AACR | Innovations in Engineered Cell Therapies: New Strategies to Overcome Current Challenges

Cell therapies represented by CAR-T have achieved remarkable efficacy in treating blood cancers. However, the widespread application of CAR-T therapy still faces several challenges. For instance, CAR-T therapy has yet to demonstrate significant efficacy in treating solid tumors, and its production remains a time-consuming and labor-intensive process. At this year's AACR conference, encouraging progress has been made in cell therapies for cancer treatment. BioNTech’s CLND6-targeted CAR-T therapy combined with an mRNA cancer vaccine has yielded positive preliminary results in treating solid tumors. Additionally, Affimed’s innate immune cell-engaging protein AFM13, used in conjunction with natural killer (NK) cells derived from umbilical cord blood, achieved a 100% remission rate in clinical trials for Hodgkin and non-Hodgkin lymphomas. In this article, the WuXi AppTec content team will share other latest advancements in improved cell therapies presented at the AACR conference.

In Vivo Generated CAR-T Therapy Successfully Eliminates B Cells

EXUMA Biotech Presents Preclinical Results for In Vivo CAR-T GenerationEXUMA Biotech has announced preclinical results for its in vivo-generated CAR-T therapy. Typically, the production of CAR-T therapy involves extracting T cells from the patient, genetically engineering them ex vivo to express chimeric antigen receptors (CARs), expanding them, and then infusing them back into the patient. This process is not only complex and time-consuming but also usually requires chemotherapy to deplete the patient’s existing T cells before the CAR-T cells can be reinfused.

EXUMA Biotech's strategy is to use self-inactivating lentiviral vectors to express the transgenes for constructing CAR-T cells, delivering these lentiviral vectors via subcutaneous injection in vivo to transfect and generate CAR-T cells within the body. This approach eliminates the complex steps of ex vivo production of CAR-T therapies and the use of chemotherapy to deplete the patient’s T-cells.

In preclinical studies presented at the AACR conference, researchers injected a self-inactivating lentiviral vector encoding CD19-targeted CAR into mice. The lentiviral vector’s capsid protein was modified to target and activate CD3-positive T cells. The results showed that the lentiviral vector successfully generated CD3-positive CAR-T cells targeting CD19 in the mice. Meanwhile, B cells in the mice continuously decreased, with complete depletion of B cells observed in some mice. The researchers stated that these findings demonstrate that in vivo delivery of lentiviral vectors infecting CD3-positive T cells can generate functionally competent CAR-T cells, offering new opportunities to address challenges related to production time, scalability, and cost in cell therapy.

NK Cell Engager Antibodies/iPSC-Derived NK Cells Show Positive Anti-Cancer Activity

Cytovia Therapeutics Presents Preclinical Results of iPSC-Derived NK Cells Combined with Multispecific NK Cell Engager Antibodies for the Treatment of Hepatocellular Carcinoma

Natural Killer (NK) cells are innate immune cells present in the human body. Like common T cells, they have the ability to attack tumor cells, but the mechanisms by which they kill tumor cells are different. In recent years, NK cells have received widespread attention as they not only directly kill tumor cells, but also rapidly express a variety of cytokines and chemokines, recruit other immune cells, and promote adaptive immune responses of T cells and B cells.

Cytovia Therapeutics' technology platform utilizes iPSCs to generate NK cells. The advantage lies in their unlimited proliferation capacity, enabling the production of large quantities of consistent NK cells. Using iPSCs also allows researchers to employ gene-editing technologies to enhance iPSC clones, thereby improving the characteristics of cell therapies. The company's Flex-NK cell-engaging antibodies feature a tetravalent, multifunctional structure that not only enhances antibody affinity but also enables the simultaneous recognition of multiple antigens on cells.

At the AACR conference, the company presented preclinical study results on the combination of CYT-303, a Flex-NK cell-engaging antibody targeting GPC3, with NK cells derived from iPSC (iNK) for the treatment of hepatocellular carcinoma. The findings demonstrated that the combination of CYT-303 and iNK exhibited stronger in vitro and in vivo anti-cancer activity compared to iNK monotherapy in hepatocellular carcinoma models. The company’s press release noted that these preclinical proof-of-concept studies support the clinical development of CYT-303 as a monotherapy or in combination with iNK cells for treating hepatocellular carcinoma.

Treating Solid Tumors: Gene Circuits Enhance CAR-NK Cell Efficacy

Senti Bio is a biotechnology company dedicated to using genetic logic circuits to control the activity of cell and gene therapies. The company presented preclinical results of its investigational CAR-NK cell therapy for solid tumors at the AACR Annual Meeting. In addition to expressing CARs that target tumor antigens, Senti Bio’s CAR-NK cells incorporate genetic circuits that enable controlled expression of IL-15, both on the cell surface and in secreted forms.

Cytokines secreted play a crucial role in stimulating the immune system to combat solid tumors, but they are often associated with systemic toxicity. Cytokines expressed on the cell surface can locally activate CAR-NK cells, yet their impact on the broader tumor microenvironment is limited. Senti Bio's innovative controlled-release technology enables CAR-NK cells to simultaneously express both surface-distributed and secreted cytokines, thereby enhancing their functionality in solid tumor models.

"We found that 62% of the mice treated with CAR-NK therapy capable of controlled release of IL-15 showed tumor shrinkage, while no tumor shrinkage was observed in the animals that received only CAR-NK cell therapy," said Dr. Alba Gonzalez, Deputy Director of Research and Development at Senti Bio. Further studies revealed that CAR-NK cells carrying multi-gene circuits expressing IL-15 and IL-21 demonstrated enhanced anti-tumor activity and persistence.

References:

[1] AACR: Exuma aims to be first to the clinic with under-the-skin cancer CAR cell therapy without complex manufacturing. Retrieved April 12, 2022, from https://www.fiercebiotech.com/research/aacr-exuma-eyes-first-clinic-under-skin-cancer-car-cell-therapy-without-complex

[2] In vivo delivery of a novel CD3-targeted lentiviral vector generates CD19 CAR-T cells in two different humanized mouse models and results in complete B cell depletion. Retrieved April 12, 2022, from https://www.abstractsonline.com/pp8/#!/10517/presentation/14071

[3] Cytovia Therapeutics Reports Preclinical Activity of its iPSC-derived NK (iNK) Cells and Flex-NK™ Cell Engagers at the 2022 AACR Annual Meeting. Retrieved April 12, 2022, from https://www.prnewswire.com/news-releases/cytovia-therapeutics-reports-preclinical-activity-of-its-ipsc-derived-nk-ink-cells-and-flex-nk-cell-engagers-at-the-2022-aacr-annual-meeting-301521105.html

[4] Senti Bio Presents New Preclinical Data on Cancer-Killing Allogeneic CAR-NK Cells at AACR Annual Meeting. Retrieved April 12, 2022, from https://www.sentibio.com/press-release/press-release-detail/view_express_entity/703

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