On October 6, 2022 Lyell Immunopharma, Inc. (Nasdaq: LYEL), a clinical‑stage T-cell reprogramming company dedicated to developing curative cell therapies for patients with solid tumors, reported that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application to initiate a Phase 1 clinical trial for LYL845 (Press release, Lyell Immunopharma, OCT 6, 2022, View Source [SID1234621772]). LYL845 is an investigational tumor infiltrating lymphocyte (TIL) therapy enhanced with Lyell’s Epi-R technology for patients with relapsed and/or refractory metastatic or locally advanced melanoma and other select solid tumors. In preclinical studies, Epi-R creates polyclonal populations of T cells that demonstrate properties of durable stemness and anti-tumor functionality. Durable stemness is the quality that enables T cells to self-renew, proliferate, persist and generate differentiated effector cell progeny.

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LYL845 is Lyell’s first TIL product candidate and second wholly owned product candidate to receive IND clearance within the past year. Patient screening for the Phase 1 trial is set to begin over the coming months, and initial clinical data is expected in 2024.

"Advancing LYL845 into the clinic represents steady progression of our mission to develop T-cell therapies that can outlast and eradicate solid tumors," said Liz Homans, chief executive officer of Lyell. "Our goal is to develop LYL845 as an effective TIL therapy for patients with solid tumor cancers such as melanoma, as well as for indications where TIL therapy has not yet been widely effective such as non-small cell lung and colorectal cancer."

"We have developed our epigenetic reprogramming technology to produce T-cell populations with more favorable attributes than those generated by standard manufacturing approaches," stated Rick Klausner, MD, chair of Lyell’s Board of Directors. "LYL845 T cells are highly polyclonal and exhibit qualities of durable stemness that have been linked with the anti-tumor functionality and improved outcomes in previous TIL clinical trials, and we look forward to clinically evaluating LYL845 and the role of these qualities in cell therapy for solid tumors."

"While TILs have previously shown clinical benefit in patients with melanoma and limited other solid tumors, we believe that TIL with properties of durable stemness and increased polyclonality are needed for adoptive cell therapies to have curative potential," said Tina Albertson, MD, PhD, chief medical officer and head of development of Lyell.

Phase 1 Trial Design

The Phase 1 clinical trial is an open-label, dose-escalation trial for patients with relapsed and/or refractory metastatic or locally advanced melanoma with expansion cohorts for patients with melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer (CRC). The primary objective of the trial is to determine safety, tolerability and a recommended phase 2 dose range of LYL845. The secondary objective is to determine antitumor activity as evaluated by response rates, duration of response, progression free survival and overall survival. Exploratory biomarkers of T-cell stemness will also be assessed.

About Melanoma, NSCLC and CRC

Melanoma accounts for only ~1% of all skin cancers but is responsible for ~80% of skin cancer-related deaths. Only ~14% of patients with metastatic melanoma survive for five years.

Lung cancer is the second most common cancer and is the leading cause of cancer mortality worldwide. NSCLC accounts for 84% of all lung cancers. For localized NSCLC, the overall 5-year survival rate is ~60%. For regional NSCLC, the 5-year survival rate is ~35%. Based on current data, when NSCLC metastasizes, the 5-year survival rate is 6%.

Colorectal cancer is the second most common cause of cancer deaths in the United States. For localized CRC, the overall 5-year survival rate is ~90% but for metastatic disease, the 5-year survival rate is 14%. Approximately 25% of patients have metastatic disease at diagnosis, and ~50% of patients with colorectal cancer will eventually develop metastases.

About LYL845

LYL845 is an autologous tumor infiltrating lymphocyte (TIL) product candidate enhanced with Epi-R reprogramming technology for patients with relapsed and/or refractory metastatic or locally advanced melanoma and select solid tumors. In preclinical studies, Epi-R creates polyclonal populations of T cells that demonstrate properties of durable stemness and anti-tumor functionality. Durable stemness is the quality that enables T cells to self-renew, proliferate, persist and generate differentiated effector cell progeny.

TIL products are created by expanding T cells taken from the patient’s own tumor. Previous clinical experiences suggest that the efficacy of adoptive transfer of ex vivo expanded TILs is largely driven by specific recognition of mutated tumor neoantigens specific to each patient. To date, broad efficacy of TIL therapies has been limited by variable and often poor product quality, lack of stemness or potential durability of expanded TILs, failure to maintain polyclonality of TILs during production, and failure to enrich the TIL product with tumor-reactive T cells.

TIL products manufactured using Lyell’s Epi-R reprogramming technology aim to overcome these challenges. Preclinical studies supporting the development of LYL845 suggest Epi-R technology improves TIL products by maintaining properties of durable stemness, which leads to superior ex vivo cell expansion and product qualities, maintenance of tumor reactive clones, and enhanced polyclonality.