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Forward-looking statements Certain matters discussed in this
presentation are "forward-looking statements" of Lyell Immunopharma, Inc, Inc. (hereinafter referred to as the "Company," "we," "us," or "our") within the meaning of the Private Securities
Litigation Reform Act of 1995 (the "PSLRA"). All such written or oral statements made in this presentation, other than statements of historical fact, are forward-looking statements and are intended to be covered by the safe harbor for
forward-looking statements provided by the PSLRA. Without limiting the foregoing, we may, in some cases, use terms such as "predicts," "believes," "potential," "continue," "estimates,"
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"should" or other words that convey uncertainty of future events or outcomes and are intended to identify forward-looking statements. Forward-looking statements are based on assumptions and assessments made in light of management's
experience and perception of historical trends, current conditions, expected future developments and other factors believed to be appropriate. Forward looking statements in this presentation are made as of the date of this presentation, and we
undertake no duty to update or revise any such statements, whether as a result of new information, future events or otherwise. Forward-looking statements are not guarantees of future performance and are subject to risks, uncertainties and other
factors, many of which are outside of our control, that may cause actual results, levels of activity, performance, achievements, timelines and developments to be materially different from those expressed in or implied by these forward-looking
statements. Important factors that could cause actual results, developments and business decisions to differ materially from forward-looking statements are described in the sections titled "Risk Factors" in our filings with the
Securities and Exchange Commission (the "SEC"), and include, but are not limited to, the following substantial known and unknown risks and uncertainties inherent in our business related to: the effects of geopolitical instability;
macroeconomic conditions and the lingering effects of the COVID-19 pandemic; our ability to submit planned INDs or initiate or progress clinical trials on the anticipated timelines, if at all; our limited experience as a company in enrolling,
conducting or completing clinical trials; our ability to manufacture and supply our product candidates for our clinical trials; the nonclinical profiles of our product candidates not translating in clinical trials; the potential for results from
clinical trials to differ from nonclinical, early clinical, preliminary or expected results; significant adverse events, toxicities or other undesirable side effects associated with our product candidates; the significant uncertainty associated with
our product candidates ever receiving any regulatory approvals; our ability to obtain, maintain, or protect intellectual property rights related to our product candidates; implementation of our strategic plans for our business and product
candidates; the sufficiency of our capital resources and the need for additional capital to achieve our goals; other risks, including general economic conditions and regulatory developments, not within our control; and those risks described under
the heading "Risk Factors" in our SEC filings, including our Quarterly Report on Form 10-Q for the quarter ended June 30, 2023 and subsequent filings with the SEC. 2 PROPRIETARY
Advancing T cell therapies for solid tumors Clinical data from two lead
programs in 2024 Two clinical programs: wholly-owned, Executing a scalable manufacturing addressing large patient populations strategy LYL797: ROR1 targeted CAR T cell Lyell's LyFE center producing current clinical supply 1H2024: P1
clinical & translational data from 20+ patients 2024: Epi-R P2 process to shorten TIL manufacturing time TNBC, NSCLC without impacting cell number and phenotype Planning for the future LYL845: Tumor Infiltrating Lymphocyte (TIL)
CAR T cell proof-of-concept collaboration with Cellares 2024: P1 clinical & translational data to build scale and reduce cost Melanoma, NSCLC, CRC Portfolio of novel reprogramming ~$633 million in cash platform
