Legend Biotech Unveils Advances in Solid Tumor and Allogeneic CAR-T Therapies at R&D Day

Today, at its R&D Day event, Legend Biotech presented its latest strategic initiatives and developments in cell therapy. cilta-cel, a CAR-T cell therapy targeting B-cell maturation antigen (BCMA) co-developed by Legend Biotech and Janssen, has demonstrated promising antitumor activity in clinical trials for the treatment of multiple myeloma. It has been granted Priority Review designation by the U.S. FDA and is expected to receive marketing approval by late November.

At today's R&D Day event, executives from Legend Biotech not only presented the latest R&D pipeline for cilta-cel, but also detailed the company's key R&D programs for solid tumor treatment, as well as breakthroughs in developing an innovative allogeneic CAR-T therapy technology platform.

Overcoming Barriers to CAR-T Therapy for Solid Tumors

Although CAR-T cell therapy has achieved significant advances in the treatment of hematologic malignancies, it has not yet demonstrated comparable efficacy in solid tumors. This is because the tumor microenvironment of solid tumors contains various immunosuppressive cells and cytokines that inhibit T-cell activity, and identifying antigens that are specifically expressed in solid tumors but not in healthy tissues remains challenging. Therefore, the development of CAR-T therapies targeting solid tumors requires multiple optimizations in therapeutic design.

▲CAR-T Therapy for Solid Tumors Needs to Overcome Multiple Challenges (Image Source: Legend Biotech Official Website)

CAR-T Cell Therapy for Gastric Cancer and Pancreatic Cancer

Legend Biotech's LB1908 is a CAR-T therapy targeting Claudin 18.2 (CLDN18.2). CLDN18.2 is expressed in cancer types such as gastric and pancreatic cancers, making it a highly sought-after target in current anticancer drug development. However, CLDN18.1, which shares high homology with it, is expressed in human lung tissue. This means that the CAR-T therapy must exhibit high specificity for CLDN18.2; otherwise, it may attack healthy lung tissue, leading to severe toxic side effects.

▲ Tissue expression of CLDN18.2 and CLDN18.1 (Image source: Legend Biotech official website)

The VHH antibody platform developed by Legend Biotech utilizes heavy-chain-only nanobodies derived from camelids. Due to the absence of conventional light chains, these antibodies are more compact than human-derived antibodies, yet they bind to antigens with an affinity comparable to conventional antibodies. Consisting solely of the variable domain fragment of the nanobody, VHH antibodies can specifically bind to novel epitopes that are inaccessible to conventional antibodies. Furthermore, linking multiple distinct VHH domains enables the simultaneous targeting of multiple different antigens.

▲Benefits of the VHH Antibody Platform for CAR-T Design (Image source: Legend Biotech official website)

LB1908 utilizes a VHH antibody design that ensures high specificity for CLDN18.2. In preclinical animal models of gastric and pancreatic cancer, it exhibits potent anticancer activity.

▲LB1908 Overview (Image source: Legend Biotech official website)

Currently, this investigational CAR-T therapy has entered a Phase 1 dose-escalation clinical trial. In the first patient treated with the lowest dose of LB1908, it demonstrated a favorable safety profile and preliminary anti-tumor activity. At 180 days post-treatment, the patient maintained stable disease, with a 15% reduction in the pelvic tumor and significant shrinkage of lesions at other body sites. The patient’s quality of life was also significantly improved.

▲ Patients receiving the lowest dose of LB1908 exhibited signs of clinical remission (Image source: Legend Biotech official website)

Legend Biotech plans to further expand its clinical trials in China and is preparing to submit an IND application for this therapy to the U.S. FDA.

"Armored" CAR-T Therapy to Overcome Tumor Microenvironment Barriers

To overcome the impact of immunosuppressive factors within the tumor microenvironment on CAR-T cell activity, Legend Biotech's proprietary technology platform conducts large-scale screening for intracellular targets that enable CAR-T cells to resist immunosuppressive signals, and leverages them to enhance the persistence and activity of the therapy within the tumor microenvironment.

Image source: Legend Biotech official website

LB2101, developed by the company, is an "armored" CAR-T therapy targeting GPC-3. In addition to expressing a chimeric antigen receptor (CAR) targeting GPC-3, it simultaneously expresses a transmembrane protein activated by signals within the tumor microenvironment. This transmembrane protein is only activated by tumor microenvironmental signals when the CAR signaling pathway is concurrently activated, thereby not compromising the specificity of the CAR-T cells. It can improve the infiltration, proliferation, and persistence of CAR-T cells.

