/Cas9 application in humans is the ex vivoprogrammed cell death protein 1 (PD1) gene deactivation in Tlymphocytes of a lung cancer patient and subsequent introduction of the edited cells into the patient, which was based on previous encouraging in vitro results 113,114. PD-1 gene modification is a promising approach that should be clinically trialed for other malignancies, but caution in trial designs with CRISPR/Cas9 needs to be taken when it comes to ethical requirements of scientific validity 115. The clinical application of CRISPR/Cas9 machinery directly in the human body is envisioned for the treatment of HPV-related cervical intraepithelial neoplasia (clinicaltrial.gov: NCT03057912).…”

Cancer diagnosis and immunotherapy in the age of CRISPR

“…Further information may soon be forthcoming, as multiple clinical trials have been initiated in the United States and China using CRISPR‐edited CAR‐T cells. A trial sponsored by the University of Pennsylvania and aimed at multiple myeloma plans to use CAR‐T cells where the TCR and the PD‐1 receptor have been deleted using CRISPR (NCT03399448) …”