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Lyell Immunopharma to Test CAR T-Cell Therapy in Variety of ROR1-Positive Cancers

NEW YORK – Lyell Immunopharma, spurred by the efficacy of its investigational ROR1-targeted CAR T-cell therapy LYL797 in triple-negative breast cancer (TNBC) in a Phase I trial, has decided to expand the study to include patients with ROR1-positive ovarian and endometrial cancer, and launch a new trial to evaluate the autologous cell therapy's activity in multiple myeloma and chronic lymphocytic leukemia.

In the ongoing Phase I trial, Lyell researchers are evaluating LYL797 as a treatment for patients with ROR1-positive relapsed or refractory TNBC or non-small cell lung cancer. The initial dataset included 16 patients with TNBC and four with NSCLC. Two out of five TNBC patients who received the highest dose of LYL797 had confirmed partial responses lasting 90 days. The objective response rate was 40 percent among TNBC patients, and the clinical benefit rate was 60 percent.

In patients without lung metastases, common treatment-related adverse events were grade 1 and grade 2 cytokine release syndrome and headache, and cytopenia due to lymphodepletion. None of the patients have experienced immune effector cell-associated neurotoxicity syndrome from LYL797. However, grade 3 or higher pneumonitis occurred in 17 percent of patients, only in those with TNBC and lung metastases, and investigators are escalating the dose of LYL797 more gradually in these patients. One patient had a fatal, grade 5 respiratory failure at day 41.

"No dose-limiting toxicities have been reported in patients without lung involvement," the company said in a statement. "All patients are now receiving prophylactic steroids prior to LYL797 treatment."

Lyell aims to design therapies that delay T-cell exhaustion and have greater potency in terms of their antitumor effect. LYL797 targets ROR1, which is highly expressed on the surface of many aggressive solid tumors, including about 60 percent of patients with TNBC and 40 percent of those with NSCLC.

Company executives highlighted the safety protocols Lyell has implemented to manage adverse events but characterized the initial Phase I data as promising. "This early validation of our anti-exhaustion technology gives us the conviction to expand our trial to include patients with ROR1-positive ovarian or endometrial cancers, while continuing to enroll patients with triple-negative breast or non-small cell lung cancers, and also to initiate a new clinical trial for patients with multiple myeloma and chronic lymphocytic leukemia," Lyell CEO Lynn Seely said in a statement.

Based on the strength of the early Phase I data readout, Lyell has also decided to submit an investigational new drug application to the US Food and Drug Administration, seeking permission to begin a trial of its next-generation ROR1-targeted CAR T-cell therapy, called LYL119, by year-end. The South San Francisco, California-based company has engineered the next-generation product with stronger anti-exhaustion properties.

The firm is also conducting a Phase I trial of an autologous tumor-infiltrating lymphocyte treatment, LYL845, in patients with advanced solid tumors, including melanoma, NSCLC, and colorectal cancer.