▲LB2101 Overview (Image source: Legend Biotech official website)

In animal experiments, this therapy demonstrated higher anti-tumor activity and greater in vivo cell expansion compared to non-"armed" CAR-T therapy.

▲ LB2101 (purple) significantly improves CAR-T therapy function (Image source: Legend Biotech official website)

CAR-T Cell Therapy for Small Cell Lung Cancer

LB2102 is a DLL3-targeted CAR-T therapy. DLL3 is a potential target widely expressed in small cell lung cancer (SCLC) and certain neuroendocrine tumors. LB2102 utilizes VHH antibody technology and "armored" CAR-T technology engineered to overcome immunosuppressive factors within the tumor microenvironment. It incorporates two VHH antibody fragments that recognize DLL3, along with a transmembrane protein activatable by signals in the tumor microenvironment.

▲ LB2102 Introduction (Image source: Legend Biotech official website)

Preclinical in vivo studies demonstrated that, compared with conventional CAR-T therapy, this treatment more effectively reduced tumor volume, with significantly increased numbers of both peripheral blood CAR-T cells and tumor-infiltrating CAR-T cells.

▲ In vivo animal study results of LB2102 (red) (Image source: Legend Biotech official website)

Non-gene-edited allogeneic CAR-T technology platform

A critical challenge for allogeneic CAR-T cell therapy is preventing the infused T cells from attacking host tissues, as well as overcoming the host's immune rejection of the allogeneic cells. Currently, most allogeneic CAR-T therapies employ gene editing to knock out the endogenous T cell receptor (TCR) and other potentially immunogenic proteins in T cells. While this strategy enables the permanent elimination of rejection-triggering proteins using various gene-editing tools, it also poses potential safety concerns, including off-target effects and the risk of chromosomal abnormalities. Notably, concerns over chromosomal abnormalities recently led the U.S. Food and Drug Administration (FDA) to place a clinical hold on an allogeneic CAR-T therapy trial.

▲ Advantages and Limitations of Developing Allogeneic CAR-T Therapy via Gene Editing (Image Source: Legend Biotech Official Website)

Legend Biotech's development strategy involves developing intracellular proteins that bind to TCR subunits. Upon binding to the α and β subunits of the TCR, these proteins impede the assembly of the normal TCR complex, thereby blocking the propagation of endogenous TCR signaling. This strategy eliminates the need for cellular gene editing. Furthermore, the proteins that block endogenous TCR signaling can be co-expressed by the viral vector carrying the CAR transgene, thereby reducing the manufacturing steps for CAR-T cell therapy.

▲Allogeneic CAR-T Technology Platform for Blocking TCR Signaling Without Relying on Gene Editing (Image Source: Legend Biotech Official Website)

The CAR-T therapy LUCAR-20S, developed using this platform, has entered Phase I clinical trials. To date, five patients with relapsed/refractory non-Hodgkin lymphoma have been dosed. Three patients (60%) achieved a partial response, and no dose-limiting toxicities have been observed. In one patient, radiological imaging 30 days post-treatment showed near-complete resolution of all lesions; however, as the bone marrow biopsy remained positive, the response was assessed as partial.

▲ Case Report of LUCAR-20S Treatment (Image source: Legend Biotech official website)

Future R&D Plans for Cilta-cel

The BCMA-targeting cilta-cel has already demonstrated exceptional efficacy in patients with multiple myeloma who have received multiple prior lines of therapy. At its R&D Day, Legend Biotech presented further clinical development plans for cilta-cel. In collaboration with Janssen Pharmaceuticals, Inc., the company has initiated a Phase 2 clinical trial to evaluate the efficacy of cilta-cel in patients with multiple myeloma who have received 1 to 3 prior lines of therapy. Meanwhile, two pivotal Phase 3 clinical trials have been launched, aimed at evaluating the potential of cilta-cel as a first-line and second-line therapy for patients with multiple myeloma.

▲Future R&D Plans for Cilta-cel (Image Source: Legend Biotech Official Website)

References:

[1] Legend Biotech R&D Day. Retrieved October 18, 2021, from https://investors.legendbiotech.com/static-files/3cb06824-4ee5-4610-951c-8a3bd8e9ec3b

[2] U.S. Food and Drug Administration Grants BCMA CAR-T Cilta-cel Priority Review for the Treatment for Relapsed/Refractory Multiple Myeloma. Retrieved October 18, 2021, from https://investors.legendbiotech.com/news-releases/news-release-details/us-food-and-drug-administration-grants-bcma-car-t-cilta-cel

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