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Soo Park, MD
Soo Park, MD
Posted: Thursday, March 28, 2024
Cristina Puig-Saus, PhD, of the David Geffen School of Medicine, University of California Los Angeles (UCLA), and colleagues developed a tyrosinase-related protein 1 (TYRP1)-targeted chimeric antigen receptor (CAR) T-cell therapy to treat patients with cutaneous and rare subtypes of melanoma who are unresponsive to immune checkpoint blockade. Their efficacy, selectivity, and toxicity findings, which were published in the journal Nature Communications, support the ongoing preparation of a phase I clinical trial.
“[The TYRP1] protein is intracellular, but a small portion gets to the plasma membrane as part of the vesicular transport of the cell; while in the cell surface, it becomes a target for the CAR T cells,” Dr. Puig-Saus commented in a UCLA press release. “While TYRP1 has previously been targeted in clinical trials using monoclonal antibodies, this new approach…improves the treatment’s overall effectiveness.”
The investigators analyzed three melanoma data sets and found that TYRP1 had more prominent surface expression in melanoma cells vs normal tissues. Using iterative CAR optimization, they subsequently developed the TYRP1-targeted CAR T-cell therapy. This novel approach appeared to demonstrate antitumor activity in vitro and in vivo in both murine- and patient-derived cutaneous, acral, and uveal melanoma models. Furthermore, in an immunocompetent murine model, no systemic or off-tumor severe toxicities were observed.
“We anticipate that approximately 30% of all melanoma patients without response or with relapse after immune checkpoint blockade therapy will express high levels of TYRP1 and will be eligible for the TYRP1 CAR T-cell clinical trial,” the investigators concluded. “Approximately 60% of patients with acral and mucosal melanoma and approximately 90% of patients with uveal melanoma overexpress TYRP1, and TYRP1 CAR T-cell therapy could potentially lead to clinical benefit in this patient subset.”
Disclosure: For full disclosures of the study authors, visit nature.com.
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