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Cell therapies seek solid ground

How mosaic antigen expression makes solid tumors hard nuts to crack

To make cell therapies work in solid tumors, drug companies will have to either master combination therapies or figure out how to make their treatments trigger broad immune responses that extend beyond the antigen specificity of the engineered cells.

That was the consensus of academic researchers who attended a two-day workshop on the topic held by NCI on Dec. 10-11.

The discussion highlighted three key challenges for translating the success of cell therapies in hematologic cancers to solid tumors: target selection, trafficking of the cells to tumors and overcoming immunosuppression in the tumor microenvironment.

Much of the meeting centered on target selection, in particular the field’s inability to identify antigens that are expressed on all cells within a solid tumor -- which is needed for amplifying efficacy -- and not on healthy cells, which matters for toxicity.

One issue is that hematologic cancers are more likely to arise from a single clone than solid tumors, which are comprised of cells harboring different mutations and different gene expression profiles. Targeting one antigen inevitably leaves some cells unscathed and free to regrow.

Researchers pointed to at least three ways of getting around the problem: creating CAR or TCR therapies that target multiple antigens, combining cell therapies with other modalities and engineering the therapies to trigger epitope spreading, a phenomenon in which the immune system learns to recognize additional antigens from the wreckage of tumor cells killed by the therapy.

Companies are at early stages of executing all three strategies. Some of the technologies are being developed for hematologic indications as well, and were on display in abstracts presented at this year’s American Society of Hematology (ASH) meeting (see “Souped-up CARs at ASH 2018”).

The presence of most solid tumor antigens on healthy tissues means

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