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GM-CSF Knock-out CAR-T Study Published in Peer-Reviewed Journal Leukemia

https://ir.humanigen.com/English/news/news-details/2022/GM-CSF-Knock-out-CAR-T-Study-Published-in-Peer-Reviewed-Journal-Leukemia/default.aspx

-CRISPR/Cas9-Mediated GM-CSF knock-out (GM-CSFko) CAR-T cells demonstrate reduced apoptosis and enhanced in vivo anti-tumor activity in preclinical models

-Phase 3 SHIELD study utilizing lenzilumab to prophylactically neutralize GM-CSF in CAR-T to begin 1H22

SHORT HILLS, N.J.--(BUSINESS WIRE)--Humanigen, Inc. (Nasdaq: HGEN) (“Humanigen”), a clinical-stage biopharmaceutical company focused on preventing and treating an immune hyper-response called ‘cytokine storm,’ announced today a peer-reviewed publication in Leukemia, a leading oncology and hematology journal, entitled “GM-CSF disruption in CART cells modulates T cell activation and enhances CART cell anti-tumor activity.”

This publication is a significant addition to the findings from a previous article in the leading hematology journal, blood, which demonstrated that neutralization of GM-CSF with lenzilumab (LENZ®) was able to break the efficacy/toxicity linkage by reducing cytokine release syndrome (CRS) and neuroinflammation (ICANS) while enhancing CAR-T function.1 The Leukemia publication demonstrates that CRISPR/Cas9-mediated GM-CSF knockout in CAR-T cells directly ameliorates CAR-T cell early activation, reduces activation-induced cell death, and results in enhanced anti-tumor activity in vivo in a xenograft model.2

Enhancing CAR-T cell in vivo efficacy by using strategies to non-specifically stimulate CAR-T cell proliferation utilizing synthetic biology or combination therapy to edit exhaustion pathways or prevent apoptosis is an important goal and is the subject of substantial ongoing research. However, while this may improve CAR-T efficacy, it is often at the cost of an increase in important toxicities, such as CRS and ICANS. In contrast, these data published in Leukemia indicate that GM-CSko CAR-T cells result in enhanced CAR-T cell proliferation and anti-tumor activity while being associated with a marked reduction in GM-CSF levels, which have been linked to CAR-T associated toxicities.

CAR-T therapies have resulted in significant advances for patients. However, for up to one-third of patients, toxicities such as severe ICANS and CRS occur, and tumor relapse is still a frequent occurrence.3 Currently, the widespread adoption of CAR-T therapy is limited, in part, by the requirement for treatment in centers that are experienced in managing the common toxicities of ICANS and CRS and by the financial and health burden that this creates. “CRS, ICANS, and tumor relapse remain challenges for physicians and patients treated with CAR-T therapy,” said Saad Kenderian, M.B., Ch.B., hematologist at Mayo Clinic Cancer Center, an author of the Leukemia paper and the primary investigator for the SHIELD study (Study on How to Improve Efficacy and toxicity with Lenzilumab in DLBCL and other NHL patients treated with CAR-T therapy). He added, “They result in additional morbidity for patients, as well as significantly increased costs for healthcare providers. Treatments that can prevent ICANS and CRS while potentially improving CAR-T efficacy could address a critical unmet need.”

This publication adds to the body of knowledge of GM-CSF depletion in CAR-T. The upcoming Phase 3 CAR-T study, known as SHIELD, will determine the efficacy and safety of prophylactic lenzilumab on the rates of ICANS, CRS, and CAR-T efficacy. “The SHIELD trial has been designed to build on the positive results from the ZUMA-19 study. The primary endpoint of SHIELD will focus on demonstrating a significant improvement in neurotoxicity associated with both Yescarta® and Tecartus®. We will also seek to explore the beneficial impact that lenzilumab may have CAR-T efficacy,” stated Dale Chappell, M.D., MBA, Chief Scientific Officer, Humanigen.