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.”
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