Novel Technology Identified Genes that Promote T Cell Exhaustion, and which are Unique from PD-1/PD-L1 Checkpoint Pathway
Engineered CAR-T Cells Lacking Exhaustion-Associated Genes Mediate Improved Tumor Killing and Sustained CAR-T Proliferation With Additive Benefit to PD-1/PD-L1 Inhibition
Additional Presentation Reports Latest Preclinical Data for EV-104, First-in-Category Multifunctional T Cell Redirecting Antibody for Select Solid Tumors
BRANFORD, Conn., April 18, 2023 (GLOBE NEWSWIRE) -- EvolveImmune Therapeutics, an immuno-oncology company developing first-in-category, multifunctional biotherapeutics to overcome cancer-driven immunodeficiency, today announced the presentation of the first data highlighting the company’s proprietary CRISPR-Cas9 T cell exhaustion screening platform. Additionally, the company presented the latest preclinical data for EV-104, the company’s first-in-category lead solid tumor program which was created using the company’s proprietary costimulatory T cell engager platform, known as EVOLVE. These presentations were delivered at the American Association for Cancer Research (AACR) Annual Meeting 2023, which is being held April 14-19, 2023, in Orlando, Florida.
In a poster presentation, the company introduced a novel CRISPR-Cas9 T cell exhaustion screen that it designed to identify molecular targets that regulate T cell exhaustion following chronic T cell receptor and CD28 costimulatory receptor activation. EvolveImmune scientists utilized this screen to identify specific genes that promote T cell exhaustion, which are associated with different signaling and regulatory pathways than the PD-1/PD-L1 checkpoint pathway. The company then identified the optimal guide RNAs for CRISPR-Cas9 knock-out, engineered anti-CD19 and anti-mesothelin CAR-T cells that lacked the exhaustion-associated genes, and evaluated their effector function in tumor co-culture assays.
Presented data highlighted that highly efficient knockout of the exhaustion-associated genes, such as BATF, CD70 and FAS, via CRISPR gene editing resulted in significantly improved tumor killing and sustained proliferation of both anti-CD19 and anti-mesothelin CAR-T cells. Combinations of gene knockouts showed better tumor killing than individual knockouts and this activity was additive to PD-1 and PD-L1 inhibition. Ongoing studies will evaluate the in vivo efficacy of anti-CD19 CAR-T cells engineered with exhaustion-associated gene knockouts in humanized mouse models of B cell lymphoma.
“We are excited to unveil our T cell exhaustion screening platform for the first time. Our initial data suggest the potential of this technology to unlock the development of novel CAR-T therapeutics engineered to overcome the significant therapeutic challenge of T cell exhaustion. Importantly, we also demonstrated that these engineered T cells drove increased tumor killing and CAR-T cell proliferation when combined with checkpoint inhibition,” said Jeremy Myers, Ph.D., senior vice president, research and development at EvolveImmune. “This initial research produced important discoveries of differentiated cellular pathways that promote T cell exhaustion and illuminated opportunities for manipulating these pathways to facilitate novel cancer treatments. We are eager to complete our ongoing in vivo studies with our engineered T cells in humanized mouse models of B cell lymphoma and continue to advance this exciting area of research.”
In a second poster presentation at AACR, EvolveImmune reported new data on EV-104, the company’s lead solid tumor program which targets an antigen present in a significant portion of bladder cancers and other solid tumors. EV-104 was derived from the EVOLVE platform, which is designed to unleash potent, selective, and integrated T cell costimulation to bypass low tumor immunogenicity, conditionally activate adaptive immunity, and reduce T cell dysfunction, to address unmet needs for the treatment of solid and hematologic tumors. This is achieved through finely tuned T cell receptor and CD2 costimulation optimized for CD8 T cells.
New data demonstrated the potential of EV-104 to rejuvenate exhausted T cells to drive more potent tumor cell killing than matched CD3 bispecific antibody controls that lack costimulatory activity. Researchers observed a 100% complete response rate for EV-104 treated animals in a CORL105 lung cancer xenograft model expressing high levels of the EV-104 tumor antigen, whereas the matched CD3 control showed limited anti-tumor efficacy. Additionally, EV-104 was well tolerated at efficacious dose levels in non-human primate studies and demonstrated acceptable pharmacokinetics.
“We continue to generate promising preclinical data which are pinpointing exciting opportunities for differentiation for multiple EVOLVE-based programs,” said Jay Fine, Ph.D., president of research and development at EvolveImmune. “Both EV-104 and our lead hematological tumor program, EV-105, are progressing well and we expect to nominate development candidates for these programs in the coming months.”
Additional information on the AACR Annual Meeting 2023 is available through the conference website at: https://www.aacr.org/meeting/aacr-annual-meeting-2023/
About EvolveImmune Therapeutics
EvolveImmune Therapeutics, Inc. is an immunotherapy platform company developing first-in-category, multifunctional biotherapeutics designed to overcome cancer-driven immunodeficiency in a range of solid tumors and hematological cancers. The company is rapidly advancing two first-in-category programs, with first-in-human clinical trials anticipated in 18 months. The company is supported by a syndicate of top-tier life science industry investors including Pfizer Ventures, Solasta Ventures, Takeda Ventures, Yonjin Ventures and Elm Street Ventures.
For more information, please visit: www.evolveimmune.com
