Conference Coverage

GSI inhibition may boost BCMA CAR T-cell therapy efficacy in myeloma


 

AT SITC 2017

– Gamma secretase inhibition may lead to improved outcomes in multiple myeloma patients treated with B-cell maturation antigen (BCMA)–specific CAR T-cell therapy, according to Margot J. Pont, PhD.

In a preclinical myeloma model, gamma secretase inhibition (GSI) increased antitumor efficacy of BCMA-specific chimeric antigen receptor modified T-cells (BCMA CAR T), Dr. Pont of Fred Hutchinson Cancer Research Center, Seattle, reported at the annual meeting of the Society for Immunotherapy of Cancer.

BCMA is expressed in most multiple myeloma patients, and can be targeted by T cells that have been transduced with an anti-BCMA CAR. Other studies have shown efficacy of BCMA CAR T cells, and Dr. Pont and her colleagues have developed and optimized a CAR, based on a previously described single-chain variable fragment (scFv), that performs at least as well as a similar CAR developed previously by another group.

Dr. Margot Pont of the Fred Hutchinson Cancer Institute, Seattle
Dr. Margot Pont
“Moving forward we wanted to see what the expression of BCMA was on patient myeloma cells,” she said. “We see uniform expression in most patients, but in 25% of patient samples we see intermediate or low-to-negative BCMA expression, which could potentially hamper [our CAR] efficacy. When we tested whether this would affect CAR T-cell function, we saw that CAR T-cell recognition correlated with antigen expression levels.”

Previous studies have found that antigen down-regulation and escape can be an important escape mechanism by the tumor, so low-to-negative antigen expression could lead to failure in CAR T-cell recognition, resulting in relapse, she explained.

“We need the antigen density to be high enough,” she said, noting that BCMA, specifically, can be susceptible to antigen down-regulation, because its extracellular component is cleaved off the cell membrane by the enzyme gamma-secretase.

“That leads to two things: It reduces the surface expression of BCMA and it sheds soluble BCMA into the circulation, so you get high concentrations of soluble BCMA in the tumor microenvironment,” she said.

Inhibiting BCMA shedding with GSI can increase surface expression and reduce levels of soluble BCMA, thereby potentially enhancing the CAR activity.

First, soluble BCMA levels were measured in bone marrow sera from myeloma patients.

“We indeed saw high levels of soluble BCMA in these patients, and they roughly correlated with tumor burden. When culturing myeloma cell lines in vitro, we detected sBCMA in the culture supernatant within 24 hours,” Dr. Pont said, adding that the introduction of recombinant BCMA to the cultures showed that increasing levels of recombinant BCMA reduced staining of the CAR, demonstrating binding to the receptor.

Next, GSI was used to increase BCMA levels, and with increasing concentrations of the drug, BCMA surface expression was increased, she said, noting that this coincided with a reduction of soluble BCMA in the culture supernatant.

This also worked in patient samples, and was achieved with low doses of GSI, which upregulated surface BCMA levels on primary multiple myeloma by up to tenfold, she said.

In vivo testing of CAR T-cell efficacy was performed in tumor-bearing mice, which were treated with either BCMA-specific CAR T cells alone or in combination with GSI.

In this preclinical model of myeloma, RO4929097 increased BCMA on tumor cells in bone marrow and decreased soluble BCMA in peripheral blood. The myeloma-bearing mice treated with both BCMA CAR T cells and intermittent doses of RO4929097 experienced improved antitumor effects of the BCMA CAR T-cell therapy, as well as increased survival versus mice that did not receive RO4929097, she said.

“We’re currently optimizing these dosing regimens,” she said, concluding that “combining GSI and BCMA CAR T is an attractive option to improve the level of efficacy and prevent the outgrowth of BCMA-low tumor cells.”

Dr. Pont reported having no relevant financial disclosures.

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