c-Jun

Accelerating IMPT-314 in large B-cell lymphoma; remain on track to initiate pivotal trial in the 3rd line+ setting in 2025 and expect to initiate a pivotal trial in the 2nd line by early 2026Presenting additional data from the ongoing Phase 1-2 trial in 3rd line+ setting and initial clinical data in 2nd line setting in mid-2025Discontinuing development of LYL119, a ROR1-targeting CAR T-cell product candidate for solid tumors, to focus resources on acceleration of pivotal trials of IMPT-314 and next-generation solid tumor CAR T cell programs in preclinical developmentExpected net cash use of $175 million - $185 million for 2025 extends cash runway further into 2027 through multiple value-creating clinical catalysts, including new pivotal programsLynn Seely, MD, President and Chief Executive Officer, to present at J.P. Morgan conference on January 15th at 9:00 a.m. PT SOUTH SAN FRANCISCO, Calif., Jan. 09, 2025 (GLOBE NEWSWIRE) -- Lyell Immunopharma, Inc. (Nasdaq: LYEL), a clinical-stage company advancing a pipeline of next-generation CAR T-cell therapies for patients with cancer, today announced pipeline updates, including its plans to advance IMPT-314, a potentially best-in-class therapy for aggressive large B-cell lymphoma, into pivotal trials. IMPT-314 is an autologous dual-targeting CD19/CD20 chimeric antigen receptor (CAR) T-cell product candidate designed to increase complete response rates and prolong the duration of the responses as compared to the approved CD19‑targeted CAR therapies for the treatment of large B-cell lymphoma. “Based on the positive initial clinical data reported at ASH and the promising emerging clinical profile, we are accelerating the development of IMPT-314 as a potentially transformative product with differentiated benefit in overall and complete response rates as well as duration of response over first-generation CD19 CAR therapies in patients with aggressive large B-cell lymphoma,” said Lynn Seely, M.D., Lyell’s President and Chief Executive Officer. “Having presented an initial dataset that demonstrated an overall response rate of 94% and a complete response rate of 71% in patients treated in the 3rd-line+ setting, we are focusing our resources on advancing IMPT-314 for patients with large B-cell lymphoma in both the 2nd and 3rd line+ settings. To ensure a sustainable cost structure that delivers multiple clinical readouts with our current balance sheet, we have streamlined and focused our pipeline and organization to prioritize investment in IMPT-314 and early-stage research programs for solid tumors.” Pipeline Focus Lyell is focused on advancing next-generation CAR T cell therapies with the potential to deliver higher response rates and longer duration of responses for patients with hematologic malignancies and solid tumors. Lyell is developing products enhanced with its novel technologies and manufacturing protocols. In hematologic malignancies, Lyell is focused on advancing products designed to deliver improved outcomes over first-generation CD19 CAR T cell therapies. Lyell’s lead program, IMPT-314, is a dual-targeting CD19/CD20 CAR T-cell product candidate designed to increase complete response rates and prolong the duration of the responses as compared to the currently approved CD19‑targeted CAR therapies for the treatment of large B-cell lymphoma. IMPT-314 is designed with a true ‘OR’ logic gate to target B-cells that express either CD19, CD20 or both and is manufactured through a process that enriches for CD62L-expressing cells to generate more naïve central memory CAR T cells with enhanced stemlike features and antitumor activity. To realize the potential of cell therapy for solid tumors, Lyell is also developing next-generation CAR T-cell product candidates enhanced with anti-exhaustion and additional arming technologies, and manufactured with proprietary protocols. These approaches are designed to endow CAR T cells with attributes needed to drive durable tumor cytotoxicity and achieve consistent and long-lasting clinical responses – the ability to resist exhaustion, maintain qualities of durable stemness and function in the hostile tumor microenvironment. Upcoming Milestones and Financial Outlook For IMPT-314, a next-generation dual-targeting CD19/CD20 CAR T-cell product candidate for the treatment of large B-cell lymphoma: Present data from the ongoing Phase 1-2 trial in mid-2025, including more mature data from the 3rd line+ cohort and initial data from the 2nd line cohortPresent more mature clinical data from the 2nd line cohort in late 2025Initiate a pivotal trial in the 3rd line+ setting in mid-2025Initiate a pivotal trial in the 2nd line setting by early 2026 For early-stage solid tumor programs: Submit first IND application for a new solid tumor CAR T-cell product candidate in 2026 To accelerate the pivotal trials of IMPT-314 and focus resources on next-generation solid tumor CAR T-cell programs in preclinical development, Lyell has streamlined its operations and is discontinuing development of LYL119, its ROR1-targeting CAR T cell product candidate, and IMPT-514, an autoimmune disease program previously initiated by ImmPACT Bio that was acquired by Lyell in connection with its acquisition of ImmPACT Bio. Lyell expects net cash use in 2025 to be $175 million - $185 million, which extends its cash runway further into 2027 through multiple clinical milestones. J.P. Morgan Healthcare Conference Members of Lyell’s senior management team will present and participate in the 43rd Annual J.P. Morgan Healthcare Conference on