technologies 1H2024: IND filing for LYL119, ROR1 targeted CAR T cell Runway into 2026 designed for enhanced potency and durability; using four of our technologies ROR1, receptor tyrosine kinase-like orphan receptor 1; TNBC,
triple-negative breast cancer; NSCLC, non-small-cell lung cancer; CRC, colorectal cancer; P1, Phase 1 3 PROPRIETARY
Lyell is developing two types of personalized cell therapy: Focused on
getting the T-cells right OUR GOAL: Reprogram T cells to defeat solid tumors Resist exhaustion Durable cytotoxicity CAR T cells Self-renewal Persistence Metastatic Durable cytotoxicity Tumor- cancer Maintain polyclonality infiltrating Right
phenotype lymphocytes Hot and cold tumors CAR, chimeric antigen receptor 4 PROPRIETARY
Lyell's T-cell reprogramming technologies are designed to address
primary barriers to success in solid tumors TO ACHIEVE SUCCESS IN SOLID TUMORS, CELL THERAPY MUST: RESIST EXHAUSTION, Maintain cancer cell killing in the immunosuppressive tumor microenvironment RETAIN FUNCTION ENHANCE DURABLE Increase ability to
self-renew and persist to drive durable tumor cytotoxicity STEMNESS 5 PROPRIETARY
Solid tumors drive T cells down a path to exhaustion Solid Hematologic
Autologous Infusion Autologous Infusion tumor malignancy CAR T cell CAR T cell Adequate cell Inadequate expansion, expansion, persistence, driven to exhaustion, and tumor killing and lack of durability Tumor cell Lack of T-cell clearance function;
cancer cells persist Riddell et al, Keystone, 2020 6 PROPRIETARY
Stackable technologies designed to generate potent T cells with durable
function GENETIC REPROGRAMMING EPIGENETIC REPROGRAMMING c-Jun NR4A3 Epi-R Stim-R overexpression knockout c-Jun and NR4A3 regulate the activator Manufacturing protocols that generate protein 1 (AP-1) transcription factor more stem-like
cells that self renew and pathway, which plays a key role in persist despite repeat antigen stimulation T-cell effector function Lynn, R. et al., Nature, 2019; Chen, J. et al., Nature, 2019 7 PROPRIETARY
A clinical-stage company with a growing pipeline of novel therapies for
solid tumors Genetic Epigenetic Product Reprogramming Reprogramming Target Phase 2 / Next Expected Candidate/ Target Preclinical Phase 1 Indications Pivotal Milestone Modality c-Jun NR4A3 Epi-R Stim-R TNBC LYL797 Initial data in NSCLC
ROR1 CAR T Cell 1H 2024 Other Solid Tumors ROR1+ LYL119 Submit IND in ROR1 CAR T Cell 1H 2024 Solid Tumors Melanoma LYL845 Multiple Initial data in CRC, NSCLC antigens Other Solid TIL 2024
Tumors 2nd Multiple Genetic and Epigenetic Solid Tumors Generation antigens Reprogramming TIL ROR1, receptor tyrosine kinase-like orphan receptor 1; IND, investigational new drug; CAR, chimeric antigen receptor; NSCLC, non-small cell lung cancer;
TNBC, triple-negative breast cancer; TIL, tumor infiltrating lymphocytes; CRC, colorectal cancer 8 PROPRIETARY
People with cancer need better therapies 90% <2 <3 Years Cancer
Years most deaths before metastatic cancer caused by cancer progresses solid patients tumors live after diagnosis seer.cancer.gov; Deaths (Estimated 2021); Survival Rates by Time Since Diagnosis, 2000-2017 CDC Nat'l Ctr for Health Statistics,
Mortality in the US, 2020 9 PROPRIETARY
Lyell product candidates target large unmet needs ~500K new cases and
~180K US deaths annually TRIPLE-NEGATIVE NON-SMALL CELL MELANOMA COLORECTAL BREAST CANCER LUNG CANCER CANCER 15% of breast cancer 84% of new lung 80% of all skin 3rd most common diagnoses in the US cancer diagnoses
cancer-related deaths form of cancer each year each year ~40,000 new cases ~200,000 new cases ~100,000 new cases ~150,000 new cases ~10,000 deaths ~110,000 deaths ~8,000 deaths ~53,000
deaths LYL797 LYL797 & LYL845 LYL845 LYL845 National Cancer Institute and the American Cancer Society and are based on US cases. (2022) 10 PROPRIETARY
Reprogramming T cells to target aggressive cancers LYL797: A
genetically and epigenetically reprogrammed ROR1 CAR T cell product candidate designed for differentiated potency and durability
LYL797 CAR T cell Phase 1 trial design Patient population
