SITC 2023: Phase 1 trial of LYL845, an autologous tumor-infiltrating lymphocyte (TIL) therapy enhanced with epigenetic reprogramming, for the treatment of advanced solid tumors

Phase 1 Trial of LYL845, an Autologous Tumor-Infiltrating Lymphocyte (TIL) Therapy Enhanced With Epigenetic Reprogramming for the Treatment of Advanced Solid Tumors

	Abstract 747	Yazan Samhouri1, Joal Beane2, Sarah Weiss3, John Hyngstrom4, Brent A. Hanks5, J. Randolph Hecht6, Martin Gutierrez7, Geoffrey Gibney8,
			Robert Eil9, Donald Lawrence10, Michael Hurwitz11, Sylvia M Lee12, Bishwa Ganguly13, Lucy Gong13, Hajime Hiraragi13, Yeonhee Kim13,
			Navid Nikoo13, and Heidi Gillenwater13
			1Allegheny Health Network, Pittsburgh, PA; 2The Ohio State University Comprehensive Cancer Center, Columbus, OH; 3Rutgers Cancer Institute of New Jersey, New Brunswick, NJ;
			4Huntsman Cancer Institute, Salt Lake City, UT; 5Duke University Medical Center, Durham, NC; 6David Geffen School of Medicine, UCLA, Los Angeles, CA; 7Hackensack University
			Medical Center, Hackensack, NJ; 8Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC; 9Oregon Health & Science University School of Medicine, Portland, OR;
			10Massachusetts General Hospital, Boston, MA; 11Yale School of Medicine Smilow Cancer Hospital, New Haven, CT; 12Fred Hutchinson Cancer Center, Seattle, WA;
			13Lyell Immunopharma, Inc., South San Francisco, CA

Background

Barriers to effective T-cell therapy in solid tumors

• Loss of tumor-reactiveT-cell clonotypes during expansion and low numbers of stem-like T cells are barriers to effective TIL therapy in solid tumors1,2

Figure 1: Lyell's Epi-R protocol versus standard TIL expansion

Figure 2: Epi-R produces products with a greater proportion of stem-like cells and a lower proportion of differentiated cells

Lyell's T-cell epigenetic reprogramming technology: Epi-R™

Standard TIL

	Markers associated with		Markers associated with
A	stem-like T cells	B	T-cell differentiation

• Epi-R manufacturing protocols are designed to generate populations of

stem-like T cells with reduced exhaustion and improved proliferation and

antitumor activity

• Epi-R manufacturing protocols control T-cell activation and differentiation

by optimizing cell culture media and other manufacturing steps (Figure 1),

resulting in preservation of stem-likequalities3-6 (Figure 2)

• T-cell products manufactured with Epi-R protocols have more durable

antitumor activity relative to products generated with existing ex vivo

expansion protocols3,6

Tumor tissue

expansion protocol	Control TIL

 Standard media, cytokines, and cell activation7

Lyell Epi-R protocol

- T cells

70

60

50

40

****

P<0.01

T cells

90

80

70

60

50

***

P<0.05

LYL845: A novel TIL product candidate

• LYL845 is an investigational autologous TIL product enhanced with epigenetic reprogramming technology designed to preserve tumor-reactiveT-cell clones with durable stemness to overcome barriers to effective TIL therapy in solid tumors
• LYL845 retains T-cell diversity, including >90% of tumor-reactiveT-cell clonotypes when expanded from melanoma cells5
• LYL845 demonstrates enhanced T-cell function as indicated by increased activation and cytotoxicity6

• Proprietary media

 Optimized cytokine	LYL845
compositions

• Stemness-preservingcell activation and expansion protocols

Short-lived effector cells	Long-livedstem-like cells

%CD8+CD39-CD69

30

20

10

0

%CD8+CD39+CD69+

Standard Epi-R preparation preparation

40

30

20

10

0

Standard Epi-R preparation preparation

Objectives

• LYL845-101 is an open-label,multi-center,dose-escalation study with expansion cohorts designed to evaluate the safety and antitumor activity of LYL845 in participants with R/R metastatic, locally advanced or unresectable melanoma, NSCLC, or CRC (Figure 3)

Primary objectives	Exploratory objectives
• Evaluate safety and tolerability	• Measurement of tumor mutational burden,
• Determine the RP2DR	clonal diversity of the TIL drug product, and
Secondary objectives	T-cell clonal expansion and persistence in
the periphery
• Evaluate antitumor activity	• Measurement of the presence of TIL drug
	product-derivedT-cell clones in the tumor
	post-infusion

LYL845-101 Design: NCT05573035

• Part A (dose escalation) will evaluate two planned dose level ranges of LYL845 using the modified toxicity probability interval-2, with a 28-daydose-limiting toxicity period. Part B (dose expansion) will treat 15 - 30 patients in each disease cohort at the RP2DR determined in Part A (Figure 3)
• After TIL tissue collection and LYL845 manufacturing, enrolled patients receive lymphodepleting chemotherapy followed by LYL845 infusion at the assigned dose level. High-dose IV IL-2 is then administered every 8 hours for up to 6 doses as tolerated (Figure 4)