Wednesday, January 15th at 9:00 am PT. A live webcast of the presentation can be accessed through the Investors section of the Company's website at www.lyell.com. Following the live presentation, a replay of the webcast will be available on the Company's website. About IMPT-314 IMPT-314 is a next-generation dual-targeting CD19/CD20 CAR T-cell product candidate designed to increase complete response rates and prolong the duration of the responses as compared to the approved CD19‑targeted CAR therapies for the treatment of large B-cell lymphoma. IMPT-314 is designed with a true ‘OR’ logic gate to target, with high potency, B cells that express either CD19, CD20 or both. IMPT-314 is manufactured to produce a CAR T-cell product with higher proportions of naïve and central memory T cells through a process that enriches for CD62L-expressing cells. This manufacturing process is designed to generate more naïve central memory CAR T cells with enhanced stemlike features and antitumor activity. IMPT-314 has received Fast Track Designation from the U.S. Food and Drug Administration for the treatment of relapsed/refractory aggressive B-cell lymphoma. Initial data from 23 patients with relapsed or refractory, CAR T-naive large B-cell lymphoma who received IMPT-314 were reported at the 2024 American Society of Hematology Annual Meeting. The efficacy evaluable population consisted of 17 patients. The overall response rate was 94% (16/17 patients), with 71% (12/17 patients) achieving a complete response by three months. The median follow up was 6.3 months (range 1.2 – 12.5 months) and 71% of patients were in response at last follow-up. In the safety evaluable population of 23 patients, no Grade 3+ CRS was reported. Grade 3 ICANS was reported in 13% (3/23) of patients with a median time to complete ICANS resolution of 5 days, and rapid improvement to Grade 2 or lower with standard therapy. About Lyell Lyell is a clinical-stage company advancing a pipeline of next-generation CAR T-cell therapies for patients with hematologic malignancies and solid tumors. To realize the potential of cell therapy for cancer, Lyell utilizes a suite of technologies to endow CAR T cells with attributes needed to drive durable tumor cytotoxicity and achieve consistent and long-lasting clinical responses – the ability to resist exhaustion, maintain qualities of durable stemness and function in the hostile tumor microenvironment. Lyell is based in South San Francisco, California with facilities in West Hills, California and Seattle and Bothell, Washington. To learn more, please visit www.lyell.com. Forward Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements expressed or implied in this press release include, but are not limited to, statements regarding: the anticipated benefits IMPT-314, including its potential to increase complete response rates and prolong duration of the responses as compared to approved CD19-targeted CAR therapies for the treatment of B-cell lymphoma; the continued clinical progress of the IMPT-314 trials and expectations around the timing of updated clinical data and the timing and design of pivotal trials of IMPT-314; the timing of the submission of an IND application for a solid tumor CAR T-cell product; Lyell’s expectation regarding its net cash use and cost structure and that its financial position and cash runway will support advancement of its pipeline through multiple clinical milestones into 2027; the ability of Lyell’s technology to generate CAR T cells with attributes needed to drive durable tumor cytotoxicity in the setting of a hostile solid tumor microenvironment, resist exhaustion and maintain qualities of durable stemness to achieve consistent and long-lasting clinical responses; Lyell’s anticipated progress, business plans, business strategy and clinical trials; and other statements that are not historical fact. These statements are based on Lyell’s current plans, objectives, estimates, expectations and intentions, are not guarantees of future performance and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, but are not limited to, risks and uncertainties related to: the inability to recognize the anticipated benefits of Lyell’s recent acquisition of ImmPACT Bio and successful integration of ImmPACT Bio’s business with Lyell’s; the effects of macroeconomic conditions, including any geopolitical instability and actual or perceived changes in interest rates and economic inflation; Lyell’s ability to submit planned INDs or initiate or progress clinical trials on the anticipated timelines, if at all; Lyell’s limited experience as a company in enrolling and conducting clinical trials, and lack of experience in completing clinical trials; Lyell’s ability to manufacture and supply its product candidates for its clinical trials; the nonclinical profiles of Lyell’s product candidates or technology 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 Lyell’s product candidates; the significant uncertainty associated with Lyell’s product candidates ever receiving any regulatory approvals; Lyell’s ability to obtain, maintain or protect intellectual property rights related to its product candidates; implementation of Lyell’s strategic plans for its business and product candidates; the sufficiency of Lyell’s capital resources and need for additional capital to achieve its goals; and other risks, including those described under the heading “Risk Factors” in Lyell’s Annual Report on Form 10-K for the year ended December 31, 2023, filed with the Securities and Exchange Commission (SEC) on February 28, 2024, and the Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, filed with the SEC on November 7, 2024. Forward-looking statements contained in this press release are made as of this date, and Lyell undertakes no duty to update such information except as required under applicable law. Contact:Ellen RoseSenior Vice President, Communications and Investor Relationserose@lyell.com

