2024-13-004 - THOR (SwiTcHable CAR fOr Cancer TReatment) - A Novel Switchable CAR Strategy for Cancer Treatment

THOR

2024-13-004

Refine UniCAR-T systems by optimizing two key elements: the tag and the nanobody. The proposed solution involves developing a novel UniCAR-T therapy based on the NbICO/ICOtag system, combining a nanobody (NbICO) with an epitope tag (ICOtag) predicted via in silico methods. Primary and secondary ischemic stroke risk prediction

Improved Treatment Outcomes: We are expecting to improve the survival of patients with glioblastoma cancer (and other cancer types) based on the expression of the biomarker EGFR and PDL-1. Expansion of Therapeutic Options: The development of this combined ATMP will offer a new line of treatment for glioblastoma cancer resistant to chemotherapy available to oncologists. We expect that the results of this study will not be limited to patients with glioblastoma cancer, as the universal CAR-T product could be combined with different "bridge" molecules specific to different tumor types.

CAR-T cell therapy has demonstrated remarkable clinical success, mainly for hematological cancers, leading to the FDA and EMA approval of six autologous CAR-T (conventional CAR-T, cCAR-T) cell therapies for treatment of several hematological malignancies. Those approved CART therapies are autologous, which means that the T cells obtained for the preparation of CAR-T cells are from the patients themselves. Despite its efficacy and promising outcomes, cCAR-T therapies present limitations and face significant challenges, including high production costs, lengthy manufacturing times, and fixed antigen specificity. Although the development of allogeneic CAR-T cells has improved accessibility, especially for critically ill patients who cannot serve as their own donors, the rigid design remains a significant limitation, increasing the risk of tumor escape and complicating the control of CAR-T cell activation and reactivity against healthy tissues. To enhance the accessibility, efficacy, and safety of cCAR-T therapy, universal CAR-Ts (UniCAR-Ts) have been developed. In this proposal we intend to develop a new technology that improves existing UniCAR-T systems by optimizing the two main elements of the system. To demonstrate the potency of our therapy, we have focused on evaluating our NbICO/ICOtag technology in a specific type of cancer, glioblastoma (GBM), which currently presents an unmet medical oncology need. However, it is important to highlight that due to the universal nature of our system, its validation in this specific tumor type can be extrapolated to other tumors simply by changing the tumor target.

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A project transfer strategy will be designed, mainly based on licensing and/or co-development of our technology. Companies specialized in the preclinical regulatory stages of CAR-T development will be identified and contacted to assess a possible co-development or licensing of the patented technology

Despite its efficacy and promising outcomes, cCAR-T therapies present limitations and face significant challenges, including high production costs, lengthy manufacturing times, and fixed antigen specificity. Although the development of allogeneic CAR-T cells has improved accessibility, especially for critically ill patients who cannot serve as their own donors, the rigid design remains a significant limitation, increasing the risk of tumor escape and complicating the control of CAR-T cell activation and reactivity against healthy tissues. To enhance the accessibility, efficacy, and safety of cCAR-T therapy, universal CAR-Ts (UniCAR-Ts) have been developed.

Cancer Glioblastoma (GBM) serves as a prime example of cancer as a significant public health issue worldwide due to its aggressive nature, poor prognosis, and limited treatment options. It is the most common and lethal primary brain tumor in adults, representing around 45-50% of all malignant brain tumors. GBM is mostly resistant to conventional therapies such as surgery, radiation, and chemotherapy.

Funding to develop: 1) Evaluation of the antitumor efficacy and safety of NbICO-CAR-T in glioblastoma (GBM) models; and 2) Optimization of the process for generating a therapeutic product under GMP conditions and preparation of an IMPD

Co-development and licensing opportunities

1. Assess the efficacy of NbICO-CAR-T and ICOTag bispecific in eliminating primary glioblastoma tumor cells in vitro 2. Evaluate the antitumor potential of NbICO-CAR-T and ICOTag_bispecific in comparison to conventional CAR-T cells targeting EGFR and/or PD-L1 in immunodeficient murine models of GBM 3. Determine the safety profile of the therapy in murine models 4. Define IPR and valorization strategy

UniCAR-T platform

IP and Regulatory barriers

Advance to TLR 4-5 and search a potencial collaborator or licensor to further develop our solution

Patentability study: done Patent: ongoing

Patent is currently being drafted and it will be filled in the second semester of 2025

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The first notable clinical success with CAR-T cell therapy was achieved in patients with chronic lymphocytic leukemia (CLL), where anti-CD19 CAR-T cells induced partial or complete remission. This breakthrough led to the FDA's approval of the first CAR-T therapy,in 2017, followed by other CAR-T therapies targeting CD19 and BCMA antigens. While CAR-T therapy has shown remarkable efficacy, conventional CAR-T (cCAR-T) therapies face several limitations, including high production costs, long manufacturing times, and fixed antigen specificity, which can lead to tumor escape and off-target effects.To overcome these challenges, universal CAR-T (UniCAR-T) therapies have been developed. UniCAR-Ts use a modular design where "switch" molecules bridge CAR-T cells and tumor antigens. This innovation allows precise control over CAR-T cell activation, making the cells switchable and reducing the risk of immune-related toxicities. Furthermore, the ability to reengineer switch molecules provides flexibility, enabling UniCAR-Ts to target various tumor antigens using a single universal product. This strategy improves production efficiency, reduces costs, and addresses challenges like tumor heterogeneity and escape. Although promising, few UniCAR-T approaches have advanced to clinical trials.