Optimized Affinity CD38 CAR-NK Therapy Shows Early Promise in Multiple Myeloma

Cancer Research

ONK Therapeutics announced Monday that its lead candidate ONKT102 showed potent anti-tumor activity both in-vivo and in-vitro versus multiple myeloma (MM).

ONKT102, the company's most advanced program, is a fully human, optimized affinity CD38 CAR-NK cell therapy. Researchers placed expanded cord blood-derived cells through CRISPR gene editing to knock out CD38 and prevent fratricide. The resulting component was genetically modified using Tc Buster's non-viral transposon approach to express CD38 CAR.

The anti-tumor efficacy of the optimization was assessed in NOD scid gamma mice that were inoculated with MM.1S-LUC cells. The mice were then exposed to weekly bioluminescent imaging to determine the tumor burden. As the study progressed, the researchers found that CD38 CAR-NK cells could reduce the tumor burden significantly and improve survival versus the control group.

"We are encouraged by these data and future work at ONK Therapeutics aims to optimize the dose and schedule, confirm the favorable safety profile and potential beneficial immune modulatory effects of our approach, as well as the added benefit of gene-editing with CRISPR/Cas9 to knock out CISH to enhance persistence," Michael O'Dwyer, founder and chief scientific officer at ONK, said during his presentation at the International Myeloma Society on August 26.

The company has an exclusive global patent license agreement with the Walter and Eliza Hall Institute of Medical Research for the latter's CISH knockout in human NK cells for cancer treatment. CISH KO is an edit in NK cells for which WEHI holds the first patent in the United States.

In a separate statement, O'Dwyer noted that "deletion of CISH in NK cells leads to an improved metabolic profile, greatly enhancing their proliferation, cytotoxicity and persistence.

"In-vivo models of cancer have shown that CISH KO NK cells are much more efficient in eliminating cancer cells, making such cells a very attractive prospect for future clinical development," he added. 

ONKT102 is one of three programs exploring off-the-shelf, optimally engineered NK cell therapies that express CAR that is modified to improve anti-tumor activity and overcome exhaustion in the microenvironment of solid tumors and hematological malignancies. The other two strategies cover a program that targets AML stem cells and one targeting ovarian, breast and non-small cell lung cancer.

The latest results on ONKT102 are significant, as they could win the company approval to conduct a first-in-human clinical trial.

In June, ONK was able to generate $21.5 million from its Series A funding round to help drive multiple programs involving next-generation optimally engineered off-the-shelf NK cell therapies.

"This financing will allow us to continue to deliver against our focused strategy, funding significant program progression, organizational development, and company growth," Chris Nowers, ONK chief executive officer, said at the time. He added that the company has the potential for multiple IND approvals within the next 18 months.

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