Currently, only three CXCR4 (C-X-C motif chemokine receptor 4) antagonists have been approved globally: Plerixafor, Motixafortide, and Mavorixafor, indicating significant market potential. With a deeper understanding of the role of CXCR4 in tumor progression, the demand for CXCR4 antagonists continues to grow. In 2024, the global CXCR4 antagonist market is valued at several billion RMB, with steady growth projected in the coming years. Key players in the global market include Sanofi, BioLineRx, X4 Pharmaceuticals, Eli Lilly, and Roche. The increasing global aging population and the rising incidence of chronic diseases such as cancer create a vast market opportunity for anti-tumor drugs like CXCR4 antagonists. Advances in drug development further inject vitality into the CXCR4 antagonist market. Global Transactions of CXCR4 Antagonists in Patsnap SynapseMechanism of Action of CXCR4 AntagonistsSchematic diagram of CXCR4[1]CXCR4 is a seven-transmembrane G-protein-coupled receptor (GPCR) widely expressed across various cell types, particularly immune cells, hematopoietic stem cells, endothelial cells, and numerous tumor cells. Its primary ligand is the chemokine CXCL12 (also known as SDF-1, stromal cell-derived factor 1). Binding of CXCL12 to CXCR4 induces conformational changes in CXCR4, activating the G-protein complex. The G-protein complex dissociates into Gα and Gβγ subunits, with Gβγ activating the PI3K and RAS-MAPK pathways. CXCL12-CXCR4/CXCR7 signaling pathway[2]Subsequently, the Gβγ subunit activates guanine nucleotide exchange factors (GEFs), such as SOS. These GEFs facilitate the exchange of GDP for GTP on RAS proteins, activating them. Activated RAS proteins, in turn, stimulate the MAPK (mitogen-activated protein kinase) and MEK1/2 (mitogen-activated protein kinase kinase 1/2) pathways. Activated MEK1/2 phosphorylates and activates ERK1/2 (extracellular signal-regulated kinases 1/2). ERK1/2 activation promotes cell proliferation and survival. Additionally, ERK1/2 can activate transcription factors such as c-Fos and c-Jun, further regulating gene expression. Once activated, ERK1/2 enters the nucleus and phosphorylates various transcription factors, including c-Fos and c-Jun, which bind to specific DNA sequences to regulate gene expression, ultimately affecting cell proliferation, differentiation, and survival. When CXCR4 interacts with CXCL12, it activates signaling pathways including RAS-MAPK, PI3K-AKT-mTOR, JAK-STAT, and PLC. These pathways play crucial roles in cell migration, proliferation, and survival. Under normal physiological conditions, CXCR4 is critical for regulating cell migration and localization during development, homeostasis, and inflammation, aiding immune system activation and facilitating cell movement. High CXCR4 expression is associated with poor prognosis and chemotherapy resistance in various cancer subtypes, partly due to enhanced interactions between cancer cells and the stroma. The CXCR4/CXCL12 signaling axis plays a central role in tumor progression through autocrine and paracrine mechanisms. Similar to other GPCRs, CXCR4 undergoes homo- or heterodimerization in its functional signaling regions on the cell surface. Receptor aggregation in dimers or oligomers significantly enhances the sensitivity and intensity of chemokine responses. Schematic representation of the signaling pathways activated by CXCR4[3]CXCR4 antagonists block the binding of CXCL12 to CXCR4, inhibiting tumor cell migration and invasion, reducing HIV infection and transmission, regulating immune cell migration, and promoting hematopoietic stem cell mobilization, showcasing significant applications across multiple fields. In oncology, CXCR4 antagonists like Motixafortide, combined with Keytruda and chemotherapy, have significantly improved objective response rates (ORR) and progression-free survival (PFS) in patients with advanced pancreatic ductal adenocarcinoma and demonstrated antitumor effects in breast and lung cancers. For HIV treatment, CXCR4 antagonists like Plerixafor and AMD3100 reduce viral infection and spread by blocking HIV-CXCR4 interactions while enhancing the host immune response. In autoimmune diseases, CXCR4 antagonists mitigate inflammatory responses by reducing immune cell migration, alleviating symptoms in conditions like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In hematopoietic stem cell mobilization, CXCR4 antagonists such as Plerixafor and Motixafortide facilitate the release of hematopoietic stem cells from bone marrow into peripheral blood for autologous transplantation in diseases like non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). Market Drivers for CXCR4 Antagonist DevelopmentWith advancements in precision medicine, targeted therapeutics are increasingly prioritized. As a critical target in various diseases, CXCR4 antagonist development aligns with the precision medicine trend. CXCR4 antagonists hold significant value in treating hematological disorders such as multiple myeloma. Furthermore, these antagonists are being explored for new indications like breast cancer, WHIM syndrome, and Waldenström’s macroglobulinemia, all of which represent