On December 12, 2022 Asher Biotherapeutics, Inc., a biotechnology company focused on developing therapies to precisely engage specific immune cells to fight cancer, reported new preclinical data demonstrating proof-of-concept for cis-targeted cytokines as a novel strategy for enhancing chimeric antigen receptor T cell (CAR-T) engraftment, expansion, and functionality culminating in the delivery of improved anti-tumor activity (Press release, Asher Biotherapeutics, DEC 12, 2022, View Source [SID1234625183]). This data will be presented in a poster at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held in New Orleans, Louisiana, December 10-13, 2022.
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"We are delighted to share new preclinical data with our cell therapy program, further highlighting the versatility of our cis-targeting cytokine platform, as well as its potential applicability across a range of hematologic malignancies and solid tumors," said Ivana Djuretic, Ph.D., Founder and Chief Scientific Officer of Asher Bio. "These data demonstrate our ability to selectively activate only CAR-T cells post-adoptive transfer and, as a result, to improve anti-tumor activity. We are particularly pleased to observe these results using two different cytokines, interleukin-2 (IL-2) and interleukin-21 (IL-21), which act through distinct, potentially complementary, mechanisms. Over time, our ability to deliver different, supportive cytokine signals could enable us to target a diverse set of cell therapies, including those based on T cell receptors, tumor-infiltrating lymphocytes, natural killer cells and regulatory T cells, to support the use of cell therapies in a diverse set of tumor types. We look forward to advancing this program as we aim to maximize the reach of our platform, with the goal of delivering better outcomes to cancer patients who remain underserved by existing therapeutic options."
CAR-T cell therapies have recently transformed the treatment of some hematological malignancies and are showing promise in solid tumors. In the clinic, the successful expansion and persistence of CAR-T cells has correlated with improved therapeutic outcomes, including durable complete responses and survival; in preclinical studies, the administration of IL-2 has been observed to enhance CAR-T engraftment, persistence and functionality. However, the clinical potential of utilizing existing IL-2 molecules in combination with CAR-T therapies is limited due to the severe toxicity of high dose IL-2 and the inadequate selectivity of existing engineered IL-2 variants, which expand multiple endogenous cell types in addition to the transferred CAR-T cells.
In order to overcome these challenges, Asher Bio developed two cis-targeted fusion molecules, one using IL-2 and the other using IL-21, which are designed to selectively activate CAR-T cells by recognizing an extracellular tag, while exhibiting minimal effects on non-engineered or endogenous cells. Both cis-targeted cytokine fusions are comprised of a targeting antibody directed against a tag expressed on the CAR-T surface, that is co-expressed with the CAR, and a cytokine mutein with attenuated binding to its cognate cytokine receptor.
In a poster titled, "Selective Support of CAR-T Cell Therapies by Cis-Targeted IL-2 or IL-21 Cytokines Results in Enhanced Anti-Tumor Activity," Asher Bio scientists and collaborators at the Perelman School of Medicine at the University of Pennsylvania presented preclinical in vitro and in vivo data that support the development of cis‑targeted cytokines directed by anti-tag antibodies as a promising approach to enhance CAR-T cell therapies. The data show:
– Cis-targeted IL-2 or IL-21 molecules targeting an exogenous tag selectively activated CAR‑T cells in vitro and enhanced anti-tumor activity and survival in vivo.
– CAR-T cell targeted IL-2 and IL-21 enhanced anti-tumor activity through distinct mechanisms.
– Cis-targeted cytokine therapies allowed for temporal control, while avoiding the negative pleiotropic effects associated with systemically administered wild-type cytokines.
The poster presentation will be available in the "Presentations and Posters" section of Asher Bio’s website: View Source