Novel CAR-T uses scorpion toxin to target brain tumors
Chimeric antigen receptor T-cell therapies have demonstrated limited antitumor activity in glioblastoma. Although the therapies have been tolerable, response rates have been low and responses lack durability.
The lack of targetable tumor antigens is one obstacle for CAR T-cell therapy in brain tumors, and a group of researchers at City of Hope has identified one naturally occurring substance as a novel treatment target: chlorotoxin.
Chlorotoxin is a component of the venom produced by the death stalker scorpion, and it has been shown to bind to glioblastoma cells in previous studies. Cell Therapy Next spoke with three of the study investigators — Michael E. Barish, PhD, professor and chair of the department of developmental and stem cell biology at City of Hope; Christine E. Brown, PhD, City of Hope’s Heritage Provider Network professor in immunotherapy; and Dongrui Wang, PhD, a recent graduate of City of Hope’s Irell & Manella Graduate School of Biological Sciences — to discuss their use of chlorotoxin-directed CAR T cells in a recently opened phase 1 clinical trial.
Q: What was your rationale for initiating this research?
We used chlorotoxin peptide in our chimeric antigen receptor design for a few reasons. First, we set out to expand the repertoire of receptors that can be targeted for brain tumor and solid tumor immunotherapy by CAR T cells, because there is currently a limited set of available, validated tumor targets. Furthermore, we set out was to develop a new CAR T cell that broadly targeted glioblastoma, with the goal of limiting the number of tumor cells that could evade therapy.
Finally, we wanted to explore the possibility of establishing a new class of CARs derived from natural peptides to add to the more common antibody-based CAR designs. Chlorotoxin is a nontoxic venom component that has been shown to have interesting and important therapeutic applications, and this is the first study to evaluate its utility for CAR therapy.
Q: What about the CAR you used makes your study novel compared with commercially available CAR T-cell therapies?
Our study is the first to use chlorotoxin in the CAR design to enable T cells to recognize and kill glioblastoma cells. Our laboratory research indicates that chlorotoxin-CAR (CLTX-CAR) T cells allow the immune system to recognize and kill the tumors of a larger proportion of patients with glioblastoma — and a higher percentage of the malignant cells within these tumors — than other immunotherapies. Chlorotoxin has been tested in previous clinical trials for delivering therapeutic molecules to tumors and shown to be well-tolerated in patients without major toxicities. What had never been done before is to demonstrate that chlorotoxin could work in the context of a CAR to reprogram cells of the immune system. Our research shows this is possible.
Q: What are the key takeaways from this research?
Two major findings from our studies have important therapeutic significance for patients. First, our studies suggest broad tumor targeting by CLTX-CAR T cells. CLTX binds to most glioblastoma tumors and a high proportion of malignant cells within these tumors. We hope to improve response rates and slow down or inhibit relapse due to antigen escape by broadly targeting most of the malignant cells within a tumor.
Our studies also indicate that CLTX-CAR T cells specifically recognize tumor cells, with no evidence of off-tumor targeting of normal brain or other tissues. We did not observe toxicity in mouse models, nor did we observe off-tumor reactions against a panel of nonmalignant human cells. These observations are consistent with other early-stage clinical trials that have reported a favorable safety profile for CLTX-based therapies. Taken together, these results support the potential safety of CLTX-CAR T cells for human testing.
Q: Has the clinical trial started enrolling, and have you treated any patients?
The phase 1 clinical trial is now open, and we will examine the clinical implications of this therapy, including broad tumor targeting and patient safety. Information on our trial can be found at clinicaltrials.gov (NCT04214392).
Q: Do you anticipate that CLTX-CAR T cells could be used for other solid tumors?
Chlorotoxin has been shown to bind to a large number of neuroectoderm-derived tumors. This observation is consistent with the idea that CLTX-CAR T cells could be effective against other solid tumors, and this is a question that we plan to address in the near future. – by Drew Amorosi
- Wang D, et al. Sci Transl Med. 2020;doi:10.1126/scitranslmed.aaw2672.
- For more information:
- Christine E. Brown, PhD, can be reached at Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010.
Disclosures: The Ivy Foundation supported the preclinical research for this study and The Marcus Foundation supports the clinical trial of the CLTX-CAR T cells.