B7-H3 stands out as future SCLC target

MDedge News


About two out of three patients with small cell lung cancer (SCLC) express B7-H3, a B7 family ligand that may one day serve as a therapeutic target, according to investigators.

Unfortunately, the findings also suggested that SCLC is adept at immune evasion, reported lead author Daniel Carvajal-Hausdorf, MD, of Yale University, New Haven, Conn., and his colleagues, who described the current prognosis for SCLC as “dismal.”

“To date, there are limited therapeutic options and the prognosis is ominous with 5-year survival rates of only around 3–6% for extensive stage SCLC,” Dr. Carvajal-Hausdorf and associates wrote in the Journal for ImmunoTherapy of Cancer.

Currently, few therapeutic choices exist for SCLC, largely because of an infrequency of actionable mutations. However, ongoing trials using a combination of checkpoint and CTLA-4 inhibition have reported an objective response rate of about 30% among patients with SCLC, which suggests that immunotherapy could have an effect.

“Despite these results, little is known about the immune composition of SCLC, and most studies characterizing immune cells or targets have used qualitative/subjective methods,” the investigators wrote. “Identification of dominant immune cell populations and/or expression of candidate immunotherapy targets in this tumor could support optimal design and interpretation of clinical trials.”

In the present, retrospective study, investigators analyzed molecular characteristics of 90 SCLC samples using multiplexed quantitative immunofluorescence and compared these findings with clinicopathological variables and survival from patient medical records. Specifically, the investigators measured tumor infiltrating lymphocyte (TIL) subsets and B7 family ligands PD-L1, B7-H3, and B7-H4.

Among B7 family ligands, B7-H3 was by far the most commonly expressed, occurring in about two out of three samples (64.9%). PD-L1 and B7-H4 occurred relatively infrequently, at rates of 7.3% and 2.6%, respectively. Expression level was also skewed toward B7-H3, which was expressed at levels 5.8-fold higher than B7-H4 and 2.3-fold higher than PD-L1. The three markers showed minimal correlation with one another, which suggests a mutually exclusive expression pattern. None of the B7 family ligands was associated with TILs or major clinicopathologic variables; however, B7-H4 expression was correlated with poorer 5-year overall survival.

Among subsets of TILs, CD3+ predominated (94%), with CD8+ (67%) and CD20+ (11%) occurring less frequently. Compared with findings from previous studies of non–small cell lung cancer (NSCLC), the SCLC samples had significantly lower levels of all TILs. The investigators also noted that CD3/CD8 ratio was much lower in SCLC than NSCLC, which indicates a less cytotoxic T-cell profile (0.37 vs 0.63; P less than .001). CD3+ was the only TIL subset associated with improved survival.

“Taken together, our data support that SCLC is a relatively ‘immune-cold’ tumor and suggests the presence of prominent immune regulatory mechanisms,” the investigators wrote. “Possible mechanisms involved in immune evasion are currently unknown but may include an altered tumor microvasculature, epigenetic silencing of immunogenic tumor epitopes, metabolic competition between tumor and immune cells and expression of multiple potent immune suppressive targets/pathways. Additional studies will be required to explore these possibilities.”

Given the relatively high prevalence of B7-H3 expression among patients with SCLC, this marker stands out as a candidate for therapeutic targeting.

“Targeting B7-H3 is currently being evaluated as an anti-cancer immunostimulatory strategy in preclinical models and in early phase clinical trials,” the investigators noted. “Enoblituzumab (MGA271, Macrogenics) is an Fc-optimized monoclonal antibody to selectively target B7-H3 and is currently in phase 1 studies alone or in combination with PD-1/CTLA-4 inhibitors. Further understanding of the modulation of B7-H3 expression, identification of its cognate receptor(s) and immuno-modulatory role in cancer will be key to support further clinical development of this pathway.”

The study was funded by FONDECYT, Lung Cancer Research Foundation (LCRF), Yale SPORE in Lung Cancer, Department of Defense, the American Cancer Society, and others. The investigators reported financial relationships with Celgene, Moderna, Shattuck, AstraZeneca, and others.

SOURCE: Carvajal-Hausdorf D et al. J Immunother Cancer. 2019 Mar 8. doi: 10.1186/s40425-019-0540-1.

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