CLINICAL TRIAL DESIGN (mTPI-2) - Relapsed/Refractory TNBC patients who have Dose Escalation Dose Expansion failed two lines of therapy The RP2D - Relapsed/Refractory NSCLC patients who have Dose Level 4 moves failed one line of therapy
forward to LYL797 TNBC expansion - ROR1 positive Dose Level 3 cohort (N = ~15) Study objectives LYL797 NSCLC Dose Level 2 - Patient safety and tolerability (N = ~15) - Assessment of cytotoxicity and duration of Dose Level 1
T-cell function - Overall response rate and durability De-escalation if required - Recommended phase 2 dose Dose Level -1 - CAR T cell pharmacokinetics Potential to expand into additional tumor types NCT05274451 Spigel et al, ESMO
2022 mTPI-2, modified toxicity probability interval 2; NSCLC, non-small-cell lung cancer; ROR1, receptor tyrosine kinase-like orphan receptor 1; TNBC, triple-negative breast cancer; RP2D, recommended Phase 2 dose 12 PROPRIETARY
ROR1 is highly expressed in many human cancers and correlates with a
poor prognosis ROR1 expression ~60% ~40% Triple-negative Non-small cell breast cancer lung cancer ~50% ~95% Chronic Ovarian cancer lymphocytic leukemia In previous clinical trials and a non-human primate ROR1 CAR T cell toxicity study, no on-target
off-tumor toxicity from ROR1-targeted therapies have been reported ROR1, receptor tyrosine kinase-like orphan receptor 1 Jeong, Medicina, 2022; Chien, Virchows Arch 2016; Zhang, PNAS, 2014; Wang, NEJM Evidence, 2022; Berger, Cancer Immunol Res,
2015; Choi, Cell Stem Cell, 2018 13 PROPRIETARY
Lyell's ROR1 assay and screening program support current and
future clinical trials Screening data with Lyell's assay consistent with ROR1 expression in the literature TRIPLE-NEGATIVE BREAST CANCER 53% ROR1+ N=77 15% of breast cancer diagnoses/year ~40,000 new cases / ~10,000 deaths 33%
ROR1+ NON-SMALL CELL LUNG CANCER N=18 84% of new lung cancer diagnoses/year ~200,000 new cases / ~110,000 deaths ROR1, receptor tyrosine kinase-like orphan receptor 1; National Cancer Institute and the American Cancer Published
literature: Balakrishnan et al, Clin Cancer Res. 2017, Society and are based on US cases (2022) TNBC ~60%, NSCLC ~40% 14 PROPRIETARY
LYL797 clinical program supported by robust preclinical data ROR1 CAR T
cell + c-Jun + Epi-R Key differentiators Tumor reduction, enhanced cytokine production and tumor infiltration in aggressive NSCLC syngeneic animal model with c-Jun Stem-like phenotype, durability and enhanced cytotoxicity with Epi-R
technology Prolonged survival by combining c-Jun and Epi-R technologies (LYL797) in xenograft NSCLC animal model 15 PROPRIETARY
Superior preclinical efficacy demonstrated with c-Jun overexpressing
ROR1 CAR T cells in aggressive NSCLC model Lymphodepletion and Syngeneic Kras/p53 model that recapitulates human NSCLC NSCLC tumor-bearing mice CAR T cell +/- c-JUN Also recapitulates the barriers in treating human NSCLC with the
ROR1 CAR T cells Day 15 21 30 Extremely difficult model in which to achieve tumor regression Enhanced intratumoral function Enhanced infiltration Tumor control in 50% of mice IFN CAR T cell frequency in tumor Tumor volume WT
ROR1 CAR T cells WT ROR1 CAR T cells WT CAR T cell-treated mice c-Jun ROR1 CAR T cells c-Jun ROR1 CAR T cells c-Jun ROR1 CAR T cell-treated mice 6/12 progressing 6/12 stable/ regressing Pre-infusion 4 weeks * is p<.05 ** is p<.01 *** is
p<.001 **** is p<.0001 Riddell Lab, Fred Hutch, unpublished data 16 PROPRIETARY %CAR+ of PE-CD8+ mm^3
Epi-R technology produces transcriptionally distinct populations
of T cells that resist exhaustion and maintain cytotoxicity Distinct gene expression profile of Epi-R expanded cells Epi-R expanded cells demonstrate prolonged vs. standard preparation cytotoxicity after removal from Epi-R conditions Sequential cell
killing assay (ROR1 CAR T cells) Standard preparation Epi-R Mock Mock Standard Standard Preparation preparation Epi-R Epi-R UMAP_1 Time (Hours) Park et al., AACR 2022 Tumor target: H1975 17 PROPRIETARY UMAP_2 Relative target cell fluorescence
LYL797 combines c-Jun and Epi-R reprogramming technologies to
prolong survival in NSCLC (H1975) xenograft model LYL797 reduces tumor burden LYL797 prolongs survival 2500 100 2000 *** 1500 50 1000 500 **** 0 0 2500 2500 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Conventional Mock Conventional mock Conventional
