Allogeneic CAR T cell therapy to enter the neuro-oncology sector

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Allogeneic treatment is unquestionably a revolutionary notion in biology. According to immunologic dogma, any foreign component will evoke an immune response. This idea is clear in solid organ and hematopoietic transplantation, where strong immunosuppression is used to protect allografts from rejection. As the area of cell-based therapy progresses, it has become clear that certain cell types - mesenchymal stem cells (MSCs) being the prototype - have the potential to evade or suppress the immune system to the extent where they can be employed as allografts without the need for concomitant immunosuppression.

Autologous T cells have traditionally been used to create CAR products, but this method has several drawbacks, including long production times, high costs, manufacturing delays, and a reliance on patient T cells with functional fitness that is frequently compromised by disease or prior treatments. Allogeneic or universal "off-the-shelf" CAR T cells offer a potential solution to these problems by enabling diverse alterations and CAR combos to target various tumour antigens and prevent tumour escape. The two main drawbacks of allogeneic CAR T cells, host allorejection, and graft-versus-host disease may be overcome because of improvements in genome editing techniques, particularly via CRISPR/Cas9.

Allogeneic cell treatments without gene editing still hold great potential despite the difficulties faced by gene-modified cell therapies like CAR-T cells. For instance,

• Zelenoleucel from Marker Therapeutics, a multi-tumor-associated antigen-specific T cell, is intended to be utilised after hematopoietic stem cell transplants (HSCT) for patients with newly diagnosed and R/R acute myeloid leukemia (AML).
• Zelenoleucel is being tested in the Phase II ARTEMIS study, and if it proves to be more effective than the standard of treatment, it may be available in the United States market as early as 2025. Additionally, there is great potential for goods that could augment or possibly take the place of HSCTs.
• The most advanced candidate is NiCord (omidubicel) from Gamida Cell, which uses cord blood-derived stem cells to help patients who lack an allogeneic HSCT donor. The FDA is now looking at NiCord's application for a biologics licence, and a review deadline of May 2023 has been established.
• Orca-T is being compared to unmodified allogeneic HSCT in the Phase III Precision-T trial and might hit the market as early as 2025.  The effectiveness of these allogenic cell therapies will spur additional R&D spending on various cell therapy approaches for AML.
• Mesoblast is trying again with regulators with its over-the-counter cell treatment. After more than two years it has formally requested that the FDA reconsider remestemcel-L, a treatment for kids with acute graft-versus-host disease that is steroid-refractory. The latest application is based on "significant new knowledge," as Mesoblast described it, that was hinted at in October 2022. More efficacy and biomarker data were included in the submitted data, a few of which were compared to a Mount Sinai medical system database of patients suffering from acute graft-versus-host disease.
• The FDA's initial request for at least one more trial when the cell therapy was initially rejected in October 2020 will be challenged by fresh findings and new applications. The decision by the corporation to forgo doing so raises the obvious concern of whether the new data package will prove to be beneficial. The resubmission will receive a speed boost from the FDA after the therapy previously earned fast-track designation and a priority review green light, cutting the review period by four months if the application is accepted.

Synthetic biology and cell engineering have essentially no boundaries, offering a platform for the creation of novel treatments. The development of more realistic experimental models and enhanced imaging methods to evaluate tumour response and CAR T cell characteristics in vivo will be part of that clinical challenge, along with the discovery of novel and highly tumor-restricted antigens.

BioIntel360 projects that allogeneic CAR T cells, designed immune cell products with numerous specificities and resistance to host rejection, will most likely enter the neuro-oncology sector over the next ten years, hopefully paving the way for improvements in patient outcomes.