substantial patient populations and offer vast market potential. The combination of CXCR4 antagonists with other therapies, such as chemotherapeutics and immune checkpoint inhibitors, markedly enhances therapeutic efficacy and addresses clinical needs. Additionally, governmental and regional policy and financial support for innovative drug development have attracted extensive attention to and support for CXCR4 antagonists as promising innovative drugs. Top 10 Indications of CXCR4 Antagonists in Patsnap SynapseTechnological advancements and innovation have significantly driven the development of CXCR4 antagonists. Novel small-molecule antagonists such as Plerixafor and Mavorixafor, as well as peptide-based antagonists like Motixafortide, have demonstrated high affinity and favorable pharmacological efficacy. The application of antibody-based therapies and nanotechnology has further enhanced drug specificity and effectiveness. Multiple clinical trials have highlighted the substantial efficacy and safety of CXCR4 antagonists across various diseases. Some of these drugs have received FDA designations as Breakthrough Therapies or Fast Track therapies, expediting their development and approval. Targets of CXCR4 Antagonists in Patsnap SynapseRegional Development Analysis of CXCR4 AntagonistsNorth America leads in the development and market adoption of CXCR4 antagonists due to its advanced medical technology and robust regulatory framework. Significant investments from both the U.S. government and private sector have spurred research by major pharmaceutical companies and biotech startups. With a substantial patient population suffering from cancers, HIV infections, immune disorders, and requiring hematopoietic stem cell transplants, demand for CXCR4 antagonists remains strong. Key drugs, including Plerixafor and Mavorixafor, have achieved notable progress in this region. Regional Distribution of CXCR4 Antagonist Research and Development in Patsnap SynapseIn Europe, biopharmaceutical R&D is highly active, with many institutions and companies advancing work on CXCR4 antagonists. While the European Medicines Agency (EMA) maintains stringent drug approval processes, it is continuously optimizing these procedures to accelerate the market entry of innovative medicines. Europe's comprehensive healthcare systems and high patient receptivity to novel therapies drive demand for CXCR4 antagonists in oncology, HIV, immune disorders, and stem cell transplantation. Prominent drugs such as Motixafortide and Balixafortide are undergoing extensive clinical trials in the region. In Asia, particularly in countries like China, Japan, and South Korea, the biopharmaceutical market is expanding rapidly, with increasing demand for innovative drugs. Rich clinical trial resources and a large patient base create favorable conditions for CXCR4 antagonist research. The region exhibits significant potential due to its high prevalence of cancers, HIV infections, immune disorders, and stem cell transplant requirements. Representative drugs, such as Balixafortide, introduced by Fosun Pharma, are undergoing clinical trials for breast cancer. Numerous Asian pharmaceutical companies and research institutions are actively developing various CXCR4 antagonists. Market Competition Landscape for CXCR4 AntagonistsDevelopment Stage Distribution of CXCR4 Antagonists in Patsnap SynapsePlerixafor was the first FDA-approved CXCR4 antagonist, primarily used in autologous hematopoietic stem cell transplantation. Sanofi holds a first-mover advantage in the CXCR4 antagonist market, with a significant market share. The successful application of Plerixafor in stem cell transplantation has provided Sanofi with valuable data and experience, enabling further exploration of additional indications. For instance, Sanofi is investigating the potential of Plerixafor in oncology, particularly in enhancing immune cell infiltration within the tumor microenvironment and improving the efficacy of immunotherapies. Moreover, Sanofi is exploring Plerixafor's application in HIV treatment, aiming to reduce viral infection and transmission by blocking the interaction between HIV and CXCR4. Major Research Institutions for CXCR4 Antagonists in Patsnap SynapseThe CXCR4 antagonist Mavorixafor, the flagship product of X4 Pharmaceuticals, has received FDA priority review designation for the treatment of WHIM syndrome. WHIM syndrome is a rare primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia, and bone marrow abnormalities. The approval of Mavorixafor represents the first targeted therapy for WHIM syndrome, addressing an unmet medical need. In Phase 3 clinical trials for WHIM syndrome, Mavorixafor demonstrated positive outcomes, including favorable safety and efficacy profiles. These clinical results not only supported its regulatory submission but also bolstered X4 Pharmaceuticals’ market presence and investor confidence. Additionally, X4 Pharmaceuticals is actively exploring the use of Mavorixafor in other conditions, such as HIV infection and certain forms of chronic neutropenia. CXCR4 Antagonist Portfolio of X4 Pharmaceuticals in Patsnap SynapseBioLineRx's Motixafortide has shown remarkable efficacy in the treatment of pancreatic cancer and other malignancies. In collaboration with major pharmaceutical companies such as Merck and Roche, BioLineRx is advancing the development and commercialization of Motixafortide. Clinical trial data indicate that the combination of Motixafortide with Keytruda and chemotherapy significantly improves objective response