2024-13-010 - CD30_200 - CAR T cells with costimulatory chimeric receptors for improving antitumor efficacy against Hodgkin lymphoma

CD30_200

2024-13-010

A novel dual CD30 CAR-T with a chimeric receptor co-stimulatory with CD200R. This novel therapy holds the potential to effectively treat HL relapsed patients while having a huge positive patient’s survival and quality of life.

Environmental: CAR-T therapy is made by biological components of the patients, therefore, no environmental concerns or impact is envisaged once the product is marketed. Social: Provision of an efficacious treatment and improved quality of life for patients Governance: Since hodgking lymphoma is a rare disease, government reimbursement would be key for the market access of this therapy.

This novel CAR-T therapy for Hodgkin lymphoma (HL) offers substantial benefits for both society and the healthcare system. For society, these therapies improve patient survival rates and quality of life, particularly in cases of advanced or relapsed HL. Patients gain more treatment options, reducing the burden on families and caregivers. For the health system, while new therapies may be expensive, they can ultimately lower costs by preventing relapses and minimizing hospital stays.

Cancer is rapidly becoming the most frequent cause of death in EU. Hodgkin’s lymphoma (HL) is a rare malignancy of the lymphatic system. Main HL subtype is classical HL which makes up 95% of all HL cases. Although HL is highly curable, with 80% of patients reaching complete remission, prognosis is worse in patients who present with advanced disease, with 30-40% relapse after initial treatment or immediate treatment failure. Different cancers have different antigens and CD30 is expressed in all cases (100%) of HL, following an intense and uniform tumour pattern expression. However, CD30 expression on normal cells is very restricted. For this reason, CD30 is an ideal therapeutic target for immunotherapy with CAR-modified T cells in CD30-expressing lymphomas. Nonetheless, HL is characterized by a severe immunosuppressive tumor microenvironment that evades immune system through different mechanisms, including tumor expression of inhibitory molecules. Despite significant clinical responses to CAR-T cell therapy against HL most of the patient’s relapse, suggesting that improved CARs designed to overcome inhibitory signals from tumor microenvironment are needed. The team has thus generated a novel dual CD30 CAR-T with a chimeric co-stimulatory receptor with the aim of improving the treatment of HL patients.

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The leading option currently under consideration is licensing the technology to an external industrial partner with the necessary infrastructure and regulatory experience to support advanced clinical development and commercialization. In this license, the team will negotiate an upfront payment, milestones and royalties from the product sale.

There is no standard treatment of relapsed or primary refractory hodgkin lymphoma (HL) disease. An unmet medical is existing for refractory/relapsed HL patients.

Relapsed/refractory patients with classical hodgkin lymphoma. Biotechs and big-pharma with experience on the development of advanced therapy in the field of oncology are the main target. The top 5 CAR-T companies include Gilead Sciences, Bristol Myers Squibb, Novartis, Janssen, JW Therapeutics.

In the next years, the team plans to complete the preclinical animal studies of the novel dual CD30 CAR-T with a chimeric co-stimulatory receptor, and CAR-T GMP production validations (N=3) (i.e., assess stability, distribution, potency, composition, etc.). Additionally, the team plans to initiate the preparation of Phase 1 clinical trial (writting of regulatory documentation - Investigator’s brochure, trial protocol, etc.).

Competitive funding for experimental proof-of-concept and phase 1 trial preparation

Competitive Project “Fondo de Investigaciones Sanitarias (FIS) - Modulación farmacológica y diseño de CARs duales inmunoestimuladores para inmunoterapia con células T de memoria stem con alta eficacia antitumoral”, granted with 111.320 € by Instituto de Salud Carlos III (ISCIII). Additionally, in relation to the manufacturing, the team has joint to the 2022 edition of the program CERTERA (Consorcio Estatal en Red para el desarrollo de Medicamentos de Terapias Avanzadas) which provides financial support to promote the development of facilities, infrastructure, skills and human resources for the production of CART medicines under GMP.

Tumor’s immunosuppressive microenvironment is characterized by the expression of inhibitory molecules. The severe immunosuppressive microenvironment of HL results in a high rate of patient’s relapse even when treated with CAR-T cell therapy. Thus, the developed an improved CAR-T cell therapy consisting of a combination of CAR30 with a chimeric costimulatory receptor (CCR) . For the obtention of this unprecedented CAR-T cell therapy, personalized vectors for genetic modification were built by the team. Tcells are transduced with a third-generation lentivirus encoding for CAR30 and a CCR . Preliminary in vitro and in vivo experiments showed promising results from this novel dual CD30 CAR-T with a chimeric co-stimulatory receptor: (1) Improved cytotoxic activity (2) Increased cytokine-secretion capacity and (3) Improved in vivo antitumor effect compared to second and third-generation CAR30-T cells against HL. This novel therapy holds the potential to effectively treat HL relapsed patients having a huge positive patient’s survival and quality of life.

Regulatory barries: This product is categorized as "somatic-cell therapy" under Advanced-Therapy Regulation Nº 1394/2007 and Directive 2001/83/EC, defining the preclinical and clinical requirements for commercialization. Manufacturing barriers: As an advanced-therapy medicinal product (ATMP), good manufacturing practices (GMP) should be followed and implemented in the research centre before beggining with clinical trials.

Preclinical Validation: Preclinical animal studies (2025 until 1S 2026) CART GMP production validations (N=3) (i.e., assess stability, distribution, potency, composition, etc.) (2025 & 2026) Phase I trial preparation: Preparation of regulatory documentation (Investigator’s brochure, trial protocol, etc.) (2026) Interaction with AEMPS and Ethic's committte endorsement (2S 2026) Transfer activities: Patent maintenance acitivities (2024 & 2025) Seek Orphan Drug Designation in the EU (2S 2025) Market analysis and identiication of licensees (2S 2025)

A patent application was submitted by Institut de Recerca Sant Pau with the Title “CAR AND MODIFIED COMBINATION” (Priority application number. EP24382133; Priority Date 01/12/2023). A PCT application is planned to be filled next year (2025) in order to seek international protection.

Patent ownership completely belongs to Institut de Recerca Sant Pau

Not Applicable

Regarding CAR-T manufacturing, the Regulation on Substances of Human Origin (SoHO) is followed since it governs on the safety and quality of blood, tissues and cells used in healthcare. It covers a wide range of activities from the registration and testing of donors, collection and processing, to human application and clinical outcome monitoring of SoHO.

Patent: EP24382133

The team has generated a novel dual CD30 CAR-T with a chimeric receptor co-stimulatory with CD200R. Preliminary in vitro and in vivo experiments showed promising results from this novel CAR30BBz-CD200R28-T cell therapy: (1) Improved cytotoxic activity (2) Increased cytokine-secretion capacity and (3) Improved in vivo antitumor effect against HL compared to second and third-generation CAR30-T cells. This novel therapy holds the potential to effectively treat HL relapsed patients while having a huge positive patient’s survival and quality of life.