2:59 PM
Jul 11, 2019
 |  BC Innovations  |  Targets & Mechanisms

The tumor stroma rises as the newest source of immuno-oncology targets

Why companies are turning to the tumor stroma to overcome resistance to checkpoint inhibitors

With a spate of therapies entering the clinic, the next frontier in the fight against resistance to checkpoint inhibitors will be the stroma. The lead target marks a resurgence of interest in TGFβ, and behind it companies are interrogating a series of other mechanisms to uncover how the stroma locks immune cells out of tumors.

At least seven therapeutic agents inhibiting TGFβ have started early stage combination trials with checkpoint inhibitors, and an eighth is slated to enter the clinic next year (see Table: “TGFβ Checkpoint Combination Trials”).

In addition, at least two companies gearing up for the clinic this year are targeting other stromal proteins, and a third plans to disclose a first-in-class stromal target in early fall. Wnt pathway modulators in checkpoint combo trials may also affect the tissue compartment.

The stroma is a collagen- and elastin-rich matrix of connective tissue surrounding tumors. As an anatomical structure, the tumor stroma has been recognized for more than 60 years, but investigators are only now beginning to understand its function in cancer immunity.

The field’s focus has largely been on cancer cells and immune cells, and the first priority for building on the success of PD-1 and PD-L1 therapies has been to test them in combination with other agents that target immune cells, or with approved chemotherapies. But disappointing readouts from several early checkpoint combination trials has turned the spotlight to resistance mechanisms, which investigators hope will yield better targets.

“In human cancers showing the immune exclusion phenotype, TGFβ1 is driving that immune exclusion.”

Alan Buckler, Scholar Rock

With increasing attention on the immunosuppressive tumor microenvironment as a major driver of resistance, and characterizations of “hot” and “cold” tumors depending on the level of immune cell infiltration, researchers have found a midway point in a stroma-driven resistance phenotype -- dubbed immune exclusion -- in which immune effector cells surround the tumor but are unable to enter it.

The phenotype has benefits over fully cold tumors which lack no immune cells in or around them. In cases of immune exclusion, there are inroads for therapeutic intervention; the challenge is breaking down the barriers that keep the immune cells out.

The growing focus on the stroma has ignited a wave of interest in TGFβ, an old target now assigned a new role in immunosuppression. TGFβ is associated with immune excluded phenotypes and is secreted by cancer-associated fibroblasts -- key components of the tumor stroma.

“In human cancers showing the immune exclusion phenotype, TGFβ1 is driving that immune exclusion. It’s pretty clear this is the driving molecule,” said Alan Buckler, CSO of Scholar Rock Holding Corp., which has a preclinical program targeting the TGFβ1 precursor.

While the target has not historically yielded much success, companies with TGFβ inhibitors are confident they have found ways around the toxicity issues of past programs, and they aren’t worried that some TGFβ inhibitors haven’t shown single-agent activity in preclinical models.

“The absence of single-agent activity is neither a surprise nor a requirement, and we feel many combinations tried in recent months or years didn’t have the same depth of scientific rationale. It was a bit more throwing spaghetti against the wall,” Nagesh Mahanthappa, CEO and president of Scholar Rock, told BioCentury.

As these clinical trials ramp up, investigators continue to unravel the mechanisms by which the stromal compartment excludes T cells from tumors. Doing so could lead to new and better therapeutic targets, though translating them will require overcoming the poorly representative preclinical models.

Table: TGFβ-checkpoint combination trials

Since a pair of studies, published just over a year ago, linked transforming growth factor β (TGFβ) to checkpoint...

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