rates (ORR) and progression-free survival (PFS) in patients. Motixafortide has also demonstrated promising results in autologous hematopoietic stem cell transplantation (ASCT). When combined with granulocyte colony-stimulating factor (G-CSF), Motixafortide substantially enhances the efficiency and quality of CD34+ stem cell collection. In the GENESIS global Phase 3 trial, the combination achieved significantly higher success rates compared to the placebo group, with 88.8% of patients achieving an optimal CD34+ cell dose in a single apheresis session and 92.5% in up to two sessions. Beyond pancreatic cancer and ASCT, BioLineRx is investigating Motixafortide in other oncology applications, including breast cancer, gastric cancer, and prostate cancer. Preliminary findings suggest that Motixafortide enhances antitumor immune responses by blocking CXCR4 receptors, reducing immunosuppressive cells in the tumor microenvironment, and increasing the infiltration of effector T cells and other antitumor immune cells. BioLineRx is also exploring combination therapies involving Motixafortide and other immunotherapies, such as PD-1 inhibitors and chemotherapeutic agents, which have demonstrated synergistic effects in early studies. CXCR4 Antagonist Portfolio of BioLineRx in Patsnap SynapseBioLineRx has established strategic partnerships with major pharmaceutical companies such as Merck and Roche to jointly develop and promote Motixafortide. These collaborations have accelerated the clinical research and market entry of Motixafortide, enhancing its global market presence. For example, BioLineRx partnered with Merck to conduct clinical trials of Motixafortide in combination with Keytruda for the treatment of pancreatic cancer. Additionally, BioLineRx collaborated with China-based Genfleet Therapeutics to develop Motixafortide for the Chinese market. Genfleet is independently responsible for designing and developing first-line combination therapies targeting advanced pancreatic ductal adenocarcinoma in mainland China. This partnership expedites Motixafortide's entry into the Chinese market, addressing the treatment needs of local patients. Fosun Pharma, through its collaboration with Polyphor, introduced Balixafortide for the treatment of breast cancer and other potential cancers. Balixafortide has demonstrated notable efficacy in breast cancer treatment. Clinical trial data from Fosun Pharma showed that Balixafortide, combined with eribulin mesylate injection, exhibited good efficacy and safety in HER2-negative metastatic breast cancer patients. In a global Phase 3 clinical trial, this combination achieved an objective response rate (ORR) of 40%, a median progression-free survival (mPFS) of 8.5 months, and a disease control rate (DCR) of 75%. Fosun Pharma is also exploring the application of Balixafortide in other cancers, such as pancreatic ductal adenocarcinoma (PDAC). According to an announcement by Spexis AG, Balixafortide demonstrated good safety and efficacy in PDAC patients, inhibiting tumor growth and metastasis. Additionally, Fosun Pharma is investigating combination therapies involving Balixafortide and other chemotherapeutic agents. For instance, the combination of Balixafortide with eribulin not only enhanced therapeutic efficacy but also reduced side effects, improving patients' quality of life. This combined therapy strategy offers new approaches to cancer treatment. ConclusionCXCR4 antagonists demonstrate immense potential across various medical fields, particularly in oncology, HIV infection, immune disorders, and hematopoietic stem cell transplantation. Advances in technology and supportive policies have provided robust backing for the development of CXCR4 antagonists, which hold promising market prospects. As more clinical trials are conducted and new drugs are approved, CXCR4 antagonists are poised to become vital tools for treating diverse diseases, offering hope and new options for patients. 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! Refrence  1.Yu, J., X. Zhou, and L. Shen, CXCR4-Targeted Radiopharmaceuticals for the Imaging and Therapy of Malignant Tumors. Molecules, 2023. 28(12).2.Yang, Y., et al., CXCL12-CXCR4/CXCR7 Axis in Cancer: from Mechanisms to Clinical Applications. Int J Biol Sci, 2023. 19(11): p. 3341-3359.3.Bianchi, M.E. and R. Mezzapelle, The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration. Front Immunol, 2020. 11: p. 2109.

Acquired ImmPACT Bio and strengthened clinical pipeline with the addition of IMPT-314, a dual-targeting CD19/CD20 CAR T-cell product candidate with strong Phase 1 clinical data in patients with aggressive relapsed/refractory B-cell non-Hodgkin’s lymphomaPresenting initial data from Phase 1 multi-center clinical trial of IMPT-314 at the American Society of Hematology 2024 (ASH) Annual MeetingPresenting three abstracts at the Society for Immunotherapy of Cancer (SITC) 2024 Annual Meeting highlighting anti-exhaustion technology and product candidates being advanced in Lyell’s pipelineCash, cash equivalents and marketable securities of $460.7 million as of September 30, 2024 funds the Company through multiple clinical milestones into 2027 SOUTH SAN FRANCISCO, Calif., Nov. 07, 2024 (GLOBE NEWSWIRE) -- Lyell Immunopharma, Inc. (Nasdaq: LYEL), a clinical‑stage T‑cell reprogramming company advancing a diverse pipeline of cell therapies for patients with solid tumors or hematologic malignancies, today reported financial results and business highlights for the third quarter ended September 30, 2024. “With our acquisition