8:45 PM
 | 
Feb 21, 2019
 |  BC Innovations  |  Targets & Mechanisms

Solid checkpoint for CARs

PD-L1 relative B7-H3 could help CAR T cells crack pediatric and solid tumors

PD-L1 family member B7-H3 could put CAR T cells in play for a slew of difficult-to-treat solid tumors, including pediatric cancers that lack targeted therapies, according to a pair of preclinical studies published this year. But questions around the target’s safety will call for close attention to the therapeutic window.

The findings, from Stanford University’s Crystal Mackall and University of North Carolina Chapel Hill’s Gianpietro Dotti, respectively, move B7-H3 up the flagpole from the class of new immuno-oncology targets to a potential difference-maker in enabling CAR Ts in new, highly underserved indications.

Mackall, a professor of pediatrics and medicine at Stanford, published a study in Clinical Cancer Research demonstrating B7-H3 is broadly expressed in pediatric cancers, mostly at high levels, and showing CAR T cells targeting B7-H3 can shrink tumors in preclinical models.

Mackall also leads the Cancer Moonshot’s Pediatric Immunotherapy Discovery and Development Network (PI-DDN).

Mackall has co-founded CAR T company Lyell Inc. with CEO Rick Klausner, a serial entrepreneur who previously founded and directed Juno Therapeutics Inc., now a subsidiary of Celgene Corp. Former Juno CEO Hans Bishop is a co-founder and board member of Lyell. Arch Venture Partners’ Bob Nelson is on the board. The company has not disclosed financing.

UNC’s Dotti extended the findings with a Feb. 11 paper in Cancer Cell demonstrating B7-H3 is highly expressed on three intractable adult cancers. As with Mackall’s study, CAR T cells against B7-H3 had potent anti-tumor effects in preclinical models. Dotti is a professor of microbiology and immunology. He is also an advisor to Cell Medica Ltd. and receives research support from bluebird bio Inc.

The studies outline how targeting B7-H3 could address two dominant hurdles facing use of CAR T therapies in solid tumors.

The first is the hostile immunosuppressive microenvironment of solid tumors. The target belongs to the B7 family of membrane proteins, which contains several immune checkpoints that inhibit the anti-tumor response, most famously PD-L1, which binds PD-1, and B7-2, which binds CTLA-4. A growing body of literature suggests B7-H3 also limits the immune response to cancer.

The second is that solid tumors are typically heterogeneous, with few targets expressed on all cells.

Mackall’s study demonstrated near homogeneous expression of B7-H3 in the tested tumors.

“This is an avenue that has to be followed in pediatric oncology.”

Rupert Handgretinger, University of Tübingen

The potential utility in pediatric cancers gives a much needed boost to that field, where drug development has lagged far behind adult cancers. While most pediatric tumor types are rare, limiting market size, a target that cuts across many pediatric indications could draw...

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