Figure 3: Dose-escalation and dose-expansion study design

Dose-escalation						Dose-expansion
(Part A)						(Part B)
Melanoma only						n = 15 - 30 per cohorta
			The RP2DR moves			Melanoma
			forward to
Dose Level 2			expansion cohort
					NSCLC
Dose Level 1
Dose Level -1						CRC
						aIncluding dose-escalation patients at RP2DR

Figure 4: Timeline of screening, treatment, and disease/safety assessments

Study ICF

Enroll

Bridging

therapy

allowed

TIL tissue collection

Lymphodepletion

High-doseIL-2

Screening

Day -7 to Day -2

begin 2hr after LYL845 infusion

LYL845 post-treatment F/U

and post-op recovery

flu 25 mg/m2/day IV on D-7 to D-2

600,000 IU/kg IV every 8 hours as

+ cy 30 mg/kg/day IV on D-7 to D-6

tolerated for up to 6 doses

Single-dose infusion LYL845

Day 1

						Disease/safety assessments
		LYL845 manufacturing
Up to 8 weeks		~6 weeks		5 Days		Up to 5 years

Tumor assessments (baseline, prior to lymphodepletion if	Biopsies	Post-treatment assessments (2d, 3d, 4d, 5d, 6d,
received bridging therapy, 28d, 2m, 3m, 6m, 9m, 12m, 18m,	•	Day 22 required	7d, 8d, 15d, 22d, 2m, 3m, 6m, 9m, 12m, 18m,
24m, 30m, 36m, 42m, 48m, 54m, and 60m)	•	Post-treatment/progression optional	24m, 30m, 36m, 42m, 48m, 54m, and 60m)

Key Eligibility Criteria

Key Inclusion Criteria

Disease

• Confirmed diagnosis of R/R metastatic or locally advanced or unresectable melanoma, NSCLC, or CRC
• Measurable disease that includes a target lesion (≥10 mm) or lymph node (≥15 mm), plus one additional lesion ~1.5 x 1.5 cm that is safely resectable

͵ Two lesions may be combined to achieve this volume

Subject Health

• ≥18 years of age at time of informed consent
• ECOG PS of 0 - 1
• Adequate organ and marrow function per protocol

Key Exclusion Criteria

Disease

• Active CNS or leptomeningeal disease
  Prior Treatment
• No prior solid organ transplant or adoptive cell therapy
  Subject Health
• Untreated or active infections at time of screening or TIL tissue collection surgery
• Uncontrolled pleural or pericardial effusion or ascites
• HIV or active acute or chronic HBV or HCV
• Other malignancy within 3 years prior unless treated with expected curative outcome
• Significant cardiovascular disease
• Required chronic anticoagulation (stable regimen may be allowed)
• Pregnant or lactating women

Participating Sites

Participating study locations

• UCLA Medical Center, Los Angeles, CA
• Yale School of Medicine, Smilow Cancer Hospital, New Haven, CT

• Georgetown University, Washington, DC

• Massachusetts General Hospital, Boston, MA

• Rutgers Cancer Institute of New Jersey,

New Brunswick, NJ

• Hackensack Meridian Health, Inc.,

Hackensack, NJ

• Duke University Medical Center, Durham, NC

• The Ohio State University Medical Center, Columbus, OH
• Oregon Health Sciences University, Portland, OR
• Allegheny General Hospital, Pittsburgh, PA
• Huntsman Cancer Institute, Salt Lake City, UT
• Fred Hutchinson Cancer Center, Seattle, WA

Abbreviations

CD, cluster of differentiation; CNS, central nervous system; CRC, colorectal cancer; cy, cyclophosphamide; d, days; ECOG PS, Eastern Cooperative Oncology Group performance status; F/U, follow up; flu, fludarabine; HBV, hepatitis B virus; HCV, hepatitis C virus;

HIV, human immunodeficiency virus; ICF, informed consent form; IL-2,interleukin-2; IV, intravenous; m, months; n, number of patients; NSCLC, non-small cell lung cancer; RP2DR, recommended phase 2 dose range; R/R, relapsed/refractory; TIL, tumor-infiltrating lymphocyte.

References

1. Krishna S, et al. Science. 2020;370(6522):1328-1334.2. Rosenberg SA, et al. Clin Cancer Res. 2011;17(13):4550-4557.3. Patel Y, et al. Poster presented at the 37th SITC Annual Meeting 2022, November 8-12, 2022. Abstract 370. 4. Park S, et al. Poster presented at the AACR Annual Meeting 2022, April 8-13, 2022. Abstract 2754. 5. Harris BD, et al. Poster presented at the 37th SITC Annual Meeting 2022, November 8-12, 2022. Abstract 340. 6. Patel Y, et al. Poster presented at the AACR Special Conference: Tumor Immunology and Immunotherapy 2022, October 21-24, 2022. Abstract A54. 7. Dudley ME, et al. J Immunother. 2003;26(4):332-342.

Acknowledgments

We would like to thank the patients, their families, and their caregivers for participation in this study as well as the study site staff for their contributions. Medical writing and editorial support were funded by Lyell Immunopharma and provided by Madison Fagan, PhD of BOLDSCIENCE, Inc.

Presented at SITC Annual Meeting 2023; Nov 1 - 5; San Diego, CA, USA