of ImmPACT now complete, we plan to accelerate the development of IMPT-314, a dual-targeting CD19‌/‌CD20 CAR T-cell product candidate we believe has the potential to deliver increased complete response rates with longer duration of response over approved CD19 CAR T-cell therapies for patients with aggressive B‑cell non‑Hodgkin’s lymphoma,” said Lynn Seely, M.D., Lyell’s President and CEO. “We look forward to presenting the initial data from the Phase 1 trial of IMPT-314 at ASH next month and expect to initiate a pivotal clinical trial in 2025. In addition, site selection and initiation is progressing well for our Phase 1 trial of LYL119, our next-generation ROR1‑targeted CAR T‑cell product candidate designed with four technologies to generate T cells with even greater capacity to resist exhaustion. Our strong cash position enables us to advance our pipeline through important clinical milestones and fund operations into 2027.” Third Quarter Updates and Recent Business Highlights Lyell is advancing two wholly-owned product candidates: IMPT-314 is in Phase 1-2 clinical development and LYL119 is entering Phase 1 clinical development. Lyell is also advancing next-generation CAR T-cell product candidates for solid tumors, which are in preclinical development. IMPT-314 – A next-generation dual-targeting CD19/CD20 CAR T-cell product candidate designed for improved response rates with enhanced durability for the treatment of large B-cell lymphoma (LBCL) IMPT-314 is an autologous CAR T-cell product candidate enriched with naïve and central memory T cells during the manufacturing process. The Phase 1-2 clinical trial is a multi-center, open-label clinical trial designed to evaluate the tolerability and clinical benefit of IMPT-314 in patients with relapsed/refractory LBCL and determine a recommended Phase 2 dose. The trial is enrolling three cohorts of patients including CAR T-naïve patients in the third-line setting, CAR T-naïve patients in the second-line setting and CAR T-experienced patients. IMPT-314 has received Fast Track Designation from the U.S. Food and Drug Administration for the treatment of relapsed/refractory aggressive B-cell lymphoma.Initial data from Phase 1-2 trial will be presented at the ASH 2024 Annual Meeting on December 9, 2024.Expect to initiate a pivotal trial in 2025 in patients with relapsed/refractory large B-cell lymphoma in the third-line setting who have not yet been exposed to CAR T-cell therapy. LYL119 – A next-generation ROR1-targeted CAR T-cell product candidate enhanced with four stackable and complementary anti-exhaustion technologies LYL119 is an autologous ROR1-targeted CAR T-cell product candidate enhanced with four novel technologies: c-Jun overexpression, NR4A3 knockout, Epi-R manufacturing protocol and Stim‑RTM T-cell activation technology designed to enable T-cells to resist exhaustion and to enhance their stem-like qualities.The Phase 1 trial is designed as an open‑label dose‑escalation and ‑expansion trial in patients with ROR1‑positive solid tumors and will initially enroll patients with ROR1‑positive platinum‑resistant ovarian cancer or endometrial cancer. It is estimated that approximately 50% of patients with ovarian cancer and approximately 50% of patients with endometrial cancer have ROR1‑positive tumors.Presenting a poster at the SITC 2024 Annual Meeting titled “Multiomic profiling of LYL119: A Reprogrammed ROR1 CAR T Product Generates T cells with Reduced Exhaustion and Enhanced Memory Characteristics Associated with Increased AP-1 and Reduced NR4A Bindings.” In a validated preclinical xenograft model of non-small cell lung cancer, LYL119 achieves complete tumor control and prolonged survival even at very low doses compared to LYL797, Lyell’s first generation ROR1-targeted CAR T‑cell product candidate. The study presents potential molecular mechanisms underlying the functional reduction of T-cell exhaustion and enhancement of memory‑related characteristics of LYL119 CAR T cells after antigen encounter in vitro and in vivo.Initial clinical data are expected in the second half of 2025. Third Quarter Financial Results Lyell reported a net loss of $44.6 million for the third quarter ended September 30, 2024, compared to a net loss of $50.9 million for the same period in 2023. Non‑GAAP net loss, which excludes non-cash stock-based compensation, non‑cash expenses related to the change in the estimated fair value of success payment liabilities and certain non-cash investment gains and charges, was $37.1 million for the third quarter ended September 30, 2024, compared to $43.0 million for the same period in 2023. GAAP and Non-GAAP Operating Expenses Research and development (R&D) expenses were $39.5 million for the third quarter ended September 30, 2024, compared to $43.8 million for the same period in 2023. The decrease in third quarter 2024 R&D expenses of $4.3 million was primarily driven by a decrease in personnel-related expenses associated with Lyell’s November 2023 reduction in workforce. Non‑GAAP R&D expenses, which exclude non-cash stock-based compensation and non-cash expenses related to the change in the estimated fair value of success payment liabilities for the third quarter ended September 30, 2024, were $35.9 million, compared to $40.5 million for the same period in 2023. The decrease in third quarter 2024 non-GAAP R&D expenses was primarily driven by a decrease in personnel-related expenses.General and administrative (G&A) expenses were $11.8 million for the third quarter ended September 30, 2024, compared to $15.5 million for