Mock Conventional mock Days after T-cell injection Days after T-cell injection Conventional ROR1 CAR T Conventional ROR1 CAR T Conventional ROR1 CAR T Conventional ROR1 CAR T 2000 2000 2500 LY LYL7 L7 9 9 77 LY LYL7 L7 9 9 77 1500 1500 100 2000 ****
1000 1000 1500 50 1000 500 500 **** 500 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Days after T-cell Injection Park et al., ASGCT 2022 Days after T-cell injection *** is p<.001 **** is p<.0001 18
PROPRIETARY 6 6 2.5 x 10 5 x 10 CAR T dose CAR T dose 3 3 Tumor volume (mm ) Tumor volume (mm ) % survival % survival
Novel stackable technologies designed to improve potency and durability
LYL119: Innovative ROR1 CAR T cell product candidate designed for enhanced cytotoxicity
LYL119 incorporates novel stackable technologies designed to improve
potency and durability ROR1 CAR T cell + c-Jun + NR4A3 KO + Epi-R + Stim-R Key Differentiators Combining NR4A3 knockout and c-Jun overexpression further reduces T cell exhaustion and enhances cytotoxicity - Reducing NR4A expression
enhances T-cell function associated with increased expression of AP-1-regulated genes - NR4A family transcription factors may contribute to T-cell exhaustion by restraining c-Jun activity Stim-R CAR T cells demonstrate prolonged
persistence and enhanced cytotoxicity in response to serial antigen stimulation Lam et al., SITC, 2022 Li et al., SITC 2022 Chen J, et al. Nature. 2019; Tirosh I, et al. Science. 2016; Liu X, et al. Nature. 2019; Odagiu I, et al. Proc Natl Acad Sci
Stim-R technology mediates precise signal-molecule presentation during
T-cell activation Stim-R technology mimics physiologic presentation: - Multiple signals presented in precise densities and stoichiometries - Controlled presentation of both soluble and surface signals Stim-R technology is a
programmable cell-signaling platform T cells Soluble bio-signals Lipid-coated silica micro-rods Surface Stim-R Targeted T cell product bio-signals Li et al., SITC 2022 21 PROPRIETARY
Peripheral blood CD3+CAR+ numbers LYL119 is potent and eliminated H1975
(NSCLC) xenograft Peripheral blood CD3+CAR+ numbers 0.4e6 CAR T cells 8 10 0.4e6 CAR T cells 8 tumors even at low doses of CAR T cells 10 6 ** * 10 ** * 6 ** * Robust CAR T cells expansion10 Elimination of xenograft tumors at ** * 4 in vivo both low
and high CAR T cell doses 10 4 8 10 10 3000 2 10 2500 6 2 **** 10 10 ** * 2000 0 10 Low Dose 4 1500 10 0 5 0 10 20 30 40 10 4x10 CAR T cells day after T cell injection 0 10 20 30 40 1000 2 10 day after T cell injection NR4A3 KO g4 + c-Jun R12 CAR
500 NR4A3 KO g4 + c-Jun R12 CAR NR4A3 KO g47 + c-Jun R12 CAR 0 0 10 NR4A3 KO g47 + c-Jun R12 CAR LYL119 0 10 20 30 40 50 60 70 Control + c-Jun R12 CAR 0 10 20 30 40 50 days after T cell injection day after T cell injection Control + c-Jun R12 CAR
Mock Mock 8 3000 10 Mock 2500 ** ** 6 **** 10 2000 High Dose 4 1500 10 6 2x10 CAR T cells 1000 2 10 500 0 0 10 0 10 20 30 40 50 60 70 0 10 20 30 40 50 Lam et al., ASGCT, 2023 days after T cell injection day after T cell injection 22 PROPRIETARY 3 3
Tumor volume (mm ) Tumor volume (mm ) Cells per mL blood Cells per mL blood Cells per mL Cells per mL blood blood
Harnessing tumor-infiltrating lymphocytes to fight cancer LYL845: A
novel epigenetically reprogrammed TIL product candidate designed for differentiated potency and durability
LYL845 TIL Phase 1 trial design Patient population CLINICAL
TRIAL DESIGN (mTPI-2) - Relapsed and/or refractory metastatic or Dose Expansion* Dose Escalation locally advanced solid tumors: (Melanoma) - Melanoma RP2D moves LYL845 Melanoma - Non-small cell lung cancer forward to Dose Level 2
(N = ~ 15) expansion - Colorectal cancer cohort Study objectives LYL845 NSCLC Dose Level 1 (N = ~ 15) - Patient safety and tolerability De-escalation if required - Overall response rate and durability LYL845 Colorectal Dose
Level -1 - Recommended Phase 2 dose (N = ~ 15) - Evaluation of expansion, phenotype, clonal diversity and persistence NCT05573035 *Potential to expand into additional tumor types mTPI-2, modified toxicity probability interval 2; NSCLC,
non-small-cell lung cancer; RP2D, recommended Phase 2 dose 24 PROPRIETARY