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Fratricide-resistant CAR T-cell therapy may have utility in acute lymphoblastic leukemia
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Patients with relapsed or refractory acute lymphoblastic leukemia may benefit from a novel fratricide-resistant chimeric antigen receptor T-cell therapy approach, according to study results.
Matthew L. Cooper, PhD, instructor in medicine in the division of oncology at Washington University School of Medicine in St. Louis, and colleagues described a so-called “off-the-shelf” CAR T-cell therapy approach, known as UCART7, that targets CD7-positive t-cell malignancies.
The method uses CRISPR/Cas9 gene editing to delete expression of CD7 and the T-cell receptor alpha chain on CAR T cells, preventing fratricide and graft-versus-host disease.
UCART7 demonstrates efficacy against T-ALL cell lines and primary T-ALL without inducing xenogeneic GVHD, researchers said. Autologous T cells are not required.
HemOnc Today spoke with Cooper about the study, the potential implications of the results, and what needs to be confirmed in subsequent research.
Question: What can be done with this approach that could not be done with other forms of CAR T-cell therapy?
Answer: Despite the success of CAR T-cell therapy against B-cell cancers, there is no CAR T-cell therapy for the treatment of T-cell malignancies in the clinic. The problem with generation CAR T against T-cell malignancies is that they share the same target proteins, and the CAR T will target and kill themselves. Using CRISPR, we deleted the target — CD7 — on the CAR T to prevent fratricide. However, this introduces another problem. It is not possible to get enough T cells from a patient with T-cell cancer without contamination with malignant cells. Gene editing of malignant cells would generate a therapy-resistant cancer when infused back into the patient. The solution is to use T cells from a donor, but this risks inducing life-threatening GVHD. To overcome this, we deleted the T-cell receptor alpha chain (TRAC) to allow the use of donor T cells without risk for life-threatening GVHD. By simultaneously deleting both CD7 and TRAC using CRISPR, we have generated a CAR T, UCART7, that is resistant to fratricide, unable to cause GVHD and can kill T-cell malignancies.
Q: Can you talk about the results you have observed in mice?
A: We demonstrated that UCART7 is effective at killing T-ALL in human primary xenograft models. Importantly, no GVHD was observed in mice that received UCART7. This suggests that UCART7 would be an effective therapy for the treatment of T-cell malignancies without the risk of causing GVHD.
Q: How can this can be applied to humans?
A: These preclinical experiments were completed using human cells against human cancers. We anticipate that UCART7 will be effective for the treatment of patients with CD7-positive malignancies. We are in the process of scaling up the manufacturing of our gene edited CAR T cells for clinical trials testing UCART7 for the treatment of T-cell malignancies, which we hope to complete at Siteman Cancer Center in St. Louis in the near future.
Q: Are there studies planned for humans?
A: Yes. We are working to get this into the clinic as soon as feasibly possible.
Q: Could this study be potentially practice-changing ?
A: T-cell malignancies represent a class of devastating blood cancers with high rates of relapse and mortality among both children and adults for whom there are currently no effective or targeted therapies. Being able to target T-cell cancers with a targeted CAR T therapy may dramatically improve outcomes for patients with T-cell malignancies. Due to the off-the-shelf nature of UCART7, patients could receive the CAR T soon after diagnosis, without requiring the personalized expansion and engineering of their own T cells. – by Rob Volansky
Reference:
Cooper ML, et al. Leukemia. 2018;doi:10.1038/s41375-018-0065-5.
For more information:
Matthew L. Cooper, PhD, can be reached at Washington University School of Medicine in St. Louis, Campus Box 8056, 660 S. Euclid Ave., Euclid Avenue, St. Louis, MO 63110; email: matthewcooper@wustl.edu.
Disclosure: Cooper reports no relevant financial disclosures.