Lyell Immunopharma, Inc., a clinical-stage T-cell reprogramming company, announced promising initial clinical data from its Phase 1 trial of LYL797, a reprogrammed
ROR1 CAR T-cell product enhanced with anti-exhaustion technology. This dataset primarily involves patients with
relapsed/refractory triple-negative breast cancer (TNBC) and demonstrates dose-dependent antitumor activity. At the highest dose of 150 x 10^6 CAR T cells, there was a 40% objective response rate (ORR) and a 60% clinical benefit rate (CBR).
This trial marks the first evidence that CAR T cells, modified with anti-exhaustion technology, can expand and infiltrate
solid tumors. Common side effects in patients without
lung metastases included
mild cytokine release syndrome (CRS) and
headache.
Pneumonitis was observed in patients with lung metastases, prompting a more gradual dose escalation in these patients. No dose-limiting toxicities were reported in patients without lung involvement, and all patients are now receiving prophylactic steroids.
Dr. David R. Spigel, Chief Scientific Officer at the Sarah Cannon Research Institute, noted the promising nature of these findings, suggesting that the
LYL797 CAR T cells’ dose-dependent antitumor activity could lead to more meaningful benefits for patients. He also pointed out that pneumonitis is a known complication of several
cancer therapies, including radiotherapy and immune checkpoint inhibitors. The protocol now includes steroids as a preventive measure for pneumonitis.
The translational program included in the LYL797 study reported that CAR T cells enhanced with anti-exhaustion technology expanded, persisted, and infiltrated solid tumors. The presence of
TIGIT, a marker of T cell exhaustion, was low in the LYL797 CAR T cells. RNA sequencing data further suggested that a significant proportion of these cells maintained a stem-like and effector memory cell phenotype.
Dr. Lynn Seely, President and CEO of Lyell, expressed optimism about these results, highlighting the clinical responses and dose-dependent antitumor activity in patients with advanced TNBC. She emphasized that the translational data showed persistent CAR T cell infiltration into solid tumors, which was associated with evidence of cancer cell killing. These early results support the expansion of the trial to include patients with ROR1+
ovarian or endometrial cancers, while continuing to enroll patients with TNBC and
non-small cell lung cancers. Additionally, a new clinical trial for patients with
multiple myeloma and
chronic lymphocytic leukemia is being initiated.
The initial Phase 1 clinical trial results involved 20 treated patients, including 16 with TNBC and four with non-small cell lung cancer. The study explored four dose levels: 50 x 10^6 cells, 100 x 10^6 cells, 150 x 10^6 cells, and 300 x 10^6 cells. The highest dose level of 150 x 10^6 cells resulted in a 40% ORR and a 60% CBR. The most common adverse events included mild CRS, pneumonitis, and headache, as well as
cytopenia from lymphodepletion.
CAR T cell expansion in peripheral blood was observed in all patients assessed, with peak expansion occurring between Days 8 and 11. The anti-exhaustion technology seemed effective, as indicated by the low presence of TIGIT. RNA sequencing data supported the role of epigenetic reprogramming in maintaining a stem-like phenotype. Tumor biopsies showed that LYL797 CAR T cells were able to infiltrate and persist in the solid tumor microenvironment, demonstrating features consistent with T cell-mediated tumor lysis.
Lyell has also completed an IND submission for LYL119, its next-generation ROR1-targeted CAR T cell product candidate, which incorporates even more advanced anti-exhaustion technologies.
Lyell Immunopharma is advancing a diverse pipeline of cell therapies aimed at solid tumors, addressing barriers such as T cell exhaustion and lack of durable stemness. The company is currently enrolling patients in Phase 1 clinical trials for LYL797 and reprogrammed tumor infiltrating lymphocytes (TIL). Lyell is based in South San Francisco, California, with facilities in Seattle and Bothell, Washington.
How to obtain the latest research advancements in the field of biopharmaceuticals?
In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery!
