8:20 PM
 | 
Dec 20, 2018
 |  BC Innovations  |  Product R&D

Cell therapies seek solid ground

How mosaic antigen expression makes solid tumors hard nuts to crack

Editor's Note: This article was updated on Dec 21, 2018 at 11:55 AM PST

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 companies have to proceed carefully, however, as there can be a fine line between juicing efficacy and triggering severe toxicity. The problem is compounded by the fact that animal models are poor predictors of how cancer therapies will affect the human immune system.

Workshop attendees were split on whether off-tumor, on-target toxicity due to expression of tumor antigens on normal tissue can be overcome. But some researchers who spoke to BioCentury suggested that targeting multiple antigens, if done correctly, could improve safety.

“Most often any target you choose is expressed on less than 50% of cells in any given tumor.”

Meenakshi Hegde, Baylor

Limited options

The meeting focused on immune cell therapies expressing CARs or TCRs. While both can target the cells to solid tumors, they have access to a different pool of antigens.

CARs target proteins found on the cell surface, whereas TCRs target intracellular proteins that have been cleaved into peptides and presented on the cell surface by MHC molecules (see Table: “Engineered Cell Therapies for Solid Tumors”).

Table: Engineered cell therapies for solid tumors

Selected genetically modified cell therapies to treat solid tumors are shown below. CAR therapies target proteins on the cell surface, whereas T cell receptor (TCR) therapies target intracellular antigens presented by major histocompatibility complex (MHC) molecules.

There are few purely tumor-selective antigens on the surface of cancer cells. Epidermal growth factor receptor variant III (EGFRvIII) is one exception that can be targeted by CARs. TCRs may have more options, such as those that target cancer-testis antigens, a group of fetal proteins, including melanoma-associated antigen A (MAGEA) family proteins, that may be re-expressed in cancer.

Antigens are also often heterogeneously expressed on tumors. Those that drive growth, such as EGFR...

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