the same period in 2023. The decrease in third quarter 2024 G&A expenses was primarily driven by decreases in non-cash stock-based compensation. Non‑GAAP G&A expenses, which exclude non-cash stock‑based compensation, for the third quarter ended September 30, 2024, were $7.8 million, compared to $9.5 million for the same period in 2023. The decrease in third quarter 2024 non-GAAP G&A expenses was primarily driven by a decrease in personnel-related expenses associated with Lyell’s November 2023 reduction in workforce. A discussion of non-GAAP financial measures, including reconciliations of the most comparable GAAP measures to non‑GAAP financial measures, is presented below under “Non-GAAP Financial Measures.” Cash, cash equivalents and marketable securities Cash, cash equivalents and marketable securities as of September 30, 2024, were $460.7 million, compared to $562.7 million as of December 31, 2023. Lyell believes that its cash, cash equivalents and marketable securities balances will be sufficient to meet working capital and capital expenditure needs into 2027. About Lyell Immunopharma, Inc. Lyell is a clinical-stage company advancing a pipeline of next-generation CAR T-cell therapies for patients with solid tumors or hematologic malignancies. Lyell’s product candidates are enhanced with novel technology designed to generate T cells that resist exhaustion and have qualities of durable stemness in order to drive durable tumor cytotoxicity and achieve consistent and long-lasting clinical response. Lyell is based in South San Francisco, California with facilities in Seattle and Bothell, Washington. To learn more, please visit www.lyell.com. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements expressed or implied in this press release include, but are not limited to, statements regarding: the anticipated benefits of Lyell’s acquisition of ImmPACT Bio; Lyell’s ability to accelerate the development of IMPT-314 and deliver increased complete response rates; Lyell’s initiation of a pivotal trial in 2025 for IMPT-314; Lyell’s development plans for LYL119 and the effectiveness of any technologies incorporated into LYL119; the ability of Lyell’s technology to enable and generate T cells that resist exhaustion and have qualities of durable stemness in order to drive durable tumor toxicity and achieve consistent and long-lasting clinical response; Lyell’s anticipated progress, business plans, business strategy and clinical trials; Lyell’s advancement of its pipeline and its research, development and clinical capabilities; the potential clinical benefits and therapeutic potential of Lyell’s product candidates; the advancement of Lyell’s technology platform; Lyell’s expectation that its financial position and cash runway will support advancement of its pipeline through multiple clinical milestones into 2027; expectations around enrollment and the timing of initial and updated clinical data from Lyell’s Phase 1-2 trial for IMPT-314 and Phase 1 trial for LYL119; and other statements that are not historical fact. These statements are based on Lyell’s current plans, objectives, estimates, expectations and intentions, are not guarantees of future performance and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, but are not limited to, risks and uncertainties related to: the inability to recognize the anticipated benefits of acquiring ImmPACT Bio and successful integration of ImmPACT Bio’s business with Lyell’s, including manufacturing IMPT-314 in Lyell’s LyFE manufacturing facility; the effects of macroeconomic conditions, including any geopolitical instability and actual or perceived changes in interest rates and economic inflation; Lyell’s ability to submit planned INDs or initiate or progress clinical trials on the anticipated timelines, if at all; Lyell’s limited experience as a company in enrolling and conducting clinical trials, and lack of experience in completing clinical trials; Lyell’s ability to manufacture and supply its product candidates for its clinical trials; the nonclinical profiles of Lyell’s product candidates or technology 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 Lyell’s product candidates; the significant uncertainty associated with Lyell’s product candidates ever receiving any regulatory approvals; Lyell’s ability to obtain, maintain or protect intellectual property rights related to its product candidates; implementation of Lyell’s strategic plans for its business and product candidates; the sufficiency of Lyell’s capital resources and need for additional capital to achieve its goals; and other risks, including those described under the heading “Risk Factors” in Lyell’s Annual Report on Form 10-K for the year ended December 31, 2023, filed with the Securities and Exchange Commission (SEC) on February 28, 2024, and the Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, being filed with the SEC today. Forward-looking statements contained in this press release are made as of this date, and Lyell undertakes no duty to update such information except as required under applicable law. Lyell Immunopharma, Inc.Unaudited Selected Consolidated Financial Data(in thousands) Statement of Operations Data: Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Revenue$34 $25 $50 $117 Operating expenses: Research and development(1) 39,500 43,849 122,935 135,950 General and administrative 11,769 15,507 37,519 53,816 Other operating income, net (730) (292) (2,796) (2,149)Total operating expenses 50,539 59,064 157,658 187,617 Loss from operations (50,505) (59,039) (157,608) (187,500)Interest income, net 5,965 6,608 19,148 16,369 Other (expense) income, net(1) (43) 1,578 402 2,352 Impairment of other investments — — (13,001) (12,923)Total other income, net 5,922 8,186 6,549 5,798 Net loss$(44,583) $(50,853) $(151,059) $(181,702) (1)Lyell’s success payment liability was recognized at fair value as Fred Hutch had provided the requisite service obligation to earn the potential success payment consideration under the continued collaboration. The change in the estimated fair value of Fred Hutch success payment liabilities beginning in Q1 2023 was recognized within other (expense) income, net in the unaudited Condensed Consolidated Statements of Operations and Comprehensive Loss. The change in the estimated fair value of Stanford success payment liabilities was recognized within research and development expenses in the unaudited Condensed Consolidated Statements of Operations and Comprehensive Loss. Balance Sheet Data: As of September 30, 2024 As of December 31, 2023 Cash, cash equivalents and marketable securities$460,659 $562,729Property and equipment, net$88,047 $102,654Total assets$619,215 $750,029Total stockholders’ equity$530,697 $654,952 Non-GAAP Financial Measures To supplement our financial results and guidance presented in accordance with U.S. generally accepted accounting principles (GAAP), we present non-GAAP net loss, non-GAAP R&D expenses and non-GAAP G&A expenses. Non‑GAAP net loss and non-GAAP R&D expenses exclude non-cash stock-based compensation expense and non-cash expenses related to the change in the estimated fair value of success payment liabilities from GAAP net loss and GAAP R&D expenses. Non-GAAP net loss further adjusts non‑cash investment gains and charges, as applicable. Non‑GAAP G&A expenses exclude non-cash stock-based compensation expense from GAAP G&A expenses. We believe that these non-GAAP financial measures, when considered together with our financial information prepared in accordance with GAAP, can enhance investors’ and analysts’ ability to meaningfully compare our results from period to period, and to identify operating trends in our business. We have excluded stock-based compensation expense, changes in the estimated fair value of success payment liabilities and non-cash investment gains and charges from our non‑GAAP financial measures because they are non-cash gains and charges that may vary significantly from period to period as a result of changes not directly or immediately related to the operational performance for the periods presented. We also regularly use these non-GAAP financial measures internally to understand, manage and evaluate our business and to make operating decisions. These non-GAAP financial measures are in addition to, and not a substitute for or superior to, measures of financial performance prepared in accordance with GAAP. In addition, these non-GAAP financial measures have no standardized meaning prescribed by GAAP and are not prepared under any comprehensive set of accounting rules or principles and, therefore, have limits in their usefulness to investors. We encourage investors to carefully consider our results under GAAP, as well as our supplemental non-GAAP financial information, to more fully understand our business. Lyell Immunopharma, Inc.Unaudited Reconciliation of GAAP to Non-GAAP Net Loss(in thousands) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Net loss - GAAP$(44,583) $(50,853) $(151,059) $(181,702)Adjustments: Stock-based compensation expense 7,622 10,516 25,061 38,621 Change in the estimated fair value of success payment liabilities (103) (2,706) (669) (3,309)Impairment of other investments — — 13,001 12,923 Net loss - Non-GAAP(1)$(37,064) $(43,043) $(113,666) $(133,467) (1)There was no income tax effect related to the adjustments made to calculate non-GAAP net loss because of the full valuation allowance on our net U.S. deferred tax assets for all periods presented. Lyell Immunopharma, Inc.Unaudited Reconciliation of GAAP to Non-GAAP Research and Development Expenses(in thousands) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Research and development - GAAP$39,500 $43,849 $122,935 $135,950 Adjustments: Stock-based compensation expense (3,625) (4,548) (11,282) (14,439)Change in the estimated fair value of success payment liabilities(1) 40 1,246 308 1,249 Research and development - Non-GAAP$35,915 $40,547 $111,961 $122,760 (1)Lyell’s success payment liability was recognized at fair value as Fred Hutch had provided the requisite service obligation to earn the potential success payment consideration under the continued collaboration. The change in the estimated fair value of Fred Hutch success payment liabilities beginning in Q1 2023 was recognized within other (expense) income, net in the unaudited Condensed Consolidated Statements of Operations and Comprehensive Loss. The change in the estimated fair value of Stanford success payment liabilities was recognized within research and development expenses in the unaudited Condensed Consolidated Statements of Operations and Comprehensive Loss. Lyell Immunopharma, Inc.Unaudited Reconciliation of GAAP to Non-GAAP General and Administrative Expenses(in thousands) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 General and administrative - GAAP$11,769 $15,507 $37,519 $53,816 Adjustments: Stock-based compensation expense (3,997) (5,968) (13,779) (24,182)General and administrative - Non-GAAP$7,772 $9,539 $23,740 $29,634 Contact:Ellen RoseSenior Vice President, Communications and Investor Relationserose@lyell.com